query: What is the mechanism of cytokine storm syndrome on the COVID-19?

positive: Recommendations for coronavirus infection in rheumatic diseases treated with biologic therapy The Coronavirus-associated disease, that was first identified in 2019 in China (CoViD-19), is a pandemic caused by a bat-derived beta-coronavirus, named SARS-CoV2. It shares homology with SARS and MERS-CoV, responsible for past outbreaks in China and in Middle East. SARS-CoV2 spread from China where the first infections were described in December 2019 and is responsible for the respiratory symptoms that can lead to acute respiratory distress syndrome. A cytokine storm has been shown in patients who develop fatal complications, as observed in past coronavirus infections. The management includes ventilatory support and broad-spectrum antiviral drugs, empirically utilized, as a targeted therapy and vaccines have not been developed. Based upon our limited knowledge on the pathogenesis of CoViD-19, a potential role of some anti-rheumatic drugs may be hypothesized, acting as direct antivirals or targeting host immune response. Antimalarial drugs, commonly used in rheumatology, may alter the lysosomal proteases that mediates the viral entry into the cell and have demonstrated efficacy in improving the infection. Anti-IL-1 and anti-IL-6 may interfere with the cytokine storm in severe cases and use of tocilizumab has shown good outcomes in a small cohort. Baricitinib has both antiviral and anti-inflammatory properties. Checkpoints inhibitors such as anti-CD200 and anti-PD1 could have a role in the treatment of CoViD-19. Rheumatic disease patients taking immunosuppressive drugs should be recommended to maintain the chronic therapy, prevent infection by avoiding social contacts and pausing immunosuppressants in case of infection. National and international registries are being created to collect data on rheumatic patients with CoViD-19.

positive: “ARDS and Cytokine Storm in SARS-CoV-2 Infected Caribbean Vervets” SARS-CoV-2 induces a wide range of disease severity ranging from asymptomatic infection, to a life-threating illness, particularly in the elderly and persons with comorbid conditions. Up to now, SARS-CoV-2 has infected more than five million and led to more than 300,000 deaths worldwide. Among those persons with serious COVID-19 disease, acute respiratory distress syndrome (ARDS) is a common and often fatal presentation. SARS-CoV-2-induced ARDS is difficult to treat clinically, and new therapeutic strategies are needed. In order to evaluate such therapeutic strategies, animal models of SARS-CoV-2 infection that manifest severe disease are needed. Here we report fatal ARDS in two African green monkeys (AGMs) infected with SARS-CoV-2 that demonstrated pathological lesions and disease similar to severe COVID-19 in humans. Moreover, we report the observation of cytokine release (cytokine storm) in three of four infected AGMs. All four animals showed increased levels of IL-6 in plasma, a predictive marker and presumptive therapeutic target in humans infected with SARS-CoV-2 infection. Our results suggest the AGM is a useful model to study disease pathogenesis of SARS-CoV-2, and for the evaluation of therapeutic interventions designed to combat serious pulmonary disease associated with this infection.

positive: Letter: low population mortality from COVID‐19 in countries south of latitude 35 degrees North supports vitamin D as a factor determining severity The recent editorial by Rhodes et al considered latitude and mentioned one mechanism that vitamin D is important in regulating and suppressing the inflammatory response of cytokines of respiratory epithelial cells and macrophages to various pathogens, including respiratory viruses and preventing cytokine storm and the subsequent acute respiratory distress syndrome (RDS) (1).

positive: Coronavirus is the trigger, but the immune response is deadly

positive: Feasibility of Tocilizumab in ICU patients with COVID‐19 Severe COVID‐19 causes cytokine release syndrome and is associated with high mortality. In this retrospective case series, all patients diagnosed with COVID‐19 by semi quantitative RT‐PCR and hyperinflammatory markers were treated with tocilizumab. The use of tocilizumab was associated with rapid apyrexia, improvement of respiratory, biological parameters and short length of hospitalization (11 days). Moreover, no adverse effect attributed to the treatment was noticed. Tocilizumab seems to be a promising and safe therapy in severe patients. This article is protected by copyright. All rights reserved.

positive: Opciones Terapéuticas En El Manejo De Covid-19 Grave: Una Perspectiva De Reumatología./ [Therapeutic options for the management of severe Covid-19: A rheumatology perspective] The novel SARS-CoV-2 human coronavirus in Wuhan, China, has triggered a worldwide respiratory disease outbreak (COVID-19). Acute respiratory distress syndrome (ARDS), multiorgan dysfunction and thrombotic events are among the leading causes of death in critically ill patients with COVID-19. The elevated inflammatory cytokines suggest that a "cytokine storm", also known as cytokine release syndrome (CRS), may play a major role in the pathology of COVID-19. In addition to anti-viral therapy and supportive treatment in critically ill patients, unique medications for this condition are also under investigation. Here we reviewed therapeutic options, including the antibody therapy that might be an immediate strategy for SARS-CoV-2 therapy.

positive: COVID-19 pandemic and troponin: indirect myocardial injury, myocardial inflammation or myocarditis? The initial mechanism for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is the binding of the virus to the membrane-bound form of ACE2, which is mainly expressed in the lung. Since the heart and the vessels also express ACE2, they both could become targets of the virus. However, at present the extent and importance of this potential involvement are unknown. Cardiac troponin levels are significantly higher in patients with more severe infections, patients admitted to intensive care units or in those who have died. In the setting of COVID-19, myocardial injury, defined by an increased troponin level, occurs especially due to non-ischaemic myocardial processes, including severe respiratory infection with hypoxia, sepsis, systemic inflammation, pulmonary thrombosis and embolism, cardiac adrenergic hyperstimulation during cytokine storm syndrome, and myocarditis. At present, there are limited reports on definite diagnosis of myocarditis caused by SARS-CoV-2 in humans and limited demonstration of the virus in the myocardium. In conclusion, although the heart and the vessels are potential targets in COVID-19, there is currently limited evidence on the direct infection of the myocardium by SARS-CoV-2. Additional pathological studies and autopsy series will be very helpful to clarify the potentiality of COVID-19 to directly infect the myocardium and cause myocarditis.

positive: IL-15 immunotherapy is a viable strategy for COVID-19. Coronavirus disease 2019 (COVID-19) is a pulmonary inflammatory disease induced by a newly recognized coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection was detected for the first time in the city of Wuhan in China and spread all over the world at the beginning of 2020. Several millions of people have been infected with SARS-CoV-2, and almost 382,867 human deaths worldwide have been reported so far. Notably, there has been no specific, clinically approved vaccine or anti-viral treatment strategy for COVID-19. Herein, we review COVID-19, the viral replication, and its effect on promoting pulmonary fibro-inflammation via immune cell-mediated cytokine storms in humans. Several clinical trials are currently ongoing for anti-viral drugs, vaccines, and neutralizing antibodies against COVID-19. Viral clearance is the result of effective innate and adaptive immune responses. The pivotal role of interleukin (IL)-15 in viral clearance involves maintaining the balance of induced inflammatory cytokines and the homeostatic responses of natural killer and CD8+ T cells. This review presents supporting evidence of the impact of IL-15 immunotherapy on COVID-19.

positive: Cytokine storm in COVID‐19 and parthenolide: preclinical evidence A group of patients with pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) were reported from China in December 2019. Although several antiviral drugs are widely tested, none of them has been approved as specific antiviral therapy for coronavirus disease 2019 (COVID‐19). Accumulating evidence established a hyperinflammatory states or cytokine storm in COVID‐19. Among these cytokines, IL‐6 plays a key role in cytokine storm and can predict the adverse clinical outcomes and fatality in these patients. Based on the evidence of the significant role of IL‐6 in cytokine storm, diabetes mellitus and cardiovascular diseases as principal comorbidities, it seems that anti‐cytokine therapy may be useful in patients with severe COVID‐19 to reduce mortality. Recent studies demonstrated that herbal‐derived natural products had immunosuppressive and anti‐inflammatory properties and exhibited exceptional act on mediators of inflammation. Parthenolide is the principal sesquiterpene lactones and the main biologically active constituent Tanacetum parthenium (commonly known as feverfew) which has could significantly reduce IL‐1, IL‐2, IL‐6, IL‐8, and TNF‐α production pathways established in several human cell line models in vitro and in vivo studies. Therefore, parthenolide may be one of the herbal candidates for clinical evaluation. This article is protected by copyright. All rights reserved.

positive: Dysregulation of immune response in patients with COVID-19 in Wuhan, China BACKGROUND: In December 2019, coronavirus disease 2019 (COVID-19) emerged in Wuhan and rapidly spread throughout China. METHODS: Demographic and clinical data of all confirmed cases with COVID-19 on admission at Tongji Hospital from January 10 to February 12, 2020, were collected and analyzed. The data of laboratory examinations, including peripheral lymphocyte subsets, were analyzed and compared between severe and non-severe patients. RESULTS: Of the 452 patients with COVID-19 recruited, 286 were diagnosed as severe infection. The median age was 58 years and 235 were male. The most common symptoms were fever, shortness of breath, expectoration, fatigue, dry cough and myalgia. Severe cases tend to have lower lymphocytes counts, higher leukocytes counts and neutrophil-lymphocyte-ratio (NLR), as well as lower percentages of monocytes, eosinophils, and basophils. Most of severe cases demonstrated elevated levels of infection-related biomarkers and inflammatory cytokines. The number of T cells significantly decreased, and more hampered in severe cases. Both helper T cells and suppressor T cells in patients with COVID-19 were below normal levels, and lower level of helper T cells in severe group. The percentage of naïve helper T cells increased and memory helper T cells decreased in severe cases. Patients with COVID-19 also have lower level of regulatory T cells, and more obviously damaged in severe cases. CONCLUSIONS: The novel coronavirus might mainly act on lymphocytes, especially T lymphocytes. Surveillance of NLR and lymphocyte subsets is helpful in the early screening of critical illness, diagnosis and treatment of COVID-19.

positive: Hydroxychloroquine and Covid-19: A Cellular and Molecular Biology Based Update As the time for finding a definitive and safe cure as a vaccine for novel Corona Virus Disease 2019 (Covid-19) is still far, there is need to study in depth about the other potential drugs, which can save millions of lives due to Covid-19 pandemic. Right at the center of the debate is the use of drug “Hydroxychloroquine” as a prophylaxis as well as a treatment strategy against Covid-19 in conjunction with azithromycin. In this review, we will study the cellular and molecular aspects of hydroxychloroquine, which had driven its use in Covid-19 patients, as well as its chemistry and pharmacokinetics along with clinical trials going on worldwide using hydroxychloroquine against Covid-19. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12291-020-00900-x) contains supplementary material, which is available to authorized users.

positive: Seven recommendations to rescue the patients and reduce the mortality from COVID-19 infection: An immunological point of view Now COVID-19 is causing a severe public health emergency and the mortality is rapidly increasing all over the world. In the current pandemic era, although there have been many efforts to diagnose a number of patients with symptoms or close contacts, there is no definite guideline for the initial therapeutic approach for them and therefore, many patients have been dying due to a hyperinflammatory immunological reaction labeled as “cytokine storm”. Severe patients are hospitalized and the treatment is done, though they have not been established yet. Currently, however, no treatment is provided for those who are isolated at home or shelter until they get severe symptoms, which will increase the harms to the patients. In this review, we discuss some important points dedicated to the management of patients with COVID-19, which should help reducing morbidity and mortality. In this era, we suggest 7 recommendations to rescue the patients and to reduce the morbidity and mortality due to COVID-19 based on the immunological point of view.

positive: Thalidomide-Revisited: Are COVID-19 Patients Going to Be the Latest Victims of Yet Another Theoretical Drug-Repurposing? The coronavirus disease 2019 (COVID-19) pandemic is a worldwide threatening health issue. The progression of this viral infection occurs in the airways of the lungs with an exaggerated inflammatory response referred to as the "cytokine storm" that can lead to lethal lung injuries. In the absence of an effective anti-viral molecule and until the formulation of a successful vaccine, anti-inflammatory drugs might offer a complementary tool for controlling the associated complications of COVID-19 and thus decreasing the subsequent fatalities. Drug repurposing for several molecules has emerged as a rapid temporary solution for COVID-19. Among these drugs is Thalidomide; a historically emblematic controversial molecule that harbors an FDA approval for treating erythema nodosum leprosum (ENL) and multiple myeloma (MM). Based on just one-case report that presented positive outcomes in a patient treated amongst others with Thalidomide, two clinical trials on the efficacy and safety of Thalidomide in treating severe respiratory complications in COVID-19 patients were registered. Yet, the absence of substantial evidence on Thalidomide usage in that context along with the discontinued studies on the efficiency of this drug in similar pulmonary diseases, might cause a significant obstacle for carrying out further clinical evaluations. Herein, we will discuss the theoretical effectiveness of Thalidomide in attenuating inflammatory complications that are encountered in COVID-19 patients while pinpointing the lack of the needed evidences to move forward with this drug.

positive: Report of the ‘Mechanisms of lung injury and immunomodulator interventions in influenza’ workshop, 21 March 2010, Ventura, California, USA Please cite this paper as: Howard et al. (2011) Report of the ‘Mechanisms of lung injury and immunomodulator interventions in influenza’ workshop, 21 March 2010, Ventura, California, USA*. Influenza and Other Respiratory Viruses 5(6), 453–e475. The clinical course of influenza and the extent of lung injury are determined by both viral and host factors, as well as sometimes secondary bacterial infections and exacerbations of underlying conditions. The balance between viral replication and the host immune responses is central to disease pathogenesis, and the extent of lung injury in severe influenza infections may be due in part to overly exuberant or dysregulated innate inflammatory responses or sometimes deficient responses. Acute respiratory distress syndrome (ARDS) is the principal cause of respiratory failure associated with severe influenza. ARDS can be triggered by both direct lung insults (e.g. respiratory pathogens) and systemic insults (e.g. sepsis), and the lung damage is exacerbated by the inflammatory response associated with either infectious or non‐infectious insults. This workshop aimed to review the current understanding of lung injury in acute influenza and describe cellular and molecular mechanisms of lung injury that are common to influenza and infections by other respiratory pathogens. In addition, therapeutic agents that target host response proteins and pathways were identified and investigational agents in development reviewed. A logical strategy would be to combine antiviral treatment with drugs that modify excessive host responses or supplement deficient ones. However, a better understanding of common cell signalling pathways associated with acute lung injury caused by influenza and other pathogens is necessary to understand immunopathologic causes of lung injury. This will help determine which immunomodulatory interventions might be useful, and to predict the appropriate timing and consequences of their use.

positive: Decreased serum albumin level indicates poor prognosis of COVID-19 patients: hepatic injury analysis from 2,623 hospitalized cases Coronavirus disease 2019 (COVID-19) is a global pandemic which has caused numerous deaths worldwide. The present study investigated the roles of hypoproteinemia in the clinical outcome and liver dysfunction of COVID-19 patients. In this retrospective study, we extracted data from 2,623 clinically confirmed adult COVID-19 patients (>18 years old) between January 29, 2020 and March 6, 2020 in Tongji Hospital, Wuhan, China. The patients were divided into three groups—non-critically ill, critically ill, and death groups—in accordance with the Chinese Clinical Guideline for COVID-19. Serum albumin, low-density lipoproteins cholesterol (LDL-C), and high-density lipoproteins cholesterol (HDL-C) concentrations and inflammatory cytokines levels were measured and compared among these three groups. The median age of these 2,623 patients was 64 years old (interquartile range (IQR), 52–71). Among the patients enrolled in the study, 2,008 (76.6%) were diagnosed as non-critically ill and 615 (23.4%) were critically ill patients, including 383 (14.6%) critically ill survivors and 232 (8.8%) critically ill deaths in the hospital. Marked hypoalbuminemia occurred in 38.2%, 71.2%, and 82.4% patients in non-critically ill, critically ill, and death groups, respectively, on admission and 45.9%, 77.7%, and 95.6% of these three groups, respectively, during hospitalization. We also discovered that serum low-density lipoprotein (LDL) and HDL levels were significantly lower in critically ill and death groups compared to non-critically ill group. Meanwhile, the patients displayed dramatically elevated levels of serum inflammatory factors, while a markedly prolonged activated partial thromboplastin time (APTT) in critically ill patients reflected coagulopathy. This study suggests that COVID-19-induced cytokine storm causes hepatotoxicity and subsequently critical hypoalbuminemia, which are associated with exacerbation of disease-associated inflammatory responses and progression of the disease and ultimately leads to death for some critically ill patients. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material is available for this article at 10.1007/s11427-020-1733-4 and is accessible for authorized users.

positive: Targeting the catecholamine-cytokine axis to prevent SARS-CoV-2 cytokine storm syndrome The mortality of Coronavirus disease 2019 (COVID-19) appears to be driven by acute respiratory distress syndrome (ARDS) and a dysregulated immune response to SARS-CoV-2. Emerging evidence suggests that a subset of COVID-19 is characterized by the development of a cytokine storm syndrome (CSS), and interleukin (IL)-6 levels are predictors of COVID-19 severity and in-hospital mortality. Targeting hyper-inflammation in COVID-19 may be critical for reducing mortality. Catecholamines enhance inflammatory injury by augmenting the production of IL-6 and other cytokines through a self-amplifying feed-forward loop in immune cells that requires alpha-1 adrenergic receptor (α1-AR) signaling. Prophylactic inhibition of catecholamine synthesis with the α1-AR antagonist prazosin reduced catecholamines and cytokine responses in mice, and resulted in markedly increased survival following various hyper-inflammatory stimuli. These findings offer a rationale for studying α1-AR antagonists in the prophylaxis of patients with COVID-19-CSS and ARDS. As high infection rates threaten to overwhelm hospital capacity during this pandemic, preventative approaches that ameliorate COVID-19 severity and reduce excessive mortality are desperately needed. We hypothesize that treatment with prazosin of individuals who test positive for SARS-CoV-2 could reduce catecholamine surges, secondary cytokine dysregulation, and mortality. To investigate a potential role for α1-AR antagonists in preventing poor outcomes in ARDS, we conducted a retrospective analysis of hospitalized patients diagnosed with ARDS. Using data from the Truven Health MarketScan Research Database (2010-2017), we identified 13,125 men (age 45-64) with ARDS, of whom 655 patients (5.0%) were prescribed α1-AR antagonists in the previous year. Applying logistic regression models, we found that patients with prior use of α1-AR antagonists had lower odds of invasive mechanical ventilation compared to non-users (adjusted OR=0.75, 95% CI 0.59-0.95, p=0.019). Perhaps more importantly, those patients had a ~36% lower incidence of both being ventilated and dying in the hospital (adjusted OR=0.59, 95% CI 0.34-0.95, p=0.042). By contrast, prior use of beta-adrenergic receptor (β-AR) antagonists was not correlated with either outcome. We extended these analyses to patients admitted with pneumonia. Of 108,956 subjects in this cohort, 5,498 patients (5.0%) were taking α1-AR antagonist. Similar to ARDS, patients with pneumonia on α1-AR antagonists (but no β-AR antagonists) had a lower odds of mechanical ventilation (adjusted OR=0.83, 95% CI 0.75-0.92, p<0.001) and of both being ventilated and dying in the hospital (adjusted OR=0.77, 95% CI 0.62-0.94, p=0.014) compared to non-users. Mirroring findings from pre-clinical models, these data support a clinical rationale to study α1-AR antagonists in the prevention of severe complications of pneumonia, ARDS, and COVID-19. Prospective, randomized clinical trials of alpha-1 receptor antagonists (e.g. prazosin) administered prior to the onset of severe symptoms are needed to assess their efficacy in preventing CSS and reducing mortality in COVID-19.

positive: Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China BACKGROUND: A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. METHODS: All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. FINDINGS: By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. INTERPRETATION: The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. FUNDING: Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.

positive: Interleukin-6 blockade for severe COVID-19 In the context of COVID-19 pandemic and growing tensions worldwide regarding healthcare facilities, there is an urgent need for effective treatments likely to reduce the crunch of ICU beds. Following the assumption by Mehta and colleagues who exhorted physicians to screen patients with severe COVID-19 for hyperinflammation and investigate immunomodulatory drugs in this setting, we relate our short-term - yet promising - experience regarding IL6 blockade with tocilizumab in 30 selected patients of less than 80 years of age, >5 days of prior disease duration, severe (i.e. requiring strictly over 6L/min of oxygen therapy) rapidly deteriorating (i.e. increase by more than 3L/min of oxygen flow within the previous 12 hours) COVID-19-related pneumonia. By comparison with a control group of patients (matched for age, gender and disease severity using the inverse probability of treatment weighted methodology) that did not receive tocilizumab. We demonstrate that, in highly selected patients, IL6 blockade could curb the "cytokine storm", prevent ICU admission and the requirement for mechanical ventilation. Notwithstanding the shortcomings of this retrospective small sample-size study, we believe that these preliminary findings support the fostering of research efforts in the fight against COVID-19-induced inflammation, especially before patients require admission to the ICU.

positive: Targeting inflammation and cytokine storm in COVID-19

positive: Anti-IL6R role in treatment of COVID-19-related ARDS

positive: Cyclosporine therapy in cytokine storm due to coronavirus disease 2019 (COVID-19)

positive: Prevention of the cytokine storm in COVID-19

positive: COVID-19: implications for immunosuppression in kidney disease and transplantation The coronavirus disease 2019 (COVID-19) pandemic poses important challenges to the care of patients with immune-mediated kidney diseases and to kidney transplant recipients. Here, we discuss the management of immunosuppression for these patients during the pandemic and suggest potential approaches that could be considered in the absence of validated strategies.

positive: Dapsone and Doxycycline could be potential treatment modalities for COVID-19

positive: Preferential loss of Th17 cells is associated with CD4 T cell activation in patients with 2009 pandemic H1N1 swine-origin influenza A infection Abstract Very limited evidence has been reported on host T cell responses to the pandemic H1N1 swine-origin influenza A virus (S-OIV) infection in humans. Therefore, we investigated the proportions of peripheral T cell subsets and analyzed the relationship of T helper subset changes with T cell activation during this infection. We found that these S-OIV-infected patients exhibited rapid lymphopenia, T cell activation and preferential loss of Th17 subset at the early stage of acute infection. Statistical analysis indicated that CD4 depletion and loss of Th17 cells, rather than Th1 or Treg cells, were correlated with CD4 T cell activation. More importantly, up-regulated IFN-α likely contributed to the functional loss of Th17 cells. Thus, rapidly generalized lymphopenia, preferential loss of Th17 population and T cell activation presented as characteristics of the early immune response in S-OIV-infected patients. These findings, therefore, may be helpful for an earlier diagnosis and further studies of immune pathogenesis of S-OIV infection.

positive: Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients BACKGROUND: Although the detection of SARS-CoV-2 viral load in respiratory specimens has been widely used to diagnose coronavirus disease-19 (COVID-19), it is undeniable that serum SARS-CoV-2 nucleic acid (RNAaemia) could be detected in a fraction of COVID-19 patients. However, it is not clear whether testing for RNAaemia is correlated with the occurrence of cytokine storms or with the specific class of patients. METHODS: This study enrolled 48 patients with COVID-19 admitted to the General Hospital of Central Theater Command, PLA, a designated hospital in Wuhan, China. The patients were divided into three groups according to the "Diagnosis and Treatment of New Coronavirus Pneumonia (6th edition)" issued by the National Health Commission of China. The clinical and laboratory data were collected. The serum viral load and IL-6 levels were determined. . RESULTS: Clinical characteristics analysis of 48 cases of COVID-19 showed that RNAaemia was diagnosed only in the critically ill group and seemed to reflect the severity of the disease. Furthermore, the level of inflammatory cytokine IL-6 in critically ill patients increased significantly, almost 10 times that in other patients. More importantly, the extremely high IL-6 level was closely correlated with the detection of RNAaemia (R = 0.902). CONCLUSIONS: Detectable serum SARS-Cov-2 RNA(RNAaemia) in COVID-19 patients was associated with elevated IL-6 concentration and poor prognosis. Because the elevated IL-6 may be part of a larger cytokine storm which could worsen outcome, IL-6 could be a potential therapeutic target for critically ill patients with an excessive inflammatory response.

positive: Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19) BACKGROUND: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed. METHODS: We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations. RESULTS: The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which 4 are best practice statements, 9 are strong recommendations, and 35 are weak recommendations. No recommendation was provided for 6 questions. The topics were: (1) infection control, (2) laboratory diagnosis and specimens, (3) hemodynamic support, (4) ventilatory support, and (5) COVID-19 therapy. CONCLUSION: The Surviving Sepsis Campaign COVID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19. When available, we will provide new recommendations in further releases of these guidelines. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00134-020-06022-5) contains supplementary material, which is available to authorized users.

positive: Extracorporeal Hemoadsorption: An Option for COVID-19 Associated Cytokine Storm Syndrome.

positive: Melatonin Inhibits COVID-19-induced Cytokine Storm by Reversing Aerobic Glycolysis in Immune Cells: A Mechanistic Analysis

positive: Is a "Cytokine Storm" Relevant to COVID-19?

positive: COVID-19 and what pediatric rheumatologists should know: a review from a highly affected country On March 11th, 2020 the World Health Organization declared COVID-19 a global pandemic. The infection, transmitted by 2019 novel coronavirus (2019-nCov), was first discovered in December 2019, in Wuhan, Hubei Province, and then rapidly spread worldwide. Italy was early and severely involved, with a critical spread of the infection and a very high number of victims. Person-to-person spread mainly occurs via respiratory droplets and contact. The median incubation period is 5 days. The spectrum of respiratory symptoms may range from mild to severe, strictly depending on the age of the patient and the underlying comorbidities. In children COVID-19 related disease is less frequent and less aggressive. In Italy 1% of positive cases are under 18 years of age, and no deaths have been recorded before 29 years of age. For patients affected by rheumatic disease, despite the concerns related to the imbalance of their immune response and the effect of immunosuppressive treatments, there are still few data to understand the real consequences of this infection. Major scientific societies have issued recommendations to help rheumatologists in caring their patients. Interestingly, some of the drugs mostly used by rheumatologists appear to be promising in critical COVID-19 infected patients, where the hyperinflammation and cytokine storm seem to drive to the multiorgan failure. Pediatric rheumatologists are expected to play a supporting role in this new front of COVID-19 pandemic, both as general pediatricians treating infected children, and as rheumatologists taking care of their rheumatic patients, as well as offering their experience in the possible alternative use of immunomodulatory drugs.

positive: COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades. We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies. While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system. Risk of severe infection and mortality increase with advancing age and male sex. Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer. The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC). Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) —a homologue of ACE—to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes. This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI). While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis. Hence, patients should not discontinue their use. Moreover, renin–angiotensin–aldosterone system (RAAS) inhibitors might be beneficial in COVID-19. Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19. Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications. Preventive measures (social distancing and social isolation) also increase cardiovascular risk. Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed.

positive: Application of plasma exchange in association with higher dose CVVH in Cytokine Storm Complicating COVID-19

positive: Combined treatment of tocilizumab and chloroquine on severe COVID-19: a case report

positive: Alternative management of Covid-19 infection Cytokine storm is a life-threatening complication of Covid-19 infection. Excessive cytokines are the products of hyperactive immune inflammatory response mounted by the host against the virus. There is no agreed treatment for cytokine storm. Three therapeutic agents with proven immune-modulatory properties in regular use in a wide range of inflammatory disorders (high dose intravenous immunoglobulin, Rituximab and thalidomide) are proposed for the treatment of cytokine storm. Safety and efficacy of the proposed treatment should be assessed by randomised controlled clinical trials. The use of the proposed treatment is expected to reduce the mortality rate and alter the overall management of the pandemic.

positive: Use of anakinra in severe COVID-19: a case report Abstract Coronavirus Disease 19 is a global healthcare emergency with high lethality rate. Relevant inflammatory cytokine storm is associated with severity of disease and IL1 inhibition is a cornerstone treatment for hyperinflammatory diseases. We present here the case of a patient with critical COVID-19 successfully treated with IL-1 receptor antagonist (anakinra).

positive: Potential of regulatory T cell-based therapies in the management of severe COVID-19 In view of dysregulated immune response, cytokine storm and inflammation-induced severe lung damage in severely ill COVID-19 patients, we propose that CD4+CD25+FoxP3+ regulatory T cell-based therapies could be considered for the patient management.

positive: Role of poly (ADP) ribose polymerase-1 inhibition by nicotinamide as a possible additive treatment to modulate host immune response and prevention of cytokine storm in COVID-19 COVID-19 is rapidly spreading contagious disease spreading across the world. Patients at risk are elderly people and those with comorbidity. Early studies done on Chinese patients who suggest cytokine storm to be responsible for lung injury. We need to understand the mechanism of modulating such robust response of immunity and resultant cytokine storm. We suggest nicotinamide, a potential poly ADP ribose polymerase (PARP) inhibitor, as a supportive treatment for the prevention of cytokine storm from injuring the lung parenchyma. Nicotinamide supplementation albeit at high dose may modulate outcome in COVID-19. Nicotinamide was used previously to reduce ventilator-induced lung injury and lung injury due to hypoxia. Nicotinamide congeners are used to treat chronic lung disease like tuberculosis. Certainly, nicotinamide is effective pharmacotherapy in lung injury – whether acute or chronic. Other measures used in treating COVID-19 are focusing on targeting interleukin-6 – a cytokine responsible for mayhem, while few are targeting granulocyte-macrophage colony- stimulating factor. We suggest targeting PARP in addition to other measures to block cytokines. By inhibiting PARP course of COVID-19 may be altered. Understanding the pathophysiology of acute lung injury is crucial. PARP plays a pivotal role on cytokine release in response to any lung injury ranging from viral infection to hypoxia. Various antiviral defenses and immune response need to be studied in detail.

positive: Opciones Terapéuticas En El Manejo De Covid-19 Grave: Una Perspectiva De Reumatología Resumen El inicio del nuevo coronavirus humano del síndrome respiratorio agudo grave (SARS-Cov-2) en Wuhan, China, ha desencadenado un brote respiratorio mundial (COVID-19). El síndrome de insuficiencia respiratoria agua (SIRA), el fallo multiorgánico y eventos trombóticos están entre las causas que llevan a la muerte en pacientes críticamente enfermos con COVID-19. Las citocinas inflamatorias elevadas sugieren que una “tormenta de citocinas”, también conocida como síndrome de liberación de citocinas (SLC), puede jugar un papel principal en la patología de COVID-19. Adicionalmente al tratamiento anti-viral y la terapia de apoyo respiratorio en pacientes críticamente enfermos, están en investigación medicamentos únicos para esta condición. En esta revisión sintetizamos la evidencia más actual de opciones terapéuticas, incluyendo anticuerpos anti-citocinas como una estrategia intermedia para la terapia de SARS-Cov-2. Abstract The novel SARS-CoV-2 human coronavirus in Wuhan, China, has triggered a worldwide respiratory disease outbreak (COVID-19). Acute respiratory distress syndrome (ARDS), multiorgan dysfunction and thrombotic events are among the leading causes of death in critically ill patients with COVID-19. The elevated inflammatory cytokines suggest that a “cytokine storm”, also known as cytokine release syndrome (CRS), may play a major role in the pathology of COVID-19. In addition to anti-viral therapy and supportive treatment in critically ill patients, unique medications for this condition are also under investigation. Here we reviewed therapeutic options, including the antibody therapy that might be an immediate strategy for SARS-CoV-2 therapy

positive: The successful use of therapeutic plasma exchange for severe COVID-19 acute respiratory distress syndrome with multiple organ failure The COVID-19 pandemic has brought about an urgent need for effective treatment, while conserving vital resources such as intensive care unit beds and ventilators. Antivirals, convalescent plasma, and biologics have been used with mixed results. The profound “cytokine storm” induced endotheliopathy and microthrombotic disease in patients with COVID-19 may lead to acute respiratory distress syndrome, sepsis, and multi-organ failure. We present a case of SARS-COV2 pneumonia with septic shock and multi-organ failure that demonstrated significant clinical improvement after therapeutic plasma exchange. A 65-year-old female with multiple comorbidities presented with progressive dyspnea and dry cough. She was found to be COVID-19 positive with pneumonia, and developed progressive hypoxemia and shock requiring vasopressors, cardioversion, and non-invasive positive pressure ventilation. Given her worsening sepsis with multi-organ failure, she underwent therapeutic plasma exchange with rapid clinical improvement. Her case supports the theory that plasma exchange may help abate the “cytokine storm” induced endotheliopathy and microthrombosis associated with COVID-19. Further studies are needed to identify markers of this pathway and the potential role of plasma exchange in these critically ill patients.

positive: Rheumatologists and Pulmonologists at Temple University weather the COVID-19 storm together. In recent commentaries from Lancet Rheumatology and The Journal of Rhuematology (1-2) the authors eloquently illustrated the connection between COVID-19 infection, the subsequent cytokine storm (CS) that ensues in a number of patients and the potential efficacy of biologics that Rheumatologists routinely use in their practices. Moreover those biologics were originally investigated by Rheumatologists for the treatment of numerous rheumatic conditions, including macrophage activating syndrome (MAS), a similar form of storm that resembles the one occurring in COVID-19 patients (3).

positive: Rapid and robust bioanalytical assays are critical for SARS-CoV-2 therapeutic and vaccine development and beyond

positive: Exploring pharmacological approaches for managing cytokine storm associated with pneumonia and acute respiratory distress syndrome in COVID-19 patients Sars-CoV-2 complications include pneumonia and acute respiratory distress syndrome (ARDS), which require intensive care unit admission. These conditions have rapidly overwhelmed healthcare systems, with detrimental effects on the quality of care and increased mortality. Social isolation strategies have been implemented worldwide with the aim of reducing hospital pressure. Among therapeutic strategies, the use of immunomodulating drugs, to improve prognosis, seems promising. Particularly, since pneumonia and ARDS are associated with a cytokine storm, drugs belonging to therapeutic classes as anti-IL-6, anti-TNF, and JAK inhibitors are currently studied. In this article, we discuss the potential advantages of the most promising pharmacological approaches.

positive: Severe COVID-19, Another Piece in the Puzzle of the Hyperferritinemic Syndrome. An Immunomodulatory Perspective to Alleviate the Storm The coronavirus disease 2019 (COVID-19), an acute respiratory disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has been declared as a worldwide public health emergency. Interestingly, severe COVID-19 is characterized by fever, hyperferritinemia, and a hyper-inflammatory process with a massive release of pro-inflammatory cytokines, which may be responsible for the high rate of mortality. These findings may advocate for a similarity between severe COVID-19 and some challenging rheumatic diseases, such as adult onset Still's disease, secondary hemophagocytic lymphohistiocytosis, and catastrophic anti-phospholipid syndrome, which have been included in the “hyperferritinemic syndrome” category. Furthermore, as performed in these hyper-inflammatory states, severe COVID-19 may benefit from immunomodulatory therapies.

positive: Storm, typhoon, cyclone or hurricane in patients with COVID-19? Beware of the same storm that has a different origin Some of the articles being published during the severe acute respiratory syndrome-coronavirus (SARS-CoV)-2 pandemic highlight a link between severe forms of coronavirus disease 2019 (COVID-19) and the so-called cytokine storm, also with increased ferritin levels. However, this scenario is more complex than initially thought due to the heterogeneity of hyperinflammation. Some patients with coronavirus 2019 disease (COVID-19) develop a fully blown secondary haemophagocytic lymphohistiocytosis (sHLH), whereas others, despite a consistent release of pro-inflammatory cytokines, do not fulfil sHLH criteria but still show some features resembling the phenotype of the hyperferritinemic syndrome. Despite the final event (the cytokine storm) is shared by various conditions leading to sHLH, the aetiology, either infectious, autoimmune or neoplastic, accounts for the differences in the various phases of this process. Moreover, the evidence of a hyperinflammatory microenvironment provided the rationale to employ immunomodulating agents for therapeutic purposes in severe COVID-19. This viewpoint aims at discussing the pitfalls and issues to be considered with regard to the use of immunomodulating agents in COVID-19, such as timing of treatment based on the viral load and the extent of cytokine/ferritin overexpression. Furthermore, it encompasses recent findings in the paediatric field about a novel multisystem inflammatory disease resembling toxic shock syndrome and atypical Kawasaki disease observed in children with proven SARS-CoV2 infection. Finally, it includes arguments in favour of adding COVID-19 to the spectrum of the recently defined 'hyperferritinemic syndrome', which already includes adult-onset Still's disease, macrophage activation syndrome, septic shock and catastrophic anti-phospholipid syndrome.

positive: Tocilizumab's efficacy in patients with Coronavirus Disease 2019 (COVID‐19) is determined by the presence of cytokine storm We read with great interest the research article written by Borku Uysal B et al which is in accordance with the so far accumulating knowledge that tocilizumab is an effective treatment for COVID-19 cytokine storm syndrome (CSS). This article is protected by copyright. All rights reserved.

positive: The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China Abstract The pandemic outbreak of coronavirus disease 2019 (COVID-19) is rapidly spreading all over the world. Reports from China showed that about 20% of patients developed severe disease, resulting in a fatality of 4%. In the past two months, we clinical immunologists participated in multi-rounds of MDT (multidiscipline team) discussion on the anti-inflammation management of critical COVID-19 patients, with our colleagues dispatched from Chinese leading PUMC Hospital to Wuhan to admit and treat the most severe patients. Here, from the perspective of clinical immunologists, we will discuss the clinical and immunological characteristics of severe patients, and summarize the current evidence and share our experience in anti-inflammation treatment, including glucocorticoids, IL-6 antagonist, JAK inhibitors and choloroquine/hydrocholoroquine, of patients with severe COVID-19 that may have an impaired immune system.

positive: Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19 As a zoonotic disease that has already spread globally to several million human beings and possibly to domestic and wild animals, eradication of coronavirus disease 2019 (COVID-19) appears practically impossible. There is a pressing need to improve our understanding of the immunology of this disease to contain the pandemic by developing vaccines and medicines for the prevention and treatment of patients. In this review, we aim to improve our understanding on the immune response and immunopathological changes in patients linked to deteriorating clinical conditions such as cytokine storm, acute respiratory distress syndrome, autopsy findings and changes in acute-phase reactants, and serum biochemistry in COVID-19. Similar to many other viral infections, asymptomatic disease is present in a significant but currently unknown fraction of the affected individuals. In the majority of the patients, a 1-week, self-limiting viral respiratory disease typically occurs, which ends with the development of neutralizing antiviral T cell and antibody immunity. The IgM-, IgA-, and IgG-type virus-specific antibodies levels are important measurements to predict population immunity against this disease and whether cross-reactivity with other coronaviruses is taking place. High viral load during the first infection and repeated exposure to virus especially in healthcare workers can be an important factor for severity of disease. It should be noted that many aspects of severe patients are unique to COVID-19 and are rarely observed in other respiratory viral infections, such as severe lymphopenia and eosinopenia, extensive pneumonia and lung tissue damage, a cytokine storm leading to acute respiratory distress syndrome, and multiorgan failure. Lymphopenia causes a defect in antiviral and immune regulatory immunity. At the same time, a cytokine storm starts with extensive activation of cytokine-secreting cells with innate and adaptive immune mechanisms both of which contribute to a poor prognosis. Elevated levels of acute-phase reactants and lymphopenia are early predictors of high disease severity. Prevention of development to severe disease, cytokine storm, acute respiratory distress syndrome, and novel approaches to prevent their development will be main routes for future research areas. As we learn to live amidst the virus, understanding the immunology of the disease can assist in containing the pandemic and in developing vaccines and medicines to prevent and treat individual patients.

positive: Potential therapeutic effect of Qingwen Baidu Decoction against Corona Virus Disease 2019: a mini review The Corona Virus Disease 2019 (COVID-19) is an acute respiratory infectious disease. At present, COVID-19 has no specific therapeutic drugs, and the main clinical treatment is symptomatic treatment and control of complications. On March 5, 2020, the National Health Commission of the People’s Republic of China issued the Guidelines for the Diagnosis and Treatment of Novel Coronavirus (2019-nCoV) Infection (Trial Version 7), which integrated traditional Chinese medicine (TCM) into the treatment of COVID-19. The purpose of this study is to summarize recent studies on the clinic application, pharmacological action, chemical substances and mechanism of Qingwen Baidu Decoction (QBD) on the treatment of various diseases. The results suggested that QBD has multiple pharmacological effects such as anti-inflammation, antiviral, antibacterial, immunomodulatory, antipyretic and so on. It has been used in the treatment of sepsis, epidemic hemorrhagic fever, epidemic cerebrospinal meningitis, infantile pneumonia, sepsis-related encephalopathy, epidemic encephalitis B and other diseases. In addition, this study attempts to explore the possible mechanism of QBD in the prevention and treatment of COVID-19. Through the analysis of the chemical substances, pharmacological action and mechanism of QBD, this paper will provide a reference theoretical basis for the prevention and treatment of COVID-19 by QBD.

positive: Potential Role of Anti-interleukin (IL)-6 Drugs in the Treatment of COVID-19: Rationale, Clinical Evidence and Risks The epidemic due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been spreading globally, raising increasing concerns. This public health emergency has triggered a race to find medications to improve the prognosis of this disease. There is currently great interest in drug repositioning to manage SARS-CoV-2 infection, that is, the evaluation of the potential benefits of a drug that has already been proven safe and effective in humans for other approved indications. As interleukin-6 (IL-6) acts as a key driver of the inflammation associated with coronavirus disease 2019 (COVID-19), IL-6 and IL-6 receptor (IL-6R) inhibition appear to be promising targets for the treatment of COVID-19 patients. It is important to critically analyze the available evidence concerning the use of the available anti-IL-6 (siltuximab) and anti-IL-6R (tocilizumab and sarilumab) agents in COVID-19 patients, in terms of both benefit and risk. In this review, the pathogenesis of the cytokine storm induced by COVID-19, the role of IL-6 in this cytokine storm, the rationale for the use of anti-IL-6 agents, and key information on potential benefits and safety monitoring of these biologicals in COVID-19 patients is discussed. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40259-020-00430-1) contains supplementary material, which is available to authorized users.

positive: Favorable COVID-19 course despite significant comorbidities in a ruxolitinib-treated patient with primary myelofibrosis COVID-19 carries a high risk of severe disease course, particularly in patients with comorbidities. Therapy of severe COVID-19 infection has relied on supportive intensive care measures. More specific approaches including drugs that limit the detrimental "cytokine storm", such as Janus-activated kinase (JAK) inhibitors, are being discussed. Here, we report a compelling case of a 55-yo patient with proven COVID-19 pneumonia, who was taking the JAK1/2 inhibitor ruxolitinib in-label for co-existing primary myelofibrosis for 15 months prior to coronavirus infection. The patient had significant comorbidities, including chronic kidney disease, arterial hypertension, and obesity, and our previous cohort suggested that he was thus at high risk for acute respiratory distress syndrome (ARDS) and death from COVID-19. Since abrupt discontinuation of ruxolitinib may cause fatal cytokine storm and ARDS, ruxolitinib treatment was continued and was well tolerated, and the patient´s condition remained stable, without the need for mechanical ventilation or vasopressors. The patient became negative for SARS-CoV-2 and was discharged home after 15 days. In conclusion, our report provides clinical evidence that ruxolitinib treatment is feasible and can be beneficial in patients with COVID-19 pneumonia, preventing cytokine storm and ARDS.

positive: Cytokine storm syndrome in severe COVID-19

positive: The possible mechanisms of action of 4-aminoquinolines (chloroquine/hydroxychloroquine) against Sars-Cov-2 infection (COVID-19): A role for iron homeostasis? The anti-malarial drugs chloroquine (CQ) and primarily the less toxic hydroxychloroquine (HCQ) are currently used to treat autoimmune diseases for their immunomodulatory and anti-thrombotic properties. They have also been proposed for the treatment of several viral infections, due to their anti-viral effects in cell cultures and animal models, and, currently, for the treatment of coronavirus disease 2019 (COVID-19), the pandemic severe acute respiratory syndrome caused by coronavirus 2 (Sars-Cov-2) infection that is spreading all over the world. Although in some recent studies a clinical improvement in COVID-19 patients has been observed, the clinical efficacy of CQ and HCQ in COVID-19 has yet to be proven with randomized controlled studies, many of which are currently ongoing, also considering pharmacokinetics, optimal dosing regimen, therapeutic level and duration of treatment and taking into account patients with different severity degrees of disease. Here we review what is currently known on the mechanisms of action of CQ and HCQ as anti-viral, anti-inflammatory and anti-thrombotic drugs and discuss the up-to-date experimental evidence on the potential mechanisms of action of CQ/HCQ in Sars-Cov2 infection and the current clinical knowledge on their efficacy in the treatment of COVID-19 patients. Given the role of iron in several human viral infections, we also propose a different insight into a number of CQ and HCQ pharmacological effects, suggesting a potential involvement of iron homeostasis in Sars-Cov-2 infection and COVID-19 clinical course.

positive: Dysregulation of the immune system as a driver of the critical course of the novel coronavirus disease 2019. Novel coronavirus disease-2019 (COVID-19) is a highly contagious respiratory-related disease induced by the newly emerged virus SARS-CoV-2. Given that inflammatory immune cells may induce severe lung injury, the involvement of immune factors in the pathogenesis of the disease cannot be overestimated. It has been demonstrated that coronaviruses (CoVs) have developed mechanisms of immune evasion, making them invisible to the immune system at an early stage of infection. The mechanism relies on inhibition of the anti-viral response of type I interferons (IFNs), which supports uncontrolled viral replication in epithelial cells. There is growing body of evidence that the fatal hyperinflammation ('cytokine storm') responsible for the severe course of COVID-19 is a consequence of massive SARS-CoV-2 replication rather than inappropriate hyperresponsiveness of the immune system. Therefore, a dampened innate anti-viral immune response seems to be the primary cause of the delayed critical cascade of uncontrolled immune events leading to fulminating systemic inflammation. The occurrence of virus transmission even in asymptomatic subjects infected with SARS-CoV-2 clearly strengthens the evidence for a key role of sufficient immune control of viral replication in a subset of cases (e.g. in children, a population with highly effective innate immune responses). Although administration of immunomodulatory therapeutics is recommended under certain conditions in the guidelines of COVID-19 management, controversies regarding treatment protocols in immunocompromised patients infected with SARS-CoV-2 still exist. Extended knowledge of clinicians on the dysregulated immune response, which is a driver of the COVID-19 outcome, may improve both therapeutic protocols and the prognosis of SARS-CoV-2 infected patients.

positive: Virus-Induced Immunopathology Several viruses cause damage to the tissue by immunopathological mechanisms. This chapter presents the principal examples of immunopathogenesis caused by the viruses, accompanied by speculations about its management. The most common mechanism of lesion development in virus induced immunopathology involves T cells. Usually, it seems that when CD8(+) T cells act as the controlling cell type, lesions are acute and the outcome is decided quickly. The classic example is provided by LCM in mice. The newest candidate may turn out to be SNV infection in humans. Lesions orchestrated primarily by CD4(+) T cells can be either acute or long-lasting. Curiously, in the LCMV example, if CD8(+) T cells are removed from the scene, immunopathological responses may still occur and these involve CD4(+) T cells. Such responses are far more chronic and of lower grade than those mediated by CD8(+) T lymphocytes. One possible sequel to chronic inflammatory responses to viruses is that autoreactive inflammatory reactions are initiated and an autoimmune disease occurs. The adage that an ounce of prevention is worth a pound of cure is certainly true in the field of viral pathogenesis. Preventing viral infection or manipulating immune processes during the initial phases of infection is far more successful than attempting to counteract pathological events once underway.

positive: Implications of COVID-19 in pediatric rheumatology COVID-19 (coronavirus disease 2019) pandemic caused by SARS-CoV-2, is a global public health issue threatening millions of lives worldwide. Although the infection is mild in most of the affected individuals, it may cause severe clinical manifestations such as acute respiratory distress syndrome or cytokine storm leading to death. Children are affected less, and most experience a milder disease. As rheumatologists, we deal with the uncontrolled response of the immune system, and most of the drugs we use are either immune modulators or immunosuppressants. Thus, the rheumatologists participate in the multidisciplinary management of COVID-19 patients. On the other hand, our patients with rheumatic diseases constitute a vulnerable group in this pandemic. In this review, a systematic literature search was conducted utilizing MEDLINE/PubMed and Scopus databases, and 231 COVID-19 patients with rheumatic diseases have been identified. Only one of these patients was a child. Among these, 9 (3.9%) died due to COVID-19. In light of the current data, the aspects of COVID-19 resembling rheumatic diseases, the possible reasons for why children are affected less severely, the hypothetic role of available vaccines in preventing COVID-19, the unique position of patients with rheumatic diseases in this pandemic, and the use of anti-rheumatic drugs in COVID-19 treatment are discussed. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00296-020-04612-6) contains supplementary material, which is available to authorized users.

positive: Tocilizumab challenge: A series of cytokine storm therapy experiences in hospitalized COVID-19 pneumonia patients To recognize the period of exaggerated cytokine response in patients with coronavirus disease 2019 (COVID-19) pneumonia, and to describe the clinical outcomes of using tocilizumab as a treatment option. The data of 12 adult COVID-19 pneumonia patients who were followed in the inpatient clinics of Biruni University Medical Faculty Hospital (Istanbul, Turkey) were retrospectively analyzed. Diagnostic tests, laboratory examinations, clinical findings, and computed tomography of the thorax imaging results were evaluated. A dramatic laboratory and clinical improvement was observed in 83% (10 out of 12) of patients after tocilizumab. In 17% (2 out of 12) of our patients, short-term ventilator support was required in the intensive care unit. The longest hospital stay was 18 days. However, in the end, all of our patients were discharged home with good health. Although arterial oxygen saturations (87.58 ± 3.12%) dropped in room air in the pre-tocilizumab period, post-tocilizumab they normalized in all patients (94.42 ± 1%). None of them had fever after tocilizumab treatment and the levels of C-reactive protein (13.08 ± 12.89) were almost within normal limits. Eosinophil values were quite low at the time of diagnosis (10 ± 17.06), but increased significantly post-tocilizumab (155.33 ± 192.69). There is currently no proven treatment for COVID-19 induced by novel coronavirus SARS-CoV-2. Based on our experience with twelve adult COVID-19 pneumonia patients,we can say that tocilizumab, an IL-6 inhibitor, is more beneficial in preventing the damage caused by excessive cytokine response in the body if administered at the right time and provides clinical and radiological recovery.

positive: SARS-CoV-2: A Storm is Raging. The pandemic coronavirus infectious disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is rapidly spreading across the globe. In this issue of the JCI, Chen and colleagues compared the clinical and immunologic characteristics between moderate versus severe COVID-19. The authors found that respiratory distress on admission is associated with unfavorable outcomes. Increased cytokine levels (IL-6, IL-10 and TNFα), lymphopenia (in CD4+ and CD8+ T cells), and decreased IFNγ expression in CD4+ T cells are associated with severe COVID-19. Overall, this study characterized the cytokine storm in severe COVID-19 and provides insights into immune therapeutics and vaccine design.

positive: Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients BACKGROUND: Although the detection of SARS-CoV-2 viral load in respiratory specimens has been widely used to diagnose coronavirus disease-19 (COVID-19), it is undeniable that serum SARS-CoV-2 nucleic acid (RNAaemia) could be detected in a fraction of COVID-19 patients. However, it is not clear whether testing for RNAaemia is correlated with the occurrence of cytokine storms or with the specific class of patients. METHODS: This study enrolled 48 patients with COVID-19 admitted to the General Hospital of Central Theater Command, PLA, a designated hospital in Wuhan, China. The patients were divided into three groups according to the “Diagnosis and Treatment of New Coronavirus Pneumonia (6(th) edition)” issued by the National Health Commission of China. The clinical and laboratory data were collected. The serum viral load and IL-6 levels were determined. . RESULTS: Clinical characteristics analysis of 48 cases of COVID-19 showed that RNAaemia was diagnosed only in the critically ill group and seemed to reflect the severity of the disease. Furthermore, the level of inflammatory cytokine IL-6 in critically ill patients increased significantly, almost 10 times that in other patients. More importantly, the extremely high IL-6 level was closely correlated with the detection of RNAaemia (R = 0.902). CONCLUSIONS: Detectable serum SARS-Cov-2 RNA(RNAaemia) in COVID-19 patients was associated with elevated IL-6 concentration and poor prognosis. Because the elevated IL-6 may be part of a larger cytokine storm which could worsen outcome, IL-6 could be a potential therapeutic target for critically ill patients with an excessive inflammatory response.

positive: COVID‐19, pulmonary mast cells, cytokine storms, and beneficial actions of luteolin

positive: Extracorporeal Hemoadsorption: An Option for COVID-19 Associated Cytokine Storm Syndrome

positive: Weathering the COVID-19 storm: Lessons from hematologic cytokine syndromes A subset of patients with severe COVID-19 develop profound inflammation and multi-organ dysfunction consistent with a "Cytokine Storm Syndrome" (CSS). In this review we compare the clinical features, diagnosis, and pathogenesis of COVID-CSS with other hematological CSS, namely secondary hemophagocytic lymphohistiocytosis (sHLH), idiopathic multicentric Castleman disease (iMCD), and CAR-T cell therapy associated Cytokine Release Syndrome (CRS). Novel therapeutics targeting cytokines or inhibiting cell signaling pathways have now become the mainstay of treatment in these CSS. We review the evidence for cytokine blockade and attenuation in these known CSS as well as the emerging literature and clinical trials pertaining to COVID-CSS. Established markers of inflammation as well as cytokine levels are compared and contrasted between these four entities in order to establish a foundation for future diagnostic criteria of COVID-CSS.

positive: Adaptive immune cells temper initial innate responses Toll-like receptors (TLRs) recognize conserved microbial structures called pathogen-associated molecular patterns. Signaling from TLRs leads to upregulation of co-stimulatory molecules for better priming of T cells and secretion of inflammatory cytokines by innate immune cells1–4. Lymphocytedeficient hosts often die of acute infection, presumably owing to their lack of an adaptive immune response to effectively clear pathogens. However, we show here that an unleashed innate immune response due to the absence of residential T cells can also be a direct cause of death. Viral infection or administration of poly(I:C), a ligand for TLR3, led to cytokine storm in T-cell- or lymphocyte-deficient mice in a fashion dependent on NK cells and tumor necrosis factor. We have further shown, through the depletion of CD4(+) and CD8(+) cells in wild-type mice and the transfer of T lymphocytes into Rag-1–deficient mice, respectively, that T cells are both necessary and sufficient to temper the early innate response. In addition to the effects of natural regulatory T cells, close contact of resting CD4(+)CD25(−)Foxp3(−) or CD8(+) T cells with innate cells could also suppress the cytokine surge by various innate cells in an antigen-independent fashion. Therefore, adaptive immune cells have an unexpected role in tempering initial innate responses.

positive: Activated macrophages are the main inflammatory cell in COVID-19 interstitial pneumonia infiltrates. Is it possible to show their metabolic activity and thus the grade of inflammatory burden with (18)F-Fluorocholine PET/CT? The recent outbreak of Covid-19 has represented a major challenge for the countries affected by the disease, not only in terms of loss of human life, economic downturn, and constraint on individual freedom, but also for the great pressure on the national health systems and hospitals. The 380 kDa virus has been a perfect storm, especially for those national health systems used to working with limited resources and high intensity rhythms, such as Italy. For the first time in the new century, a virtually unknown fast-spreading disease has caused a public health emergency thus forcing most countries to deal with an insurmountable logistic gap. Hence, every branch of Medicine, even though not directly involved in the treatment, has been called upon to provide its contribution to resolve the crisis. It is now becoming more apparent that Covid-19 is not solely a lung disease, but a complex systemic disease involving several organs and systems. This is due to an abnormal inflammatory response which eventually leads to multisystemic coagulopathy which mainly, but not uniquely, targets the lungs. Although the pathophysiology of this syndrome is still not fully understood, macrophages and their immune complex system seem to play a key role. It is not yet clear why some patients develop the violent immune response which results in pneumonitis while others do not. There are clues indicating that the systemic hyper-inflammation defined as macrophage activation syndrome (MAS), or cytokine storm, requires an increase in choline consumption to synthesize phosphatidylcholine and stimulate phagocytosis, organelle biogenesis, secretory functions, and endocytosis. (18)F-Fluorocholine is a synthetic analog of the naturally occurring choline normally used for PET/CT imaging of prostate cancer patients. (18)F-Fluorocholine could image and quantify the macrophage activity in pulmonary interstitial infiltrates of Covid-19 pneumonia. If the hypothesis is confirmed experimentally, (18)F-Fluorocholine PET/CT could be used to in vivo image and quantify the degree of lung inflammation and potentially stratify the gravity of this disease.

positive: First case of COVID-19 in a kidney transplant recipient treated with belatacept

positive: Why tocilizumab could be an effective treatment for severe COVID-19? A severe pneumonia-associated respiratory syndrome caused by a new coronavirus was identified in December 2019 (COVID-19), spread rapidly and has become a world-wide public health challenge. About 25% of COVID-19 patients experienced severe complications including acute respiratory distress syndrome (ARDS), and even progressed into an intensive care unit (ICU) admission and died. The exploration for the mortality causes and advancing novel therapeutic development of severe COVID-19 is crucial at the moment. The biopsy samples analysis at autopsy suggested that increased alveolar exudate caused by aberrant host immune response and inflammatory cytokine storm probably impedes alveolar gas exchange and contributes to the high mortality of severe COVID-19 patients. Our research has identified that pathogenic T cells and inflammatory monocytes incite inflammatory storm with large amount of interleukin 6, therefore monoclonal antibody that targets the IL-6 pathways may potentially curb inflammatory storm. Moreover, Tocilizumab treatment that blocking IL-6 receptors showed inspiring clinical results including temperature returned to normal quickly and respiratory function improved. Therefore, we suggest that Tocilizumab is an effective treatment in severe patients of COVID-19 to calm the inflammatory storm and reduce mortality.

positive: Obese communities among the best predictors of COVID-19-related deaths INTRODUCTION: Coronavirus disease 2019 (COVID-19) is the largest outbreak to strike the world since the Spanish flu in 1918. Visual examination of the world map shows a wide variation of death tolls between countries. The main goal of our series is to determine the best predictors of such discrepancy. METHODS: This is a retrospective study in which the rate of COVID-19 deaths was correlated with each of the following independent variables: total tests per 1 million population, gross domestic product (GDP), average temperatures per country, ultraviolet index, median age, average BMI per country, food supply, Bacille Calmette-Guerin compulsory status, and passenger traffic. RESULTS: BMI per country proved to be the second best predictor of death rate with an R value of 0.43, and GDP being the best predictor with R = 0.65. CONCLUSION: This article shows a tight correlation between average BMI, food supply per country, and COVID-19-related deaths. Such predisposing factors might operate by upregulating the inflammation pathway in heavily struck countries, leading to easier triggering of the infamous cytokine storm syndrome. Obesity also increases cardiovascular and respiratory morbidities, which are coupled to increased ICU demand and deaths among infected cases. Video abstract: http://links.lww.com/CAEN/A25.

positive: Inflammasomes and Pyroptosis as Therapeutic Targets for COVID-19. The inflammatory response to severe acute respiratory syndrome-related coronavirus 2 infection has a direct impact on the clinical outcomes of coronavirus disease 2019 patients. Of the many innate immune pathways that are engaged by severe acute respiratory syndrome-related coronavirus 2, we highlight the importance of the inflammasome pathway. We discuss available pharmaceutical agents that target a critical component of inflammasome activation, signaling leading to cellular pyroptosis, and the downstream cytokines as a promising target for the treatment of severe coronavirus disease 2019-associated diseases.

positive: Immunopathology and immunotherapeutic strategies in severe acute respiratory syndrome coronavirus 2 infection The outbreak of coronavirus disease 2019 (COVID-19) and pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a major concern globally. As of 14 April 2020, more than 1.9 million COVID-19 cases have been reported in 185 countries. Some patients with COVID-19 develop severe clinical manifestations, while others show mild symptoms, suggesting that dysregulation of the host immune response contributes to disease progression and severity. In this review, we have summarized and discussed recent immunological studies focusing on the response of the host immune system and the immunopathology of SARS-CoV-2 infection as well as immunotherapeutic strategies for COVID-19. Immune evasion by SARS-CoV-2, functional exhaustion of lymphocytes, and cytokine storm have been discussed as part of immunopathology mechanisms in SARS-CoV-2 infection. Some potential immunotherapeutic strategies to control the progression of COVID-19, such as passive antibody therapy and use of interferon αß and IL-6 receptor (IL-6R) inhibitor, have also been discussed. This may help us to understand the immune status of patients with COVID-19, particularly those with severe clinical presentation, and form a basis for further immunotherapeutic investigations.

positive: Clinical and pathological investigation of severe COVID-19 patients. BACKGROUND Severe acute respiratory coronavirus 2 (SARS-CoV-2) caused coronavirus disease 2019 (COVID-19) has become a pandemic. This study addressed the clinical and immunopathological characteristics of severe COVID-19. METHODS Sixty-nine COVID-19 patients were classified into as severe and non-severe groups to analyze their clinical and laboratory characteristics. A panel of blood cytokines was quantified over time. Biopsy specimens from two deceased cases were obtained for immunopathological, ultrastructural, and in situ hybridization examinations. RESULTS Circulating cytokines, including IL8, IL6, TNFα, IP10, MCP1, and RANTES, were significantly elevated in severe COVID-19 patients. Dynamic IL6 and IL8 were associated with disease progression. SARS-CoV-2 was demonstrated to infect type II, type I pneumocytes and endothelial cells, leading to severe lung damage through cell pyroptosis and apoptosis. In severe cases, lymphopenia, neutrophilia, depletion of CD4+ and CD8+ T lymphocytes, and massive macrophage and neutrophil infiltrates were observed in both blood and lung tissues. CONCLUSIONS A panel of circulating cytokines could be used to predict disease deterioration and inform clinical interventions. Severe pulmonary damage was predominantly attributed to both SARS-CoV-2 caused cytopathy and immunopathologic damage. Strategies that encourage pulmonary recruitment and overactivation of inflammatory cells by suppressing cytokine storm might improve the outcomes of severe COVID-19 patients.

positive: The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease Severe COVID-19 associated pneumonia patients may exhibit features of systemic hyper-inflammation designated under the umbrella term of macrophage activation syndrome (MAS) or cytokine storm, also known as secondary haemophagocytic lymphohistocytosis (sHLH). This is distinct from HLH associated with immunodeficiency states termed primary HLH -with radically different therapy strategies in both situations. COVID-19 infection with MAS typically occurs in subjects with adult respiratory distress syndrome (ARDS) and historically, non-survival in ARDS was linked to sustained IL-6 and IL-1 elevation. We provide a model for the classification of MAS to stratify the MAS-like presentation in COVID-19 pneumonia and explore the complexities of discerning ARDS from MAS. We discuss the potential impact of timing of anti-cytokine therapy on viral clearance and the impact of such therapy on intra-pulmonary macrophage activation and emergent pulmonary vascular disease.

positive: TNFα inhibitor may be effective for severe COVID-19: learning from toxic epidermal necrolysis Increased inflammatory cytokines [such as tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6)] are observed in COVID-19 patients, especially in the severe group. The phenomenon of a cytokine storm may be the central inducer of apoptosis of alveolar epithelial cells, which leads to rapid progression in severe group patients. Given the similarities of clinical features and pathogenesis between toxic epidermal necrolysis (TEN) and COVID-19, we hypothesize that the application of etanercept, an inhibitor of TNFα, could attenuate disease progression in severe group COVID-19 patients by suppressing systemic auto-inflammatory responses. The reviews of this paper are available via the supplemental material section.

positive: Gaining insights on immune responses to the novel coronavirus, COVID-19 and therapeutic challenges SARS-CoV-2 is a new member of coronaviruses that its sudden spreading put the health care system of most countries in a tremendous shock. For controlling of the new infection, COVID-19, many efforts have been done and are ongoing to defeat this virus in the combat field. In this review, we focused on how the immune system behaves toward the virus and the relative possible consequences during their interactions. Then the therapeutic steps and potential vaccine candidates have been described in a hope to provide a better prospective of effective treatment and preventive strategies to the novel SARS-CoV in near future.

positive: Use of Tocilizumab for COVID-19-Induced Cytokine Release Syndrome A Cautionary Case Report Novel coronavirus disease 2019 (COVID-19) emerged in late December 2019 in Wuhan, China. Since then, COVID-19 has become a pandemic affecting more than 1.5 million people worldwide. Patients with COVID-19 have a wide spectrum of manifestations, one being cytokine release syndrome (CRS) and its fatal correlate, secondary hemophagocytic lymphohistiocytosis (sHLH). Anti-cytokine therapy such as tocilizumab, an IL-6 receptor antagonist, is a potential treatment for COVID-19; however, data regarding the efficacy of this anti-IL-6 therapy are currently lacking. We report two cases of patients who received a diagnosis of COVID-19 complicated by CRS and were treated with tocilizumab. Both patients progressed to sHLH despite treatment with tocilizumab, and one developed viral myocarditis, challenging the safety and clinical usefulness of tocilizumab in the treatment of COVID-19-induced CRS. These cases highlight the need for clinical trials to determine optimal patient selection and timing for the use of tocilizumab during this disease process.

positive: Hypothesis for the management and treatment of the COVID-19-induced acute respiratory distress syndrome and lung injury using mesenchymal stem cell-derived exosomes Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the coronaviridae that causes respiratory disorders. After infection, large amounts of inflammatory cytokines are secreted, known as the cytokine storm. These cytokines can cause pulmonary damage induced by inflammation resulting in acute respiratory distress syndrome (ARDS), and even death. One of the therapeutic approaches for treatment of ARDS is a mesenchymal stem cell (MSC). MSCs suppress inflammation and reduce lung injury through their immunomodulatory properties. MSCs also have the potential to prevent apoptosis of the lung cells and regenerate them. But our suggestion is using MSCs-derived exosomes. Because these exosomes apply the same immunomodulatory and tissue repair effects of MSCs and they don’t have problems associated to cell maintenance and injections. For investigation the hypothesis, MSCs should be isolated from tissues and characterized. Then, the exosomes should be isolated from the supernatants and characterized. These exosomes should be injected into a transgenic animal for COVID-19. In the final section, lung function assessment, histological examination, micro-CT, differential leukocyte, viral load analysis, cytokine assay, and CRP level analysis can be investigated. COVID-19 treatment is currently focused on supportive therapies and no vaccine has not been developed for it, so, numerous research studies are needed to find potential. Since the pathogenesis of this disease was identified in previous studies and can cause lung injury with ARDS, so, investigation of the therapeutic approaches that can suppress inflammation, cytokine storm and ARDS can be helpful in finding a novel therapeutic approach for this disease.

positive: COVID 19 and low-glucose levels : is there a link ?

positive: Thoughts on prevention and treatment of coronavirus disease 2019 (COVID-19) by traditional Chinese medicine/ 新型冠状病毒肺炎（COVID-19）中医药防治的思考 The etiology and pathogenesis of coronavirus disease 2019 (COVID-19), which was discovered in Wuhan in late 2019 and has spread to the world, were expounded. In view of the application of traditional Chinese medicine (TCM) in the plague over these years, the therapeutic advantages of TCM in different stages of COVID-19 were expounded as “strengthening body resistance and eliminating evil, meeting changes with constancy”, “Syndrome differentiation and treatment, meeting change with variance”, with aim to reduce the sequelae caused by hormone and other drugs and the mortality. It is suggested that Chinese medicine of clearing heat and removing toxin should be used to prevent the uninfected people from COVID-19, and intervene in the early stage of the disease and control the development of it to be severe by inhibiting the “cytokine storm”. In order to refine the dialectical classification according to the theory of “defensing-qi-nutrient-blood syndrome differentiation”, to give full play to the individual advantages of TCM in the prevention and treatment of COVID-19. We should pay attention to the rational use of TCM in the prevention and treatment of COVID-19, collect the real world clinical data, and integrate TCM and Western medicine with TCM as the main part. The COVID-19 database of integrated TCM and Western medicine can be used to prepare for the prevention and treatment of COVID-19.

positive: Combined IL‐6 and JAK‐STAT inhibition therapy in COVID‐19 related sHLH, potential game changer Coronavirus disease 2019 (COVID‐19), caused by novel SARS‐CoV‐2, leads to significant mortality and morbidity with increasing evidence for inflammatory pathways being implicated in the lung damage it causes. (1,2) Severe COVID‐19 patients present with increased inflammatory markers, akin to secondary haemophagocytic lymphohistiocytosis (sHLH), that have been shown to predict mortality. (3,4) There is emerging evidence for the use of an interleukin 6 (IL‐6) inhibitor, tocilizumab (TCZ), for suppression of the inflammatory cytokine storm in this context. (5–7) Ruxolitinib (RXB), a JAK‐STAT inhibitor, has also been shown to have proven efficacy in the treatment of sHLH. (8) Both agents appear to be promising in the fight against SARS‐CoV‐2 infection, (9,10) leading to an increasing number of trials being registered with their use. (11,12) Until this point, no single agent has shown a survival benefit against SARS‐CoV‐2 and it is possible that monotherapy may not suppress inflammation enough to overcome the COVID‐19 related cytokine storm and hyper‐inflammation.

positive: [Study on treatment of "cytokine storm" by anti-2019-nCoV prescriptions based on arachidonic acid metabolic pathway]. Since the outbreak of 2019-nCoV, the epidemic has developed rapidly and the situation is grim. LANCET figured out that the 2019-nCoV is closely related to "cytokine storm". "Cytokine storm" is an excessive immune response of the body to external stimuli such as viruses and bacteria. As the virus attacking the body, it stimulates the secretion of a large number of inflammatory factors: interleukin(IL), interferon(IFN), C-X-C motif chemokine(CXCL) and so on, which lead to cytokine cascade reaction. With the exudation of inflammatory factors, cytokines increase abnormally in tissues and organs, interfering with the immune system, causing excessive immune response of the body, resulting in diffuse damage of lung cells, pulmonary fibrosis, and multiple organ damage, even death. Arachidonic acid(AA) metabolic pathway is principally used to synthesize inflammatory cytokines, such as monocyte chemotactic protein 1(MCP-1), tumor necrosis factor(TNF), IL, IFN, etc., which is closely related to the occurrence, development and regression of inflammation. Therefore, the inhibition of AA metabolism pathway is benefit for inhibiting the release of inflammatory factors in the body and alleviating the "cytokine storm". Based on the pharmacophore models of the targets on AA metabolic pathway, the traditional Chinese medicine database 2009(TCMD 2009) was screened. The potential herbs were ranked by the number of hit molecules, which were scored by pharmacophore fit value. In the end, we obtained the potential active prescriptions on "cytokine storm" according to the potential herbs in the "National novel coronavirus pneumonia diagnosis and treatment plan(trial version sixth)". The results showed that the hit components with the inhibitory effect on AA were magnolignan Ⅰ, lonicerin and physcion-8-O-β-D-glucopy-ranoside, which mostly extracted from Magnoliae Officinalis Cortex, Zingiberis Rhizoma Recens, Lonicerae Japonicae Flos, Rhei Radix et Rhizoma, Salviae Miltiorrhizae Radix et Rhizoma, Scutellariae Radix, Gardeniae Fructus, Ginseng Radix et Rhizoma, Arctii Fructus, Dryopteridis Crassirhizomatis Rhizoma, Paeoniaeradix Rubra, Dioscoreae Rhizoma. Finally the anti-2019-nCoV prescriptions were analyzed to obtain the potential active prescriptions on AA metabolic pathway, Huoxiang Zhengqi Capsules, Jinhua Qinggan Granules, Lianhua Qingwen Capsules, Qingfei Paidu Decoction, Xuebijing Injection, Reduning Injection and Tanreqing Injection were found that may prevent 2019-nCoV via regulate cytokines. This study intends to provide reference for clinical use of traditional Chinese medicine to resist new coronavirus.

positive: Cytokine storm and the prospects for immunotherapy with COVID-19. Knowledge about the pathobiology of SARS-COV-2 as it interacts with immune defenses is limited. SARS-COV-2 is spread by droplets that come into contact with mucous membranes. COVID-19 is characterized by 3 stages: asymptomatic-paucisymptomatic incubation, nonsevere symptomatic illness for 80% of those infected, and severe respiratory illness. A syndrome characterized by hypercytokinemic inflammation referred to as a "cytokine storm" can occur in patients with advanced disease. Effective antiviral agents that can prevent viral infection in exposed individuals are needed.

positive: Covid-19 and drug therapy, what we learned COVID-19, the disease associated in December 2019 with the novel coronavirus SARS-CoV-2, was observed for the first time in China and then spread worldwide becoming pandemic. Currently, there is still no licensed specific antiviral treatment for the human coronavirus disease and a vaccine will not be ready soon. However, based on experience from the use of other antiviral agents to treat similar virusses, some treatment options have been tried with some efficacy. Clinical trials for future therapies are still ongoing. In the meantime, prevention, control, active communication and investment in research are the only ways to overcome this challenge.

positive: Hydroxychloroquine application is associated with a decreased mortality in critically ill patients with COVID-19 Importance: Coronavirus disease 2019 (COVID-19) is a pandemic with no specific drugs and high mortality. The most urgent thing is to find effective treatments. Objective: To determine whether hydroxychloroquine application may be associated with a decreased risk of death in critically ill COVID-19 patients and what is potential mechanism. Design, Setting and Patients: This retrospective study included all 568 critically ill COVID-19 patients who were confirmed by pathogen laboratory tests despite antiviral treatment and had severe acute respiratory distress syndrome, PAO2/FIO2 <300 with need of mechanical ventilation in Tongji Hospital, Wuhan, between February 1 of 2020 to April 8 of 2020. All 568 patients received comparable basic treatments including antiviral drugs and antibiotics, and 48 of them additionally received oral hydroxychloroquine (HCQ) treatment (200 mg twice a day for 7-10 days). Primary endpoint is mortality of patients, and inflammatory cytokines levels were compared between hydroxychloroquine and non-hydroxychloroquine (NHCQ) treatments. MAIN OUTCOMES AND MEASURES: In-hospital death and hospital stay time (day) were obtained, level of inflammatory cytokine (IL-6) was measured and compared between HCQ and NHCQ treatments. RESULTS: The median age of 568 critically ill patients is 68 (57, 76) years old with 37.0% being female. Mortalities are 18.8% (9/48) in HCQ group and 45.8% (238/520) in NHCQ group (p<0.001). The time of hospital stay before patient death is 15 (10-21) days and 8 (4 - 14) days for the HCQ and NHCQ groups, respectively (p<0.05). The level of inflammatory cytokine IL-6 was significantly lowered from 22.2 (8.3-118.9) pg/mL at the beginning of the treatment to 5.2 (3.0-23.4) pg/ml (p<0.05) at the end of the treatment in the HCQ group but there is no change in the NHCQ group. CONCLUSIONS AND RELEVANCE: Hydroxychloroquine treatment is significantly associated with a decreased mortality in critically ill patients with COVID-19 through attenuation of inflammatory cytokine storm. Therefore, hydroxychloroquine should be prescribed for treatment of critically ill COVID-19 patients to save lives.

positive: Immune environment modulation in pneumonia patients caused by coronavirus: SARS-CoV, MERS-CoV and SARS-CoV-2 Currently, we are on a global pandemic of Coronavirus disease-2019 (COVID-19) which causes fever, dry cough, fatigue and acute respiratory distress syndrome (ARDS) that may ultimately lead to the death of the infected. Current researches on COVID-19 continue to highlight the necessity for further understanding the virus-host synergies. In this study, we have highlighted the key cytokines induced by coronavirus infections. We have demonstrated that genes coding interleukins (Il-1α, Il-1β, Il-6, Il-10), chemokine (Ccl2, Ccl3, Ccl5, Ccl10), and interferon (Ifn-α2, Ifn-β1, Ifn2) upsurge significantly which in line with the elevated infiltration of T cells, NK cells and monocytes in SARS-Cov treated group at 24 hours. Also, interleukins (IL-6, IL-23α, IL-10, IL-7, IL-1α, IL-1β) and interferon (IFN-α2, IFN2, IFN-γ) have increased dramatically in MERS-Cov at 24 hours. A similar cytokine profile showed the cytokine storm served a critical role in the infection process. Subsequent investigation of 463 patients with COVID-19 disease revealed the decreased amount of total lymphocytes, CD3+, CD4+, and CD8+ T lymphocytes in the severe type patients which indicated COVID-19 can impose hard blows on human lymphocyte resulting in lethal pneumonia. Thus, taking control of changes in immune factors could be critical in the treatment of COVID-19.

positive: Profiling COVID-19 pneumonia progressing into the cytokine storm syndrome: results from a single Italian Centre study on tocilizumab versus standard of care OBJECTIVE: Approximately 5% of patients with coronavirus disease 2019 (COVID-19) develop a life-threatening pneumonia that often occurs in the setting of increased inflammation or “cytokine storm”. Anti-cytokine treatments are being evaluated but optimal patient selection remains unclear, and the aim of our study is to address this point. METHODS: Between February 29 to April 6, 2020, 111 consecutive hospitalized patients with COVID-19 pneumonia were evaluated in a single centre retrospective study. Patients were divided in two groups: 42 severe cases (TOCI) with adverse prognostic features including raised CRP and IL-6 levels, who underwent anti-cytokine treatments, mostly tocilizumab, and 69 standard of care patients (SOC). RESULTS: In the TOCI group, all received anti-viral therapy and 40% also received glucocorticoids. In TOCI, 62% of cases were ventilated and there were 3 deaths (17.8 ± 10.6 days, mean follow up) with 7/26 cases remaining on ventilators, without improvement, and 17/26 developed bacterial superinfection. One fatality occurred in the 15 TOCI cases treated on noninvasive ventilation and 1 serious bacterial superinfection. Of the 69 cases in SOC, there was no fatalities and no bacterial complications. The TOCI group had higher baseline CRP and IL-6 elevations (p < 0.0001 for both) and higher neutrophils and lower lymphocyte levels (p = 0.04 and p = 0.001, respectively) with the TOCI ventilated patients having higher markers than non-ventilated TOCI patients. CONCLUSION: Higher inflammatory markers, more infections and worse outcomes characterized ventilated TOCI cases compared to ward based TOCI. Despite the confounding factors, this suggests that therapy time in anti-cytokine randomized trials will be key.

positive: Understanding the COVID‐19 coagulopathy spectrum The SARS‐Cov‐2 (COVID‐19) pandemic has already claimed over 200,000 lives. Quite early on in this pandemic, it was recognised that the virus triggers the immune system leading to a cytokine storm in some severely ill patients [1]. This hyper‐responsiveness has been suggested to be the predominant aetiology for clinical deterioration and mortality in patients with this infection [2]. More recently, there have been several reports of increased thrombotic events in these patients [3‐6]. From a laboratory perspective, this hypercoagulability is reflected in the marked elevation of the fibrinolytic marker, D‐dimer, in almost all hospitalised COVID‐19 patients [7]. We must, therefore, ask ourselves what is the link between the extremes of the immune system, presenting as cytokine storm, and the extremes of coagulation, presenting as arterial and venous thromboembolism?

positive: Cytokinstormer ved covid-19?/ Cytokinstormer ved covid-19?/ Cytokine storms in COVID-19 cases?

positive: The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease Abstract Severe COVID-19 associated pneumonia patients may exhibit features of systemic hyper-inflammation designated under the umbrella term of macrophage activation syndrome (MAS) or cytokine storm, also known as secondary haemophagocytic lymphohistocytosis (sHLH). This is distinct from HLH associated with immunodeficiency states termed primary HLH -with radically different therapy strategies in both situations. COVID-19 infection with MAS typically occurs in subjects with adult respiratory distress syndrome (ARDS) and historically, non-survival in ARDS was linked to sustained IL-6 and IL-1 elevation. We provide a model for the classification of MAS to stratify the MAS-like presentation in COVID-19 pneumonia and explore the complexities of discerning ARDS from MAS. We discuss the potential impact of timing of anti-cytokine therapy on viral clearance and the impact of such therapy on intra-pulmonary macrophage activation and emergent pulmonary vascular disease.

positive: SARS-CoV-2 and COVID-19: is interleukin-6 (IL-6) the 'culprit lesion' of ARDS onset? What is there besides Tocilizumab? SGP130Fc Since the outbreak of COVID-19 many studies have been published showing possible therapies, here the author discusses the end of stage disease related drugs, like Tocilizumab which is currently being used in ARDS patients. In some patients, disease progression leads to an enormous secretion of cytokines, known as cytokine storm, among those cytokines IL-6 plays an important role. Here the author shows how IL-6 has both pro and anti-inflammatory properties, depending on the pathway of transduction: soluble (trans-signaling) or membrane-related (classic signaling), and suggests how targeting only the pro-inflammatory pathway, with SGP130Fc, could be a better option then targeting them both. Other possible IL-6 pathway inhibitors such as Ruxolitinib and Baricinitib are then analyzed, underlying how they lack the benefit of targeting only the pro-inflammatory pathway.

positive: Metabolic host response and therapeutic approaches to influenza infection Based on available metabolomic studies, influenza infection affects a variety of cellular metabolic pathways to ensure an optimal environment for its replication and production of viral particles. Following infection, glucose uptake and aerobic glycolysis increase in infected cells continually, which results in higher glucose consumption. The pentose phosphate shunt, as another glucose-consuming pathway, is enhanced by influenza infection to help produce more nucleotides, especially ATP. Regarding lipid species, following infection, levels of triglycerides, phospholipids, and several lipid derivatives undergo perturbations, some of which are associated with inflammatory responses. Also, mitochondrial fatty acid β-oxidation decreases significantly simultaneously with an increase in biosynthesis of fatty acids and membrane lipids. Moreover, essential amino acids are demonstrated to decline in infected tissues due to the production of large amounts of viral and cellular proteins. Immune responses against influenza infection, on the other hand, could significantly affect metabolic pathways. Mainly, interferon (IFN) production following viral infection affects cell function via alteration in amino acid synthesis, membrane composition, and lipid metabolism. Understanding metabolic alterations required for influenza virus replication has revealed novel therapeutic methods based on targeted inhibition of these cellular metabolic pathways.

positive: Practical aspects of targeting IL-6 in COVID-19 disease Severe cases of COVID-19 are often attended by a syndrome that has been described as "cytokine storm," with some features shared with macrophage activation syndrome. A variety of experimental therapies targeting this hyperinflammatory state are now being applied in hospitals around the world. Among the most widely used treatments are monoclonal antibodies targeting interleukin-6 (IL-6) or the IL-6 receptor. Anti-IL-6 drugs are being widely used experimentally and as off-label therapy for patients with COVID-19 who are sick and deteriorating but have a reasonable chance of recovering, but they are still unproven and unapproved for this use. The pandemic has created major ethical and practical questions about patient selection and nonapproved use vs use in the context of a randomized clinical trial.

positive: Targeting potential drivers of COVID-19: Neutrophil extracellular traps Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory disease that in ∼10–15% of patients progresses to acute respiratory distress syndrome (ARDS) triggered by a cytokine storm. In this Perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils—the ability to form neutrophil extracellular traps (NETs)—may contribute to organ damage and mortality in COVID-19. We show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to COVID-19. We discuss prior reports linking aberrant NET formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19.

positive: Macrophage polarization and its role in the pathogenesis of acute lung injury/acute respiratory distress syndrome PURPOSE: Macrophages are highly plastic cells. Under different stimuli, macrophages can be polarized into several different subsets. Two main macrophage subsets have been suggested: classically activated or inflammatory (M1) macrophages and alternatively activated or anti-inflammatory (M2) macrophages. Macrophage polarization is governed by a highly complex set of regulatory networks. Many recent studies have shown that macrophages are key orchestrators in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and that regulation of macrophage polarization may improve the prognosis of ALI/ARDS. A further understanding of the mechanisms of macrophage polarization is expected to be helpful in the development of novel therapeutic targets to treat ALI/ARDS. Therefore, we performed a literature review to summarize the regulatory mechanisms of macrophage polarization and its role in the pathogenesis of ALI/ARDS. METHODS: A computer-based online search was performed using the PubMed database and Web of Science database for published articles concerning macrophages, macrophage polarization, and ALI/ARDS. RESULTS: In this review, we discuss the origin, polarization, and polarization regulation of macrophages as well as the role of macrophage polarization in various stages of ARDS. According to the current literature, regulating the polarized state of macrophages might be a potential therapeutic strategy against ALI/ARDS.

positive: Three Novel Prevention, Diagnostic and Treatment Options for COVID-19 Urgently Necessitating Controlled Randomized Trials PURPOSE: Asymptomatic or minimally symptomatic infection with COVID-19 can result in silent transmission to large numbers of individuals, resulting in expansion of the pandemic with a global increase in morbidity and mortality. New ways of screening the general population for COVID-19 are urgently needed along with novel effective prevention and treatment strategies. HYPOTHESIS: A hypothetical three-part prevention, diagnostic, and treatment approach based on an up-to-date scientific literature review for COVID- 19 is proposed. Regarding diagnosis, a validated screening questionnaire and digital app for COVID-19 could help identify individuals who are at risk of transmitting the disease, as well as those at highest risk for poor clinical outcomes. Global implementation and online tracking of vital signs and scored questionnaires that are statistically validated would help health authorities properly allocate essential health care resources to test and isolate those at highest risk for transmission and poor outcomes. Second, regarding prevention, no validated protocols except for physical distancing, hand washing, and isolation exist, and recently ivermectin and the antimalarial drugs chloroquine and hydroxychloroquine has been published to have anti-viral properties against COVID-19. A randomized trial of ivermectin or hydroxychloroquine alone, and/or nutraceuticals that have been published to support immune function including Vitamin C, zinc, and immunomodulatory supplements (3,6 Beta glucan) could be beneficial in preventing transmission or lessening symptomatology but requires statistical validation. Third, concerning treatment, COVID-19 induced inflammation and “cytokine storm syndrome” with hemophagocytic lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) have resulted in extreme morbidity and mortality in those with certain comorbidities, secondary to “acute respiratory distress syndrome” (ARDS) and multiorgan dysfunction with disseminated intravascular coagulation (DIC). Deficiency in red blood cell, serum and alveolar glutathione has been published in the medical literature for ARDS, as well as viral and bacterial pneumonias, resulting from increased levels of free radical/oxidative stress. A randomized controlled trial of blocking NFKappa B and cytokine formation using glutathione precursors (N-acetyl-cysteine [NAC] and alpha lipoic acid) and PO/IV glutathione should be performed, along with an evaluation of Nrf2 activators (curcumin, sulforaphane glucosinolate) which have been scientifically proven to lower inflammation. Since high mortality rates from sepsis induced DIC due to COVID 19 infection has also been associated with thrombotic events and elevated levels of D-dimer, randomized controlled trials of using anticoagulant therapy with heparin is urgently required. This is especially important in patients on ventilators who have met certain sepsis induced coagulopathy (SIC) criteria. The use of acetazolamide with or without sildenafil also needs to be explored with or without heparin, since increased oxygen delivery to vital organs through prevention of thrombosis/pulmonary emboli along with carbonic anhydrase inhibition may help increase oxygenation and prevent adverse clinical outcomes. CONCLUSION AND IMPLICATIONS: a three-part prevention, diagnostic, and treatment plan is proposed for addressing the severe complications of COVID-19. Digital monitoring of symptoms to clinically diagnose early exposure and response to treatment; prevention with hydroxychloroquine and/or ivermetin as well as nutritional therapies that support a healthy immune response; treatment with anti-inflammatory therapies that block NFKappaB and activate Nrf2 pathways, as well as novel therapies that address COVID-19 pneumonia and ARDS with DIC including anticoagulation and/ or novel respiratory therapies with or without acetazolamide and sildenafil. These three broad-based interventions urgently need to be subjected to randomized, controlled trials.

positive: Cytokine storm and immunomodulatory therapy in COVID-19: role of chloroquine and anti-IL-6 monoclonal antibodies • Discussion of the role of immunomodulatory agents to reduce the cytokine storm in severe cases of COVID-19. • Potential immunomodulatory agents currently used in the treatment of COVID-19 (chloroquine, hydroxychloroquine and tocilizumab) are discussed. • Other immunomodulatory agents with good safety profiles may be considered for use in combination with antiviral drugs for the treatment of severe or critical cases of COVID-19.

positive: An insertion unique to SARS-CoV-2 exhibits superantigenic character strengthened by recent mutations Multisystem Inflammatory Syndrome in Children (MIS-C) associated with Coronavirus Disease 2019 (COVID-19) is a newly recognized condition in which children with recent SARS-CoV-2 infection present with a constellation of symptoms including hypotension, multiorgan involvement, and elevated inflammatory markers. These symptoms and the associated laboratory values strongly resemble toxic shock syndrome, an escalation of the cytotoxic adaptive immune response triggered upon the binding of pathogenic superantigens to MHCII molecules and T cell receptors (TCRs). Here, we used structure-based computational models to demonstrate that the SARS-CoV-2 spike (S) exhibits a high-affinity motif for binding TCR, interacting closely with both the α- and β-chains variable domains’ complementarity-determining regions. The binding epitope on S harbors a sequence motif unique to SARS-CoV-2 (not present in any other SARS coronavirus), which is highly similar in both sequence and structure to bacterial superantigens. Further examination revealed that this interaction between the virus and human T cells is strengthened in the context of a recently reported rare mutation (D839Y/N/E) from a European strain of SARS-CoV-2. Furthermore, the interfacial region includes selected residues from a motif shared between the SARS viruses from the 2003 and 2019 pandemics, which has intracellular adhesion molecule (ICAM)-like character. These data suggest that the SARS-CoV-2 S may act as a superantigen to drive the development of MIS-C as well as cytokine storm in adult COVID-19 patients, with important implications for the development of therapeutic approaches.

positive: Rationale for Evaluating PDE4 Inhibition for Mitigating against Severe Inflammation in COVID-19 Pneumonia and Beyond BACKGROUND: In the absence of definitive anti-viral therapy, there is considerable interest in mitigating against severe inflammatory reactions in coronavirus disease-2019 (COVID-19) pneumonia to improve survival. These reactions are sometimes termed cytokine storm. PDE4 inhibitors (PDE4i) have anti-inflammatory properties with approved indications in inflammatory skin and joint diseases as well as chronic obstructive pulmonary disease (COPD). Furthermore, multiple animal models demonstrate strong anti-inflammatory effects of PDE4i in respiratory models of viral and bacterial infection and also after chemically mediated lung injury. The rationale for PDE4i use in COVID-19 patients comes from the multimodal mechanism of action with cytokine, chemokine, and other key pathway inhibition all achieved with an excellent safety profile. We highlight how PDE4i could be an overlooked treatment from the rheumatologic and respiratory armamentarium, which has potential beneficial immune-modulation for treating severe COVID-19 pneumonia associated with cytokine storms. The proposed use of PDE4i is also supported by age-related immune changes in inflammation severity in PDE4i modifiable pathways in primate coronavirus disease. In conclusion, over-exuberant anti-viral immune responses in older patients with COVID-19 may pose a substantial risk to patient survival and mitigation against such hyper-inflammation with PDE4i, especially with anti-viral agents, is a strategy that need to be pursed, especially in older patients.

positive: [Advances in the research of cytokine storm mechanism induced by Corona Virus Disease 2019 and the corresponding immunotherapies] Corona Virus Disease 2019 (COVID-19) has seriously affected the treatment of patients and social stability. In the later stage of disease, some COVID-19 patients may develop into acute respiratory distress syndrome or even multiple organ failure. However, one of the most important mechanism underlying the deterioration of disease is cytokine storm. At present, some therapies such as interleukin-6 antibody blocker, stem cell therapy, and transfusion of convalescent plasma have been applied to counteract the cytokine storm and have made some progress. This article reviews the influences of cytokine storm syndrome on the COVID-19 and the corresponding immunotherapies to resist cytokine storm.

positive: Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies Coronavirus-19 (COVI-19) involves humans as well as animals and may cause serious damage to the respiratory tract, including the lung: coronavirus disease (COVID-19). This pathogenic virus has been identified in swabs performed on the throat and nose of patients who suffer from or are suspected of the disease. When COVI-19 infect the upper and lower respiratory tract it can cause mild or highly acute respiratory syndrome with consequent release of pro-inflammatory cytokines, including interleukin (IL)-1ß and IL-6. The binding of COVI-19 to the Toll Like Receptor (TLR) causes the release of pro-IL-1ß which is cleaved by caspase-1, followed by inflammasome activation and production of active mature IL-1ß which is a mediator of lung inflammation, fever and fibrosis. Suppression of pro-inflammatory IL-1 family members and IL-6 have been shown to have a therapeutic effect in many inflammatory diseases, including viral infections. Cytokine IL-37 has the ability to suppress innate and acquired immune response and also has the capacity to inhibit inflammation by acting on IL-18Rα receptor. IL-37 performs its immunosuppressive activity by acting on mTOR and increasing the adenosine monophosphate (AMP) kinase. This cytokine inhibits class II histocompatibility complex (MHC) molecules and inflammation in inflammatory diseases by suppressing MyD88 and subsequently IL-1ß, IL-6, TNF and CCL2. The suppression of IL-1ß by IL-37 in inflammatory state induced by coronavirus-19 can have a new therapeutic effect previously unknown. Another inhibitory cytokine is IL-38, the newest cytokine of the IL-1 family members, produced by several immune cells including B cells and macrophages. IL-38 is also a suppressor cytokine which inhibits IL-1ß and other pro-inflammatory IL-family members. IL-38 is a potential therapeutic cytokine which inhibits inflammation in viral infections including that caused by coronavirus-19, providing a new relevant strategy.

positive: Considerations for Statin Therapy in Patients with COVID‐19 Current coronavirus pandemic named coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is the third coronavirus outbreak during the current century after severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses.1 Acute respiratory distress syndrome (ARDS) is an immunopathologic event and main cause of death following COVID-19. The main mechanism of ARDS is uncontrolled systemic inflammatory response and cytokine storm following release of proinflammatory cytokines (such as interferons (IFN), interleukines (IL), tumor necrosis factor (TNF)-α) and chemokines.2-3 So, some Chinese researchers proposed or used anti-inflammatory agents in the treatment regimen of patients with COVID-19.3-4.

positive: COVID-19: Pathogenesis, cytokine storm and therapeutic potential of interferons ABSTRACT The outbreak of the novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) responsible for coronavirus disease 2019 (COVID-19) has developed into a major health hazard across the globe. The rapid escalation of the COVID-19 and the considerable associated illness leading to death has transformed it into a critical global public health issue. The current clinical investigation in patients with COVID-19 has showed strong upregulation of cytokine and interferon production after critical infection with SARS-CoV2- induced pneumonia. The current research suggests that few groups of patients with COVID-19 might have a cytokine storm syndrome. Thus, identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. To date, no specific therapeutic drug or vaccine has been discovered to treat this COVID-19. Intensive research is in progress to identify a promising drug therapy. Hence, several options were proposed to control this fast-emerging pandemic, including antiviral drugs, vaccines, small-molecules, monoclonal antibodies, oligonucleotides, peptides, and interferons (IFNs).

positive: Feasibility of Therapeutic Effects of the Cholinergic Anti-Inflammatory Pathway on COVID-19 Symptoms

positive: Use of anakinra in severe COVID-19: a case report Coronavirus Disease 19 is a global healthcare emergency with high lethality rate. Relevant inflammatory cytokine storm is associated with severity of disease and IL1 inhibition is a cornerstone treatment for hyperinflammatory diseases. We present here the case of a patient with critical COVID-19 successfully treated with IL-1 receptor antagonist (anakinra).

positive: Corona (COVID-19) time musings: Our involvement in COVID-19 pathogenesis, diagnosis, treatment and vaccine planning

positive: Can Hypericum perforatum (SJW) prevent cytokine storm in COVID‐19 patients?

positive: Combined IL-6 and JAK-STAT inhibition therapy in COVID-19 related sHLH, potential game changer Coronavirus disease 2019 (COVID-19), caused by novel SARS-CoV-2, leads to significant mortality and morbidity with increasing evidence for inflammatory pathways being implicated in the lung damage it causes. (1,2) Severe COVID-19 patients present with increased inflammatory markers, akin to secondary haemophagocytic lymphohistiocytosis (sHLH), that have been shown to predict mortality. (3,4) There is emerging evidence for the use of an interleukin 6 (IL-6) inhibitor, tocilizumab (TCZ), for suppression of the inflammatory cytokine storm in this context. (5-7) Ruxolitinib (RXB), a JAK-STAT inhibitor, has also been shown to have proven efficacy in the treatment of sHLH. (8) Both agents appear to be promising in the fight against SARS-CoV-2 infection, (9,10) leading to an increasing number of trials being registered with their use. (11,12) Until this point, no single agent has shown a survival benefit against SARS-CoV-2 and it is possible that monotherapy may not suppress inflammation enough to overcome the COVID-19 related cytokine storm and hyper-inflammation.

positive: COVID‐19: lambda interferon against viral load and hyperinflammation Coronavirus disease 2019 (COVID‐19), triggered by the betacoronavirus SARS‐CoV‐2, has become one of the worst pandemics of our time that has already caused more than 250,000 deaths (JHU data‐05/06/2020, https://coronavirus.jhu.edu/). Effective therapeutic approaches are urgently needed to reduce the spread of the virus and its death toll. Here, we assess the possibility of using interferon‐lambda (IFNλ), a third type of interferon sharing low homology with type I IFNs and IL‐10, for treating COVID‐19 patients. We discuss the unique role of IFNλ in fine‐tuning antiviral immunity in the respiratory tract to achieve optimal protection and minimal host damage and review early evidence that SARS‐CoV‐2 may impair IFNλ induction, leading to a delayed type I IFN‐dominated response that triggers hyperinflammation and severe disease. We also consider the potential windows of opportunity for therapeutic intervention with IFNλ and potential safety considerations. We conclude that IFNλ constitutes a promising therapeutic agent for reducing viral presence and hyperinflammation in a single shot to prevent the devastating consequences of COVID‐19 such as pneumonia and acute respiratory distress syndrome (ARDS).

positive: Absence of severe complications from SARS-CoV-2 infection in children with rheumatic diseases treated with biologic drugs We read with interest the Editorial by Cron and Chatam (1) suggesting a cytokine storm syndrome (CSS) occurring in response to SARS-CoV-2 infection and, consequently, a possible role for targeted approaches to blocking inflammatory cytokines.

positive: No indications for overt innate immune suppression in critically ill COVID-19 patients At the end of March 2020, there were in excess of 800.000 confirmed cases of coronavirus disease 2019 (COVID-19) worldwide. Several reports suggest that, in severe cases, COVID-19 may cause a hyperinflammatory 'cytokine storm'. However, unlike SARS-CoV infection, high levels of anti-inflammatory mediators have also been reported in COVID-19 patients. One study reported that 16% of COVID-19 patients who died developed secondary infection, which might indicate an immune-suppressed state. We explored kinetics of mHLA-DR expression, the most widely used marker of innate immune suppression in critically ill patients, in COVID-19 patients admitted to the ICU. Twenty-four confirmed COVID-19 patients were included, of which 75% was male and 79% had comorbidities. All patients were mechanically ventilated and exhibited large high levels of inflammatory parameters such as CRP and PCT. mHLA-DR expression levels were mostly within the normal range of 15000 - 45000 mAb/cell and showed no change over time. COVID-19 patients displayed notably higher mHLA-DR expression levels compared with bacterial septic shock patients. None of the COVID-19 patients developed a secondary infection. In conclusion, despite a pronounced inflammatory response, mHLA-DR expression kinetics indicate no overt innate immune suppression in COVID-19 patients. These data signify that innate immune suppression as a negative feedback mechanism following PAMP-induced inflammation appears not to be present in COVID-19.

positive: Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages The COVID-19 pandemic caused by infection with SARS-CoV-2 has led to more than 200,000 deaths worldwide. Several studies have now established that the hyperinflammatory response induced by SARS-CoV-2 is a major cause of disease severity and death in infected patients. Macrophages are a population of innate immune cells that sense and respond to microbial threats by producing inflammatory molecules that eliminate pathogens and promote tissue repair. However, a dysregulated macrophage response can be damaging to the host, as is seen in the macrophage activation syndrome induced by severe infections, including in infections with the related virus SARS-CoV. Here we describe the potentially pathological roles of macrophages during SARS-CoV-2 infection and discuss ongoing and prospective therapeutic strategies to modulate macrophage activation in patients with COVID-19.

positive: The immune system and COVID-19: Friend or foe? AIM: Coronavirus disease 2019 (COVID-19) is a novel highly contagious infection caused by SARS-CoV-2, which has been became a global public health challenge. The pathogenesis of this virus is not yet clearly understood, but there is evidence of a hyper-inflammatory immune response in critically ill patients, which leads to acute respiratory distress syndrome (ARDS) and multi-organ failure. MATERIAL AND METHODS: A literature review was performed to identify relevant articles on COVID-19 published up to April 30, 2020. The search resulted in 361 total articles. After reviewing the titles and abstracts for inclusion, some irrelevant papers were excluded. Additional relevant articles were identified from a review of citations referenced. KEY FINDINGS: SARS-CoV-2, directly and indirectly, affects the immune system and avoids being eliminated in early stages. On the other hand, the secretion of inflammatory cytokines creates critical conditions that lead to multi-organ failure. SIGNIFICANCE: The immune system which is affected by the virus tries to respond via a cytokine storm and hyperinflammation, which itself leads to further multi-organ damage and even death.

positive: Humoral Immune Responses in COVID-19 Patients: A Window on the State of the Art The novel SARS-CoV-2 is a recently emerging virus causing a human pandemic. A great variety of symptoms associated with COVID-19 disease, ranging from mild to severe symptoms, eventually leading to death. Specific SARS-CoV-2 RT-PCR is the standard method to screen symptomatic people; however, asymptomatic subjects and subjects with undetectable viral load escape from the screening, contributing to viral spread. Currently, the lock down imposed by many governments is an important measure to contain the spread, as there is no specific antiviral therapy or a vaccine and the main treatments are supportive. Therefore, there is urgent need to characterize the virus and the viral-mediated responses, in order to develop specific diagnostic and therapeutic tools to prevent viral transmission and efficiently cure COVID-19 patients. Here, we review the current studies on two viral mediated-responses, specifically the cytokine storm occurring in a subset of patients and the antibody response triggered by the infection. Further studies are needed to explore both the dynamics and the mechanisms of the humoral immune response in COVID-19 patients, in order to guide future vaccine design and antibody-based therapies for the management of the disease.

positive: Can tocilizumab calm the cytokine storm of COVID-19?

positive: Adjunct immunotherapies for the management of severely ill COVID-19 patients Abstract Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has infected millions with more than 181,000 fatal cases as of 22nd April 2020. Currently, there are no specific COVID-19 therapies. Most patients depend on mechanical ventilation. Current COVID-19 data clearly highlight that cytokine storm and activated immune cell migration to the lungs characterize the early immune response to COVID-19 that causes severe lung damage and development of acute respiratory distress syndrome. In view of uncertainty associated with immunosuppressive treatments such as corticosteroids and their possible secondary effects, including risks of secondary infections, we suggest immunotherapies as an adjunct therapy in severe COVID-19 cases. Such immunotherapies based on inflammatory cytokine neutralization, immunomodulation and passive viral neutralization, not only reduce inflammation, inflammation-associated lung damage, or viral load, but could also prevent intensive care unit hospitalization and dependency on mechanical ventilation both of which are limited resources.

positive: Continuous Intravenous Anakinra Infusion to Calm the Cytokine Storm in Macrophage Activation Syndrome OBJECTIVE: The objective of this study was to report the benefit of a therapeutic approach consisting of intravenous (IV) continuous anakinra (recombinant human interleukin‐1 receptor antagonist) infusions in treating severely ill adult patients with secondary hemophagocytic lymphohistiocytosis or macrophage activation syndrome (MAS). METHODS: A retrospective chart review of five patients treated at Regions Hospital from 2016 to 2019 was conducted. Demographic, clinical, and laboratory characteristics and outcomes were recorded. RESULTS: Continuous IV anakinra infusions up to 2400 mg/d resulted in rapid serologic, then clinical response in 4 of 5 severely ill patients who were refractory to all other therapies, including subcutaneous anakinra. Subsequently, 3 of 5 patients have been maintained on anakinra or canakinumab, with no recurrence of MAS. CONCLUSION: Continuous infusion of IV anakinra may result in rapid serologic and subsequent clinical improvement in adult patients with MAS. This method for treating cytokine storm should be considered in the current COVID‐19 pandemic in the subgroup of patients with severe disease who have a cytokine storm presentation.

positive: Assessment of ACE2, CXCL10 and Their co-expressed Genes: An In-silico Approach to Evaluate the Susceptibility and Fatality of Lung Cancer Patients towards COVID-19 Infection Background COVID-19 is a recent pandemic that started to spread out worldwide from Wuhan, China. This disease is caused by a newly discovered strain of the coronavirus, namely SARS CoV-2. Lung cancer patients are reported to be more susceptible to COVID-19 infection. To evaluate the probable reasons behind the excessive susceptibility and fatality of lung cancer patients to COVID-19 infection, we targeted two most crucial biomarkers of COVID-19, ACE2 and CXCL10. ACE2 plays a vital role in the SARS CoV-2 entry into the host cell while CXCL10 is a cytokine mainly responsible for the lung cell damage involving in a cytokine storm. Methods Firstly, we used the TIMER, UALCAN and GEPIA2 databases to analyze the expression and correlation of ACE2 and CXCL10 in LUAD and LUSC. After that, using the cBioPortal database, we performed an analytical study to determine the genetic changes in ACE2 and CXCL10 protein sequences that are responsible for lung cancer development. Finally, we analyzed different functional approaches of ACE2, CXCL10 and their co-expressed genes associated with lung cancer and COVID-19 development by using the PANTHER database. Results Initially, we observed that ACE2 and CXCL10 are mostly overexpressed in LUAD and LUSC. We also found the functional significance of ACE2 and CXCL10 in lung cancer development by determining the genetic alteration frequency in their amino acid sequences. Lastly, by doing the functional assessment of the targeted genes, we identified that ACE2 and CXCL10 along with their commonly co-expressed genes are respectively involved in the binding activity and immune responses in case of lung cancer and COVID-19 infection. Conclusions Finally, on the basis of this systemic analysis, we came to the conclusion that ACE2 and CXCL10 are possible biomarkers responsible for the higher susceptibility and fatality of lung cancer patients towards the COVID-19.

positive: The current understanding and potential therapeutic options to combat COVID-19 Abstract The ongoing wreaking global outbreak of the novel human beta coronavirus (CoV) pathogen was presumed to be from a seafood wholesale market in Wuhan, China, belongs to the Coronaviridae family in the Nidovirales order. The virus is highly contagious with potential human-human transmission which was named as the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has spread across six continents and emerged as a global pandemic in short span with alarming levels of spread and severity. This virus associated symptoms and infectious respiratory illness is designated as coronavirus disease 19 (COVID-19). The SARS-CoV-2 possesses enveloped club-like spike protein projections with positive-sense large RNA genome and has a unique replication strategy. This virus was believed to have zoonotic origin with genetical identity to bat and pangolin CoV. In the current review, we introduce a general overview about the human CoVs and the associated diseases, the origin, structure, replication and key clinical events that occur in the COVID-19 pathogenicity. Furthermore, we focused on possible therapeutic options such as repurposing drugs including antimalarials, antivirals, antiparasitic drugs, and anti-HIV drugs, as well as monoclonal antibodies, vaccines as potential treatment options. Also we have summarized the latest research progress on the usage of stem cell therapy, human convalescent serum, interferon's, in the treatment of COVID-19.

positive: Potential role for tissue factor in the pathogenesis of hypercoagulability associated with in COVID-19 In December 2019, a new and highly contagious infectious disease emerged in Wuhan, China. The etiologic agent was identified as a novel coronavirus, now known as Severe Acute Syndrome Coronavirus-2 (SARS-CoV-2). Recent research has revealed that virus entry takes place upon the union of the virus S surface protein with the type I transmembrane metallo-carboxypeptidase, angiotensin converting enzyme 2 (ACE-2) identified on epithelial cells of the host respiratory tract. Virus triggers the synthesis and release of pro-inflammatory cytokines, including IL-6 and TNF-α and also promotes downregulation of ACE-2, which promotes a concomitant increase in levels of angiotensin II (AT-II). Both TNF-α and AT-II have been implicated in promoting overexpression of tissue factor (TF) in platelets and macrophages. Additionally, the generation of antiphospholipid antibodies associated with COVID-19 may also promote an increase in TF. TF may be a critical mediator associated with the development of thrombotic phenomena in COVID-19, and should be a target for future study.

positive: COVID-19 and ECMO: the interplay between coagulation and inflammation—a narrative review Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has presently become a rapidly spreading and devastating global pandemic. Veno-venous extracorporeal membrane oxygenation (V-V ECMO) may serve as life-saving rescue therapy for refractory respiratory failure in the setting of acute respiratory compromise such as that induced by SARS-CoV-2. While still little is known on the true efficacy of ECMO in this setting, the natural resemblance of seasonal influenza’s characteristics with respect to acute onset, initial symptoms, and some complications prompt to ECMO implantation in most severe, pulmonary decompensated patients. The present review summarizes the evidence on ECMO management of severe ARDS in light of recent COVID-19 pandemic, at the same time focusing on differences and similarities between SARS-CoV-2 and ECMO in terms of hematological and inflammatory interplay when these two settings merge.

positive: COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression ;Journal of Antimicrobial Chemotherapy ;Oxford Academic A novel coronavirus disease (COVID-19), caused by infection with SARS-CoV-2, has swept across 31 provinces in China and over 40 countries worldwide The transition from first symptoms to acute respiratory distress syndrome (ARDS) is highly likely to be due to uncontrolled cytokine release There is an urgent need to identify safe and effective drugs for treatment Chloroquine (CQ) exhibits a promising inhibitory effect However, the clinical use of CQ can cause severe side effects We propose that hydroxychloroquine (HCQ), which exhibits an antiviral effect highly similar to that of CQ, could serve as a better therapeutic approach HCQ is likely to attenuate the severe progression of COVID-19, inhibiting the cytokine storm by suppressing T cell activation It has a safer clinical profile and is suitable for those who are pregnant It is cheaper and more readily available in China We herein strongly urge that clinical trials are performed to assess the preventive effects of HCQ in both disease infection and progression

positive: A Double-Edged Sword—Cardiovascular Concerns of Potential Anti-COVID-19 Drugs Coronavirus disease 2019 (COVID-19) is a pandemic infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). COVID-19 significantly affects multiple systems including the cardiovascular system. Most importantly, in addition to the direct injury from the virus per se, the subsequent cytokine storm, an overproduction of immune cells and their activating compounds, causes devastating damage. To date, emerging anti-SARS-CoV-2 treatments are warranted to control epidemics. Several candidate drugs have been screened and are currently under investigation. These primarily include antiviral regimens and immunomodulatory regimens. However, beyond the anti-SARS-CoV-2 effects, these drugs may also have risks to the cardiovascular system, especially altering cardiac conduction. Herein, we review the cardiovascular risks of potential anti-COVID-19 drugs.

positive: COVID-19: risk for cytokine targeting in chronic inflammatory diseases? COVID-19, caused by the SARS-CoV-2 virus, has become pandemic. With sharply rising infection rates, patient groups characterized by an enhanced infection risk will be challenged by the virus. In this context, patients with chronic immune-mediated inflammatory diseases are of particular interest, as these diseases are characterized by an intrinsic immune dysfunction leading to inflammation that may enhance risk for severe infection.

positive: Into the eye of the cytokine storm. The cytokine storm has captured the attention of the public and the scientific community alike, and while the general notion of an excessive or uncontrolled release of proinflammatory cytokines is well known, the concept of a cytokine storm and the biological consequences of cytokine overproduction are not clearly defined. Cytokine storms are associated with a wide variety of infectious and noninfectious diseases. The term was popularized largely in the context of avian H5N1 influenza virus infection, bringing the term into popular media. In this review, we focus on the cytokine storm in the context of virus infection, and we highlight how high-throughput genomic methods are revealing the importance of the kinetics of cytokine gene expression and the remarkable degree of redundancy and overlap in cytokine signaling. We also address evidence for and against the role of the cytokine storm in the pathology of clinical and infectious disease and discuss why it has been so difficult to use knowledge of the cytokine storm and immunomodulatory therapies to improve the clinical outcomes for patients with severe acute infections.

positive: Alpha-1 adrenergic receptor antagonists for preventing acute respiratory distress syndrome and death from cytokine storm syndrome In severe viral pneumonias, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by a hyperinflammatory reaction ('cytokine storm syndrome') that leads to acute respiratory distress syndrome and death, despite maximal supportive care. Preventing hyperinflammation is key to avoiding these outcomes. We previously demonstrated that alpha-1 adrenergic receptor antagonists ($\alpha$-blockers) can prevent cytokine storm syndrome and death in mice. Here, we conduct a retrospective analysis of patients with acute respiratory distress or pneumonia (n = 13,125 and n = 108,956, respectively) from all causes; patients who were incidentally taking $\alpha$-blockers had a reduced risk of requiring ventilation (by 35% and 16%, respectively), and a reduced risk of being ventilated and dying (by 56% and 20%, respectively), compared to non-users. Beta-adrenergic receptor antagonists had no significant effects. These results highlight the urgent need for prospective trials testing whether prophylactic $\alpha$-blockers improve outcomes in diseases with a prominent hyperinflammatory component such as COVID-19.

positive: The pathogenesis and treatment of the `Cytokine Storm' in COVID-19 Cytokine storm is an excessive immune response to external stimuli. The pathogenesis of the cytokine storm is complex. The disease progresses rapidly, and the mortality is high. Certain evidence shows that, during the coronavirus disease 2019 (COVID-19) epidemic, the severe deterioration of some patients has been closely related to the cytokine storm in their bodies. This article reviews the occurrence mechanism and treatment strategies of the COVID-19 virus-induced inflammatory storm in attempt to provide valuable medication guidance for clinical treatment.

positive: Multiscale Biofluidic and Nanobiotechnology Approaches for Treating Sepsis in Extracorporeal Circuits Infectious diseases and their pandemics periodically attract public interests due to difficulty in treating the patients and the consequent high mortality. Sepsis caused by an imbalanced systemic inflammatory response to infection often leads to organ failure and death. The current therapeutic intervention mainly includes “the sepsis bundles,” antibiotics (antibacterial, antiviral, and antifungal), intravenous fluids for resuscitation, and surgery, which have significantly improved the clinical outcomes in past decades; however, the patients with fulminant sepsis are still in desperate need of alternative therapeutic approaches. One of the potential supportive therapies, extracorporeal blood treatment, has emerged and been developed for improving the current therapeutic efficacy. Here, I overview how the treatment of infectious diseases has been assisted with the extracorporeal adjuvant therapy and the potential utility of various nanobiotechnology and microfluidic approaches for developing new auxiliary therapeutic methods.

positive: COVID-19: disease pathways and gene expression changes predict methylprednisolone can improve outcome in severe cases

positive: Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome SARS-CoV-2 has been identified as the causative agent of a global outbreak of respiratory tract disease (COVID-19). In some patients the infection results in moderate to severe acute respiratory distress syndrome (ARDS), requiring invasive mechanical ventilation. High serum levels of IL-6, IL-10 and an immune hyperresponsiveness referred to as a 'cytokine storm' have been associated with poor clinical outcome. Despite the large numbers of COVID-19 cases and deaths, information on the phenotype and kinetics of SARS-CoV-2-specific T cells is limited. Here, we studied 10 COVID-19 patients who required admission to an intensive care unit and detected SARS-CoV-2-specific CD4+ and CD8+ T cells in 10 out of 10 and 8 out of 10 patients, respectively. We also detected low levels of SARS-CoV-2-reactive T cells in 2 out of 10 healthy controls not previously exposed to SARS-CoV-2, which is indicative of cross-reactivity due to past infection with 'common cold' coronaviruses. The strongest T-cell responses were directed to the spike (S) surface glycoprotein, and SARS-CoV-2-specific T cells predominantly produced effector and Th1 cytokines, although Th2 and Th17 cytokines were also detected. Furthermore, we studied T-cell kinetics and showed that SARS-CoV-2-specific T cells are present relatively early and increase over time. Collectively, these data shed light on the potential variations in T-cell responses as a function of disease severity, an issue that is key to understanding the potential role of immunopathology in the disease, and also inform vaccine design and evaluation.

positive: COVID-19: consider cytokine storm syndromes and immunosuppression

positive: Potential Immunotherapeutic Targets For Hypoxia Due to COVI-FLU. The world is currently embroiled in a pandemic of coronavirus disease 2019 (COVID-19), a respiratory illness caused by the novel betacoronavirus SARS-CoV-2. The severity of COVID-19 disease ranges from asymptomatic to fatal acute respiratory distress syndrome (ARDS). In few patients, the disease undergoes phenotypic differentiation between 7-14 days of acute illness, either resulting in full recovery or symptom escalation. However, the mechanism of such variation is not clear, but the facts suggest that patient's immune status, co-morbidities, and the systemic effects of the viral infection (potentially depending on the SARS-CoV-2 strain involved) play a key role. Subsequently, patients with the most severe symptoms tend to have poor outcomes, manifest severe hypoxia, and possess elevated levels of pro-inflammatory cytokines (including IL-1β, IL-6, IFN-γ, and TNF-α) along with elevated levels of the anti-inflammatory cytokine IL-10, marked lymphopenia, and elevated neutrophil-to-lymphocyte ratios. Based on the available evidence, we propose a mechanism wherein SARS-CoV-2 infection induces direct organ damage while also fueling an IL-6-mediated cytokine release syndrome (CRS) and hypoxia, resulting in escalating systemic inflammation, multi-organ damage, and end-organ failure. Elevated IL-6 and hypoxia together predisposes patients to pulmonary hypertension, and the presence of asymptomatic hypoxia in COVID-19 further compounds this problem. Due to the similar downstream mediators, we discuss the potential synergistic effects and systemic ramifications of SARS-CoV-2 and influenza virus during co-infection, a phenomenon we have termed "COVI-Flu." Additionally, the differences between CRS and cytokine storm are highlighted. Finally, novel management approaches, clinical trials, and therapeutic strategies toward both SARS-CoV-2 and COVI-Flu infection are discussed, highlighting host response optimization and systemic inflammation reduction.

positive: Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19 Abstract Background The inflammatory response plays a critical role in coronavirus disease 2019 (COVID-19), and inflammatory cytokine storm increases the severity of COVID-19. Objective To investigate the ability of interleukin-6 (IL-6), C-reactive protein (CRP), and procalcitonin (PCT) to predict mild and severe cases of COVID-19. Study design This retrospective cohort study included 140 patients diagnosed with COVID-19 from January 18, 2020, to March 12, 2020. The study population was divided into two groups according to disease severity: a mild group (MG) (n = 107) and a severe group (SG) (n = 33). Data on demographic characteristics, baseline clinical characteristics, and the levels of IL-6, CRP, and PCT on admission were collected. Results Among the 140 patients, the levels of IL-6, CRP, and PCT increased in 95 (67.9 %), 91 (65.0 %), and 8 (5.7 %) patients on admission, respectively. The proportion of patients with increased IL-6, CRP, and PCT levels was significantly higher in the SG than in the MG. Cox proportional hazard model showed that IL-6 and CRP could be used as independent factors to predict the severity of COVID-19. Furthermore, patients with IL-6 > 32.1 pg/mL or CRP > 41.8 mg/L were more likely to have severe complications. Conclusion The serum levels of IL-6 and CRP can effectively assess disease severity and predict outcome in patients with COVID-19.

positive: Tocilizumab en niño con leucemia linfoblástica aguda y síndrome de liberación de citoquinas asociado a COVID-19./ [Tocilizumab in a child with acute lymphoblastic leukaemia and COVID-19-related cytokine release syndrome]

positive: Tocilizumab's efficacy in patients with Coronavirus Disease 2019 (COVID-19) is determined by the presence of cytokine storm

positive: Plasma IL-6 Levels following Corticosteroid Therapy as an Indicator of ICU Length of Stay in Critically ill COVID-19 Patients Intensive Care Unit (ICU) admissions and mortality in severe COVID-19 patients are driven by cytokine storms and acute respiratory distress syndrome (ARDS). Interim clinical trial results suggest that the corticosteroid dexamethasone displays superior 28-day survival in severe COVID-19 patients requiring ventilation or oxygen. Among 16 patients with plasma IL-6 measurement post-corticosteroid administration, a higher proportion of patients with an IL-6 value over 10 pg/mL have worse outcomes (i.e. ICU Length of Stay > 15 days or death) when compared to 41 patients treated with non-corticosteroid drugs including antivirals, tocilizumab, azithromycin, and hydroxychloroquine (p-value = 0.0024). Given this unexpected clinical association between post-corticosteroid IL-6 levels and COVID-19 severity, we hypothesized that the Glucocorticoid Receptor (GR or NR3C1) may be coupled to IL-6 expression in specific cell types that govern cytokine release syndrome (CRS). Examining single cell RNA-seq data from bronchoalveolar lavage fluid of severe COVID-19 patients and nearly 2 million human cells from a pan-tissue scan shows that alveolar macrophages, smooth muscle cells, and endothelial cells co-express both NR3C1 and IL-6. The mechanism of Glucocorticoid Receptor (GR) agonists mitigating pulmonary and multi-organ inflammation in some COVID-19 patients with respiratory failure, may be in part due to their successful antagonism of IL-6 production within lung macrophages and vasculature.

positive: The role of a cytokine storm in severe COVID-19 disease in pregnancy

positive: Silencing of immune activation with methotrexate in patients with COVID-19

positive: The mechanism and treatment of gastrointestinal symptoms in patients with COVID-19 In addition to the typical respiratory response, new coronavirus pneumonia (COVID-19) is also associated with very common gastrointestinal symptoms. Cases with gastrointestinal symptoms are more likely to be complicated by liver injury and acute respiratory distress syndrome (ARDS), and diarrhea can also lead to electrolyte disturbances, causing nausea and vomiting, headache, fatigue, etc. If not treated in time, coma and circulatory failure may ensue. As SARS-CoV-2 infects the human body through the combination of ACE2 in the gastrointestinal tract, the mechanism underlying the gastrointestinal symptoms may involve damage to the intestinal mucosal barrier and promotion of the production of inflammatory factors, causing cytokine storms. Indeed, after cells in the lungs become infected by SARS-CoV-2, effector CD4+ T cells reach the small intestine through the gut-lung axis, causing intestinal immune damage and diarrhea; early extensive use of antibacterial and antiviral drugs can also lead to diarrhea in patients. Thus, treatment options for COVID-19 patients should be promptly adjusted when they have gastrointestinal symptoms. Additionally, when drug-induced diarrhea occurs, drugs should be withdrawn or reduced, and microecological regulators should be applied to maintain the intestinal microecological balance and prevent secondary bacterial infections. To guarantee effective treatment, attention should be paid to the patient's enteral nutrition and digestive tract function. As SARS-CoV-2 has been detected in the feces of COVID-19 patients, future prevention and control efforts must consider the possibility of fecal-oral transmission of the virus.

positive: Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation: challenges and opportunities The COVID-19 pandemic is a global public health crisis, with considerable mortality and morbidity exerting pressure on health-care resources, including critical care. An excessive host inflammatory response in a subgroup of patients with severe COVID-19 might contribute to the development of acute respiratory distress syndrome (ARDS) and multiorgan failure. Timely therapeutic intervention with immunomodulation in patients with hyperinflammation could prevent disease progression to ARDS and obviate the need for invasive ventilation. Granulocyte macrophage colony-stimulating factor (GM-CSF) is an immunoregulatory cytokine with a pivotal role in initiation and perpetuation of inflammatory diseases. GM-CSF could link T-cell-driven acute pulmonary inflammation with an autocrine, self-amplifying cytokine loop leading to monocyte and macrophage activation. This axis has been targeted in cytokine storm syndromes and chronic inflammatory disorders. Here, we consider the scientific rationale for therapeutic targeting of GM-CSF in COVID-19-associated hyperinflammation. Since GM-CSF also has a key role in homoeostasis and host defence, we discuss potential risks associated with inhibition of GM-CSF in the context of viral infection and the challenges of doing clinical trials in this setting, highlighting in particular the need for a patient risk-stratification algorithm.

positive: SARS-CoV-2-A Tough Opponent for the Immune System Coronaviruses recently returned with a new one, SARS-CoV-2, related to a potentially severe respiratory disease-called the coronavirus disease (COVID-19). Research shows that the SARS-CoV-2 can be clustered with the Bat SARS-like coronavirus. Bats possess an additional, innate ability for antiviral defense, and, on the other hand, the potential to go hand-in-hand with the virus to generate variability. Besides the high potential of the novel coronavirus in compromising the respiratory system, its rapid transmission and ability to engage many hosts in severe forms of infections or immunopathological complications make it a tough opponent for the immune system. The interactions between SARS-CoV2 and the host immune system result in unleashing tremendous amounts of cytokines, and these cytokines make a storm that would determine the outcome (recovery or death) of the lungs of the patient.

positive: Recognizing COVID-19-related myocarditis: the possible pathophysiology and proposed guideline for diagnosis and management Abstract Human coronavirus-associated myocarditis is known, and a number of COVID-19-related myocarditis cases have been reported. The pathophysiology of COVID-19-related myocarditis is thought to be a combination of direct viral injury and cardiac damage due to the host’s immune response. COVID-19 myocarditis diagnosis should be guided by insights from previous coronavirus and other myocarditis experience. The clinical findings include changes in ECG, cardiac biomarkers, and impaired cardiac function. When cardiac MRI is infeasible, cardiac CT angiography with delayed myocardial imaging may serve to exclude significant coronary artery disease and identify myocardial inflammatory patterns. Because many COVID-19 patients have cardiovascular comorbidities, myocardial infarction should be considered. Where the diagnosis remains uncertain, an endomyocardial biopsy may help identify active cardiac infection through viral genome amplification and possibly refine the treatment risks of systemic immunosuppression. Arrhythmias are not uncommon in the COVID-19 patients; however, its pathophysiology is still speculative. Nevertheless, clinicians should be vigilant to provide prompt monitoring and treatments. The long-term impact of COVID-19 myocarditis, including in the majority of mild cases remains unknown.

positive: A review on possible modes of action of chloroquine/hydroxychloroquine: repurposing against SAR-CoV-2 (COVID-19) pandemic Chloroquine (CQ) and its analogue hydroxychloroquine (HCQ) have long been used worldwide as frontline drugs for the treatment and prophylaxis of human malaria. Since the first reported cases in Wuhan, China, in late December 2019, humans have been under threat from coronavirus disease 2019 (COVID-19) caused by the novel coronavirus SARS-CoV-2 (previously known as 2019-nCoV), subsequently declared a pandemic. While the world is searching for expedited approval for a vaccine, which may be only preventative and not a cure, physicians and country leaders are considering several concerted clinical trials suggesting that the age-old antimalarial drugs CQ/HCQ could be a potent therapeutic against COVID-19. Based on accumulating scientific reports, here we highlight the possible modes of action of CQ/HCQ that could justify its use against viral infections. Considering the global health crisis of the COVID-19 pandemic, the option of repurposing old drugs, e.g. CQ/HCQ, particularly HCQ, for the treatment of SARS-CoV-2 infection could be a good choice. CQ/HCQ has diverse modes of action, including alteration of the acidic environment inside lysosomes and late endosomes, preventing endocytosis, exosome release and phagolysosomal fusion, and inhibition of the host cytokine storm. One or more diverse mechanisms might work against viral infections and reduce mortality. As there is no cure for COVID-19, clinical testing of HCQ is urgently required to determine its potency against SARS-CoV-2, as this is the currently available treatment option. There remains a need to find other innovative drug candidates as possible candidates to enter clinical evaluation and testing.

positive: Brief annotations on cytokine release syndrome and interleukin-6 therapeutic blockage in SARS-CoV-2/COVID-19.

positive: COVID-19: Consider IL-6 receptor antagonist for the therapy of cytokine storm syndrome in SARS-CoV-2 infected patients COVID-19 leads to mortality of several patients and the cytokine storm is reportedly critical in the patients. To reduce the cytokine storm, we would like to propose the interleukin (IL) 6 receptor (IL-6R) antagonist therapy for the COVID-19 patients. Two humanized monoclonal antibodies are in clinical trial following IL-6R antagonist therapies namely tocilizumab and sarilumab. However, researchers and physicians should look for more IL-6R antagonists for the therapy of cytokine storm syndrome severe acute respiratory syndrome coronavirus 2 infected persons to enhance the therapeutic options for cytokine storm.

positive: In Reply–The “Perfect Cytokine Storm” of COVID-19

positive: Colchicina: una herramienta terapéutica potencial frente a COVID-19. Experiencia en 5 pacientes./ [Colchicine: a potential therapeutic tool against COVID-19. Experience of 5 patients] COVID-19 is a newly emerged disease that has become a global public health challenge. Due to a lack of knowledge about the virus, a significant number of potential targets for using a particular drug have been proposed. Five cases with a clinical history of biopolymers in the gluteal region that developed iatrogenic allogenosis (IA) are presented here. The 5 cases were put under colchicine treatment for IA crisis and had non-specific symptoms (headache, cough without dyspnoea, and arthralgias) with a positive SARS-CoV-2 test. Their close contacts had mild to severe symptoms and three of them died. In the SARS-CoV-2 infection different inflammatory pathways are altered where colchicine reduces cytokine levels as well as the activation of macrophages, neutrophils, and the inflammasome. The possible mechanisms that colchicine may use to prevent acute respiratory distress syndrome (ARDS) in patients with COVID-19 infection are also reviewed in this article.

positive: Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection Cytokine storm during viral infection is a prospective predictor of morbidity and mortality, yet the cellular sources remain undefined. Here, using genetic and chemical tools to probe functions of the S1P(1) receptor, we elucidate cellular and signaling mechanisms important in initiating cytokine storm. While S1P(1) receptor is expressed on endothelial cells and lymphocytes within lung tissue, S1P(1) agonism suppresses cytokines and innate immune cell recruitment in wild-type and lymphocyte deficient mice, identifying endothelial cells as central regulators of cytokine storm. Furthermore, our data reveal immune cell infiltration and cytokine production as distinct events both orchestrated by endothelial cells. Moreover, we demonstrate that suppression of early innate immune responses through S1P(1) signaling results in reduced mortality during infection with a human pathogenic strain of influenza virus. Modulation of endothelium with a specific agonist suggests that diseases where amplification of cytokine storm is a significant pathological component could be chemically tractable.

positive: Controversies about COVID-19 and anticancer treatment with immune checkpoint inhibitors

positive: SARS-CoV-2: a storm is raging The pandemic coronavirus infectious disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is rapidly spreading across the globe. In this issue of the JCI, Chen and colleagues compared the clinical and immunological characteristics between moderate and severe COVID-19. The authors found that respiratory distress on admission is associated with unfavorable outcomes. Increased cytokine levels (IL-6, IL-10, and TNF-α), lymphopenia (in CD4+ and CD8+ T cells), and decreased IFN-Î³ expression in CD4+ T cells are associated with severe COVID-19. Overall, this study characterized the cytokine storm in severe COVID-19 and provides insights into immune therapeutics and vaccine design.

positive: Analysis of the molecular mechanism of Pudilan (PDL) treatment for COVID-19 by network pharmacology tools BACKGROUND: Pudilan (PDL), a four-herb prescription with the traditional function of heat-clearing and detoxifying, has been clinically used as an anti-SARS-CoV-2 infectory agent in China for decades. PDL might also have therapeutic potentials for COVID-19 while the underlying mechanisms remain to be clarified. METHODS: We used network pharmacology analysis and selected 68 co-targeted genes/proteins as targets of both PDL and COVID-19. These co-targeted genes/proteins were predicted by SwissDock Server for their high-precision docking simulation, and analyzed by STRING for proteins to protein interaction (PPI), pathway and GO (gene ontology) enrichment. The therapeutic effect for PDL treatment on COVID-19 was validated by the TCMATCOV (TCM Anti COVID-19) platform. RESULTS: PDL might prevent the entrance of SARS-CoV-2 entry into cells by blocking the angiotensin-converting enzyme 2 (ACE2). It might inhibit the cytokine storm by affecting C-reactive protein (CRP), interferon-γ (IFN-γ), interleukin- 6 (IL-6), interleukin- 10 (IL-10), tumor necrosis factor (TNF), epidermal growth factor receptor (EGFR), C-C motif chemokine ligand 5 (CCL5), transforming growth factor-β1 (TGFβ1), and other proteins. PDL might moderate the immune system to shorten the course of the disease, delay disease progression, and reduce the mortality rate. CONCLUSION: PDL might have a therapeutic effect on COVID-19 through three aspects, including the moderate immune system, anti-inflammation, and anti-virus entry into cells.

positive: COVID-19 and immunomodulation in IBD The current coronavirus pandemic is an ongoing global health crisis due to COVID-19, caused by severe acute respiratory syndrome coronavirus 2. Although COVID-19 leads to little or mild flu-like symptoms in the majority of affected patients, the disease may cause severe, frequently lethal complications such as progressive pneumonia, acute respiratory distress syndrome and organ failure driven by hyperinflammation and a cytokine storm syndrome. This situation causes various major challenges for gastroenterology. In the context of IBD, several key questions arise. For instance, it is an important question to understand whether patients with IBD (eg, due to intestinal ACE2 expression) might be particularly susceptible to COVID-19 and the cytokine release syndrome associated with lung injury and fatal outcomes. Another highly relevant question is how to deal with immunosuppression and immunomodulation during the current pandemic in patients with IBD and whether immunosuppression affects the progress of COVID-19. Here, the current understanding of the pathophysiology of COVID-19 is reviewed with special reference to immune cell activation. Moreover, the potential implications of these new insights for immunomodulation and biological therapy in IBD are discussed.

positive: In the eye of the COVID-19 cytokine storm

positive: Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment COVID-19 infection has a heterogenous disease course; it may be asymptomatic or causes only mild symptoms in the majority of the cases, while immunologic complications such as macrophage activation syndrome also known as secondary hemophagocytic lymphohistiocytosis, resulting in cytokine storm syndrome and acute respiratory distress syndrome, may also occur in some patients. According to current literature, impairment of SARS-CoV-2 clearance due to genetic and viral features, lower levels of interferons, increased neutrophil extracellular traps, and increased pyroptosis and probable other unknown mechanisms create a background for severe disease course complicated by macrophage activation syndrome and cytokine storm. Various genetic mutations may also constitute a risk factor for severe disease course and occurrence of cytokine storm in COVID-19. Once, immunologic complications like cytokine storm occur, anti-viral treatment alone is not enough and should be combined with appropriate anti-inflammatory treatment. Anti-rheumatic drugs, which are tried for managing immunologic complications of COVID-19 infection, will also be discussed including chloroquine, hydroxychloroquine, JAK inhibitors, IL-6 inhibitors, IL-1 inhibitors, anti-TNF-α agents, corticosteroids, intravenous immunoglobulin (IVIG), and colchicine. Early recognition and appropriate treatment of immunologic complications will decrease the morbidity and mortality in COVID-19 infection, which requires the collaboration of infectious disease, lung, and intensive care unit specialists with other experts such as immunologists, rheumatologists, and hematologists.

positive: COVID-19 cytokine storm: the interplay between inflammation and coagulation

positive: Dysregulation of the immune system as a driver of the critical course of the novel coronavirus disease 2019 Novel coronavirus disease-2019 (COVID-19) is a highly contagious respiratory-related disease induced by the newly emerged virus SARS-CoV-2. Given that inflammatory immune cells may induce severe lung injury, the involvement of immune factors in the pathogenesis of the disease cannot be overestimated. It has been demonstrated that coronaviruses (CoVs) have developed mechanisms of immune evasion, making them invisible to the immune system at an early stage of infection. The mechanism relies on inhibition of the anti-viral response of type I interferons (IFNs), which supports uncontrolled viral replication in epithelial cells. There is growing body of evidence that the fatal hyperinflammation ('cytokine storm') responsible for the severe course of COVID-19 is a consequence of massive SARS-CoV-2 replication rather than inappropriate hyperresponsiveness of the immune system. Therefore, a dampened innate anti-viral immune response seems to be the primary cause of the delayed critical cascade of uncontrolled immune events leading to fulminating systemic inflammation. The occurrence of virus transmission even in asymptomatic subjects infected with SARS-CoV-2 clearly strengthens the evidence for a key role of sufficient immune control of viral replication in a subset of cases (e.g. in children, a population with highly effective innate immune responses). Although administration of immunomodulatory therapeutics is recommended under certain conditions in the guidelines of COVID-19 management, controversies regarding treatment protocols in immunocompromised patients infected with SARS-CoV-2 still exist. Extended knowledge of clinicians on the dysregulated immune response, which is a driver of the COVID-19 outcome, may improve both therapeutic protocols and the prognosis of SARS-CoV-2 infected patients.

positive: Cytokine storm intervention in the early stages of COVID-19 pneumonia Abstract Clinical intervention in patients with corona virus disease 2019 (COVID-19) has demonstrated a strong upregulation of cytokine production in patients who are critically ill with SARS-CoV2-induced pneumonia. In a retrospective study of 41 patients with COVID-19, most patients with SARS-CoV-2 infection developed mild symptoms, whereas some patients later developed aggravated disease symptoms, and eventually passed away because of multiple organ dysfunction syndrome (MODS), as a consequence of a severe cytokine storm. Guidelines for the diagnosis and treatment of SARS-CoV-2 infected pneumonia were first published January 30th, 2020; these guidelines recommended for the first time that cytokine monitoring should be applied in severely ill patients to reduce pneumonia related mortality. The cytokine storm observed in COVID-19 illness is also an important component of mortality in other viral diseases, including SARS, MERS and influenza. In view of the severe morbidity and mortality of COVID-19 pneumonia, we review the current understanding of treatment of human coronavirus infections from the perspective of a dysregulated cytokine and immune response.

positive: Tocilizumab: A Therapeutic Option for the Treatment of Cytokine Storm Syndrome in COVID-19 Abstract Presently, we need more therapeutic molecules for this COVID-19 outbreak. The severity and mortality of the disease is associated with a high level of release of cytokine in the patients which is known as CRS (cytokine release syndrome) or cytokine storm syndrome. IL-6 is a type of pro-inflammatory cytokine which release in the severe COVID-19 patients. This cytokine initiates CRS the JAK-STAT pathway. Tocilizumab, a humanized monoclonal antibody, is designed to bind both mIL-6R (membrane bound receptor for IL-6) and sIL-6R (soluble receptor for IL-6) and inhibit the JAK-STAT signaling pathway. It finally stops the cytokine storm syndrome. However, we need to understand that how tocilizumab is bound with mIL-6R or sIL-6R. Similarly, we also need to understand more about the real molecular mechanism of activity of tocilizumab.

positive: First case of drug-induced liver injury associated with the use of tocilizumab in a patient with COVID-19 BACKGROUND AND AIMS: Tocilizumab (TCZ; interleukine-6 receptor antagonist) has been proposed to treat severe forms of Coronavirus disease-19 (COVID-19) because interleukine-6 plays an important role in COVID-19-induced cytokine storm. Several clinical studies have shown very good effects of TCZ in patients with COVID-19, with a few minor side effects reported. Only eight serious liver injuries caused by TCZ were reported before being used in the treatment of patients with COVID-19. Considering the significantly increased use of TCZ for the treatment of COVID-19, we would like to warn of its rare but possible serious hepatotoxicity, especially when used together with other hepatotoxic drugs. METHODS: We describe a patient with COVID-19-induced cytokine storm who developed drug-induced liver injury associated with the use of TCZ. RESULTS: One day after TCZ administration, serum transaminase levels increased 40-fold. Nevertheless, TCZ had a positive effect on clinical and laboratory parameters in cytokine storm, with transaminases values normalizing in 10 days. CONCLUSIONS: This is the first reported case of DILI caused by TCZ in a COVID-19 patient. Intensive liver function monitoring is imperative in COVID-19 patients, because of frequent polypharmacy with potentially hepatotoxic drugs.

positive: A glimpse into the eye of the COVID-19 cytokine storm

positive: SARS-CoV-2 and Cardiovascular Complications: from Molecular Mechanisms to Pharmaceutical Management The coronavirus disease 2019 (COVID-19), elicited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is a pandemic public health emergency of global concern. Other than the profound severe pulmonary damage, SARS-CoV-2 infection also leads to a series of cardiovascular abnormalities, including myocardial injury, myocarditis and pericarditis, arrhythmia and cardiac arrest, cardiomyopathy, heart failure, cardiogenic shock, and coagulation abnormalities. Meanwhile, COVID-19 patients with preexisting cardiovascular diseases are often at a much higher risk of increased morbidity and mortality. Up–to-date, a number of mechanisms have been postulated for COVID-19-associated cardiovascular damage including SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) activation, cytokine storm, hypoxemia, stress and cardiotoxicity of antiviral drugs. In this context, special attention should be given towards COVID-19 patients with concurrent cardiovascular diseases, and special cardiovascular attention is warranted for treatment of COVID-19.

positive: Mapping the innate signaling cascade essential for cytokine storm during influenza virus infection. During pathogenic influenza virus infection, robust cytokine production (cytokine storm), excessive inflammatory infiltrates, and virus-induced tissue destruction all contribute to morbidity and mortality. Earlier we reported that modulation of sphingosine-1-phosphate-1 receptor (S1P1R) signaling provided a chemically tractable approach for the effective blunting of cytokine storm, leading to the improvement of clinical and survival outcomes. Here, we show that S1P1R agonist treatment suppresses global cytokine amplification. Importantly, S1P1R agonist treatment was able to blunt cytokine/chemokine production and innate immune cell recruitment in the lung independently of endosomal and cytosolic innate sensing pathways. S1P1R signaling suppression of cytokine amplification was independent of multiple innate signaling adaptor pathways for myeloid differentiation primary response gene 88 (MyD88) and IFN-β promoter stimulator-1 signaling, indicating a common pathway inhibition of cytokine storm. We identify the MyD88 adaptor molecule as responsible for the majority of cytokine amplification observed following influenza virus challenge.

positive: A Putative Role of de-Mono-ADP-Ribosylation of STAT1 by the SARS-CoV-2 Nsp3 Protein in the Cytokine Storm Syndrome of COVID-19 As more cases of COVID-19 are studied and treated worldwide, it had become apparent that the lethal and most severe cases of pneumonia are due to an out-of-control inflammatory response to the SARS-CoV-2 virus. I explored the putative causes of this specific feature through a detailed genomic comparison with the closest SARS-CoV-2 relatives isolated from bats, as well as previous coronavirus strains responsible for the previous epidemics (SARS-CoV and MERS-CoV). The high variability region of the nsp3 protein was confirmed to exhibit the most variations between closest strains. It was then studied in the context of physiological and molecular data available in the literature. A number of convergent findings suggest de-mono-ADP-ribosylation (de-MARylation) of STAT1 by the SARS-CoV-2 nsp3 as a putative cause of the cytokine storm observed in the most severe cases of COVID-19. This may suggest new therapeutic approaches and help in designing assays to predict the virulence of naturally circulating SARS-like animal coronaviruses.

positive: Models of cytokine dynamics in the inflammatory response of viral zoonotic infectious diseases Inflammatory responses to an infection from a zoonotic pathogen, such as avian influenza viruses, hantaviruses and some coronaviruses, are distinctly different in their natural reservoir versus human host. While not as well studied in the natural reservoirs, the pro-inflammatory response and viral replication appear controlled and show no obvious pathology. In contrast, infection in humans results in an initial high viral load marked by an aggressive pro-inflammatory response known as a cytokine storm. The key difference in the course of the infection between the reservoir and human host is the inflammatory response. In this investigation, we apply a simple two-component differential equation model for pro-inflammatory and anti-inflammatory responses and a detailed mathematical analysis to identify specific regions in parameter space for single stable endemic equilibrium, bistability or periodic solutions. The extensions of the deterministic model to two stochastic models account for variability in responses seen at the cell (local) or tissue (global) levels. Numerical solutions of the stochastic models exhibit outcomes that are typical of a chronic infection in the natural reservoir or a cytokine storm in human infection. In the chronic infection, occasional flare-ups between high and low responses occur when model parameters are in a region of bistability or periodic solutions. The cytokine storm with a vigorous pro-inflammatory response and less vigorous anti-inflammatory response occurs in the parameter region for a single stable endemic equilibrium with a strong pro-inflammatory response. The results of the model analyses and the simulations are interpreted in terms of the functional role of the cytokines and the inflammatory responses seen in infection of the natural reservoir or of the human host.

positive: Imiquimod - A toll like receptor 7 agonist - Is an IDEAL OPTION for MANAGEMENT of COVID 19 According to numerous recent publications, the COVID-19 patients have lymphopenia, higher infection-related biomarkers and several elevated inflammatory cytokines (i.e. tumor necrosis factor (TNF)-α, interleukin IL-2R and IL-6). The total number of B cells, T cells and NK cells are significantly decreased. RNA viruses, SARS-CoV-2 included, hit the innate immune system in order to cause infection, through TLRs 3, 7 and 8. Imiquimod is an immune-stimulator that activates TLR 7 and can be used to enhance the innate and adaptive immunity. Preclinical and clinical trials are proposed.

positive: COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression A novel coronavirus disease (COVID-19), caused by infection with SARS-CoV-2, has swept across 31 provinces in China and over 40 countries worldwide. The transition from first symptoms to acute respiratory distress syndrome (ARDS) is highly likely to be due to uncontrolled cytokine release. There is an urgent need to identify safe and effective drugs for treatment. Chloroquine (CQ) exhibits a promising inhibitory effect. However, the clinical use of CQ can cause severe side effects. We propose that hydroxychloroquine (HCQ), which exhibits an antiviral effect highly similar to that of CQ, could serve as a better therapeutic approach. HCQ is likely to attenuate the severe progression of COVID-19, inhibiting the cytokine storm by suppressing T cell activation. It has a safer clinical profile and is suitable for those who are pregnant. It is cheaper and more readily available in China. We herein strongly urge that clinical trials are performed to assess the preventive effects of HCQ in both disease infection and progression.

positive: Higher levels of IL‐6 early after tocilizumab distinguish survivors from non‐survivors in COVID‐19 pneumonia: a possible indication for deeper targeting IL‐6 INTRODUCTION: The most serious COVID‐19 deriving from severe acute respiratory syndrome coronavirus 2 causes cytokine release storm and it is associated with worse outcomes. In COVID‐19 patients, Interleukin (IL)‐6 levels are significantly elevated. Blocking IL‐6 preliminary resulted in the improvement of this hyperinflammatory state. It is unknown which patients could require higher doses of tocilizumab to get out of the cytokine storm. MATERIALS AND METHODS: Twenty‐four patients affected by COVID‐19 pneumonia were included. All the patients underwent tocilizumab 8 mg/kg intravenously and were tested for serum IL‐6 24‐48 hours before and 12‐48 hours after tocilizumab infusion. Comparisons between survivors and non‐survivors were performed. RESULTS: Eighteen patients were discharged, while six patients died, with no clinical or laboratory differences between the two groups at baseline. IL‐6 was not different at baseline (p=0.41), while 24‐48h post‐tocilizumab IL‐6 serum levels were significantly higher in non‐survivors than in survivors [2398.5 (430.5‐9372) pg/mL vs 290.5 (58.5‐1305.5) pg/mL, p=0.022)]. Serum IL‐6 post‐tocilizumab showed a good predictive ability to discriminate survivors from non‐survivors (AUC 0.815 95%CI 0.63‐0.99, p=0.02). CONCLUSION: Repeated measurement of serum level of IL‐6 early after tocilizumab may distinguish non‐survivors from survivors and support the choice of deeper targeting IL‐6 in COVID‐19 pneumonia. This article is protected by copyright. All rights reserved.

positive: Use of subcutaneous tocilizumab in patients with COVID‐19 pneumonia Over the last months, pandemic SARS‐CoV‐2 caused a significant challenge for clinicians. Unfortunately, no approved and validated treatments are available. Intravenous tocilizumab, an antirheumatic drug, seems to be promising in counteracting cytokine storm caused by SARS‐CoV‐2 infection with associated clinical improvements. We report herein a case series of patients with COVID‐19 pneumonia who were treated with tocilizumab administrated, for the first time, subcutaneously with good clinical and radiological outcomes. This article is protected by copyright. All rights reserved.

positive: Cytokine Release Syndrome in COVID-19 Patients, A New Scenario for an Old Concern: The Fragile Balance between Infections and Autoimmunity On 7 January 2020, researchers isolated and sequenced in China from patients with severe pneumonitis a novel coronavirus, then called SARS-CoV-2, which rapidly spread worldwide, becoming a global health emergency. Typical manifestations consist of flu-like symptoms such as fever, cough, fatigue, and dyspnea. However, in about 20% of patients, the infection progresses to severe interstitial pneumonia and can induce an uncontrolled host-immune response, leading to a life-threatening condition called cytokine release syndrome (CRS). CRS represents an emergency scenario of a frequent challenge, which is the complex and interwoven link between infections and autoimmunity. Indeed, treatment of CRS involves the use of both antivirals to control the underlying infection and immunosuppressive agents to dampen the aberrant pro-inflammatory response of the host. Several trials, evaluating the safety and effectiveness of immunosuppressants commonly used in rheumatic diseases, are ongoing in patients with COVID-19 and CRS, some of which are achieving promising results. However, such a use should follow a multidisciplinary approach, be accompanied by close monitoring, be tailored to patient’s clinical and serological features, and be initiated at the right time to reach the best results. Autoimmune patients receiving immunosuppressants could be prone to SARS-CoV-2 infections; however, suspension of the ongoing therapy is contraindicated to avoid disease flares and a consequent increase in the infection risk.

positive: The amount of cytokine-release defines different shades of Sars-Cov2 infection. The recent outbreak of coronavirus disease (COVID 19), spreading from China all around the world in early 2020, has led scientists to investigate the immuno-mediated mechanisms underlying the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) infection. Depending on the amount of cytokines released as the result of the immunological activation induced by SARS-CoV2, three major clinical phenotypes can be identified: "mild",symbolized as a "drizzle" of cytokines, severe as a "storm", and critical as a "hurricane". In patients with mild symptoms, the release of pro-inflammatory cytokines is balanced to obtain a defense response against the virus which is often self-limiting and overcomes without tissue damage. In severe phenotype, resembling a "cytokine-release syndrome", SARS-CoV2 causes the lysis of the immune-mediators leading to a cytokine storm able to induce lung epithelium damage and acute respiratory distress syndrome. In critical patients, the immune response may become uncontrolled, thus the cytokine burst resembles a form of secondary hemophagocytic lymphohistiocytosis which may result in a multi organ failure. In addition to the standard of care, an immune-modulatory therapy tailored to each one of the different phenotypes should be used in order to prevent or reduce the release of cytokines responsible for organ damage and disease progression.

positive: Vitamin D Receptor stimulation to reduce Acute Respiratory Distress Syndrome (ARDS) in patients with Coronavirus SARS-CoV-2 infections: Revised Ms SBMB 2020_166 Coronavirus infection is a serious health problem awaiting an effective vaccine and/or antiviral treatment. The major complication of coronavirus disease 2019 (COVID-19), the Acute Respiratory Distress syndrome (ARDS), is due to a variety of mechanisms including cytokine storm, dysregulation of the renin-angiotensin system, neutrophil activation and increased (micro)coagulation. Based on many preclinical studies and observational data in humans, ARDS may be aggravated by vitamin D deficiency and tapered down by activation of the vitamin D receptor. Several randomized clinical trials using either oral vitamin D or oral Calcifediol (25OHD) are ongoing. Based on a pilot study, oral calcifediol may be the most promising approach. These studies are expected to provide guidelines within a few months.

positive: Identification of Human Immune Cell Subtypes Most Vulnerable to IL-1β-induced Inflammatory Signaling Using Mass Cytometry IL-1β has emerged as a key mediator of the cytokine storm linked to high morbidity and mortality from COVID-19 and blockade of the IL-1 receptor (IL-1R) with Anakinra has entered clinical trials in COVID-19 subjects. Yet, knowledge of the specific immune cell subsets targeted by IL-1β and IL-1β-induced signaling pathways in humans is limited. Utilizing mass cytometry (CyTOF) of human peripheral blood mononuclear cells, we identified effector memory CD4 T cells and CD4−CD8low/-CD161+ T cells as the circulating immune subtypes with the greatest expression of p-NF-κB in response to IL-1β stimulation. Notably, CCR6 distinctly identified T cells most responsive to IL-1β. Other subsets including CD11c myeloid dendritic cells (mDCs), classical monocytes (CM), two subsets of natural killer cells (CD16−CD56brightCD161− and CD16−CD56dimCD161+) and a population of lineage−(Lin-) cells expressing CD161 and CD25 also showed IL-1β-induced expression of p-NF-kB. The IL-1R antagonist, Anakinra significantly inhibited IL-1β-induced p-NF-kB in the CCR6+ T cells and CD11c mDCs with a trending inhibition in CD14 monocytes and Lin−CD161+CD25+ cells. IL-1β also induced a rapid but much less robust increase in p-p38 expression as compared to p-NF-kB in the majority of these same immune cell subsets. Prolonged IL-1β stimulation greatly increased p-STAT3 and to a much lesser extent p-STAT1 and p-STAT5 in T cell subsets, monocytes, DCs and the Lin−CD161+CD25+ cells suggesting IL-1β-induced production of downstream STAT-activating cytokines, consistent with its role in cytokine storm. Interindividual heterogeneity and inhibition of this activation by Anakinra raises the intriguing possibility that assays to measure IL-1β-induced p-NF-kB in CCR6+ T cell subtypes could identify those at higher risk of cytokine storm and those most likely to benefit from Anakinra therapy.

positive: Consideration of Severe Coronavirus Disease 2019 As Viral Sepsis and Potential Use of Immune Checkpoint Inhibitors Taking into consideration the multisystemic clinical and autopsy findings in “severe” coronavirus disease 2019 patients, viral sepsis would be a more accurate term to describe the whole clinical picture. The most significant pathophysiological components of this picture are intense cytokine release, prolonged inflammation, immunosuppression with T cell exhaustion, and the development of organ dysfunctions. Currently, the optimal treatment for severe coronavirus disease 2019 is uncertain. Supportive treatment and immunomodulators have a critical place in the treatment of severe patients until effective antivirals are developed. Interleukin-6 antagonists, one of the immunomodulating agents, appears to be effective in the treatment of cytokine storm, but some patients continue to have severe lymphopenia and immunosuppression. We believe it can be useful as immunomodulator therapy in critical coronavirus disease 2019 patients because of the benefits of immune checkpoint inhibitors in cancer and sepsis patients.

positive: The first case of COVID-19 treated with the complement C3 inhibitor AMY-101 Acute respiratory distress syndrome (ARDS) is a devastating clinical manifestation of COVID-19 pneumonia and is mainly based on an immune-driven pathology. Mounting evidence suggests that COVID-19 is fueled by a maladaptive host inflammatory response that involves excessive activation of innate immune pathways. While a "cytokine storm" involving IL-6 and other cytokines has been documented, complement C3 activation has been implicated as an initial effector mechanism that exacerbates lung injury in preclinical models of SARS-CoV infection. C3-targeted intervention may provide broader therapeutic control of complement-mediated inflammatory damage in COVID-19 patients. Herein, we report the clinical course of a patient with severe ARDS due to COVID-19 pneumonia who was safely and successfully treated with the compstatin-based complement C3 inhibitor AMY-101.

positive: The Imperfect Cytokine Storm: Severe COVID-19 with ARDS in Patient on Durable LVAD Support As health systems worldwide grapple with the COVID-19 pandemic, patients on durable LVAD support represent a unique population at risk for the disease. We outline such a patient who developed COVID-19 complicated by "cytokine storm" with severe ARDS and myocardial injury; and describe the challenges that arose during management.

positive: Nuclear factor k B: a pivotal role in the systemic inflammatory response syndrome and new target for therapy

positive: Cerebrovascular events in COVID-19 patients. Neurological manifestations in patients with COVID-19 are more frequently being reported. Cerebrovascular events have been reported in around 3% of patients. In this review we summarize the published literature on cerebrovascular events in patients with COVID-19 as available on the PubMed database. So far, 3 studies have reported cerebrovascular events. Cerebrovascular events were identified on screening patients with decreased consciousness or in the presence of focal neurological deficits. These events were common in elderly, critically ill patients and in patients with prior cardio-cerebrovascular comorbidities. The diagnosis of cerebrovascular events was confirmed with computed tomography of the brain in most studies reporting neurological events. Multiple pathological mechanisms have been postulated regarding the process of neurological and vascular injury among which cytokine storm is shown to correlate with mortality. Patients with severe illness are found to have a higher cardio- cerebrovascular comorbidity. With an increasing number of cases and future prospective studies, the exact mechanism by which these cerebrovascular events occur and attribute to the poor outcome will be better understood.

positive: Covid-19 and immunomodulation in IBD The current coronavirus pandemic is an ongoing global health crisis due to covid-19, caused by severe acute respiratory syndrome coronavirus 2. Although covid-19 leads to little or mild flu-like symptoms in the majority of affected patients, the disease may cause severe, frequently lethal complications such as progressive pneumonia, acute respiratory distress syndrome and organ failure driven by hyperinflammation and a cytokine storm syndrome. This situation causes various major challenges for gastroenterology. In the context of IBD, several key questions arise. For instance, it is an important question to understand whether patients with IBD (eg, due to intestinal ACE2 expression) might be particularly susceptible to covid-19 and the cytokine release syndrome associated with lung injury and fatal outcomes. Another highly relevant question is how to deal with immunosuppression and immunomodulation during the current pandemic in patients with IBD and whether immunosuppression affects the progress of covid-19. Here, the current understanding of the pathophysiology of covid-19 is reviewed with special reference to immune cell activation. Moreover, the potential implications of these new insights for immunomodulation and biological therapy in IBD are discussed.

positive: Infection with SARS-CoV-2 causes abnormal laboratory results of multiple organs in patients Aim: To evaluate the clinical value of abnormal laboratory results of multiple organs in patients with coronavirus disease 2019 (COVID-2019) and to help clinicians perform correct treatment. Results: Elevated neutrophil-to-LYM ratio (NLR), D-dimer(D-D), interleukin (IL)-6, IL-10, IL-2, interferon-Y, and age were significantly associated with the severity of illness. However, significant and sustained decreases were observed in the LYM subset (p<0.05). D-D, T cell counts, and cytokine levels in severe COVID-19 patients who survived the disease gradually recovered at later time points to levels that were comparable to those of mild cases. Second, D-D increased from 0.5 to 8, and the risk ratio increased from 2.75 to 55, eventually leading to disseminated intravascular coagulation. Moreover, the acute renal function damage occurred earlier than abnormal heart and liver functions (p<0.05). Conclusions: The degrees of lymphopenia and proinflammatory cytokine storm were higher in severe COVID-19 patients than in mild cases. The degree was associated with the disease severity. Advanced age, NLR, D-D, and cytokine levels may serve as useful prognostic factors for the early identification of severe COVID-19 cases. Methods: Peripheral blood samples were collected from 93 confirmed COVID-19 patients. The samples were examined for lymphocyte (LYM) subsets by flow cytometry and cytokine profiles by specific immunoassays. The receiver operating characteristic curve was applied to determine the best diagnostic thresholds for laboratory results, and principal component analysis was used to screen the major risk factors. The prognostic values were assessed using the Kaplan–Meier curve and univariate and multivariate COX regression models.

positive: Dysregulation of lung myeloid cells in COVID-19

positive: T follicular regulatory cells infiltrate the human airways during the onset of acute respiratory distress syndrome and regulate the development of B regulatory cells T follicular regulatory (Tfr) cell is a CXCR5(+)Foxp3(+) subset of T regulatory (Treg) cell with critical roles in regulating germinal center responses and modulating the immune environment in the lymph nodes. Studies have shown that the proportion of Tfr cells may increase during acute inflammation. In this study, we investigated the role of Tfr cells in acute respiratory distress syndrome (ARDS). We found that Tfr cells were significantly enriched in peripheral blood and in mini-bronchoalveolar lavage (BAL) during the onset of ARDS. Notably, Tfr cells represented the majority of Treg cells in the mini-BAL samples. Tfr cells also showed CTLA-4, IL-10, and TGF-β expression, but compared to the non-Tfr Treg cells, the CTLA-4 and IL-10 expression by Tfr cells were slightly reduced. Both Tfr cells and non-Tfr Treg cells suppressed the proliferation of autologous CD4(+)CD25(−) T cells; however, the Tfr cells displayed slightly reduced suppression capacity. Subsequently, B cells were co-incubated with autologous Tfr cells or non-Tfr Treg cells. Interestingly, we found that the frequency of IL-10(+) Breg cells was significantly higher following incubation with Tfr cells than with non-Tfr Treg cells, which suggested that Tfr cells were more potent at inducing IL-10(+) Breg cells. Together, these results demonstrated that Tfr cells were a similar but distinctive subset of Treg cells. Given that Tfr cells were strongly enriched in ARDS patients, especially in the lung infiltrates, they may exert critical ameliorating effects in ARDS.

positive: Immunology of COVID-19: current state of the science Abstract The coronavirus disease 2019 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide, igniting an unprecedented effort from the scientific community to understand the biological underpinning of COVID19 pathophysiology. In this review, we summarize the current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death. We also discuss the rationale and clinical outcome of current therapeutic strategies as well as prospective clinical trials to prevent or treat SARS-CoV-2 infection.

positive: Rethinking interleukin-6 blockade for treatment of COVID-19 Interleukin-6 (IL-6) is a pleiotropic cytokine with effects in immune regulation, inflammation, and infection. The use of drugs that inhibit IL-6 biological activity has been proposed as a treatment for patients with Coronavirus Disease 2019 (COVID-19). The rationale for this approach includes commitment to the concept that inflammation is a cause of lung damage in COVID-19 and belief that IL-6 is a pro-inflammatory molecule. Observational data thought to support IL-6 inhibition include elevated circulating IL-6 levels in COVID-19 patients and association between elevated IL-6 and poor clinical outcomes. However, IL-6 has significant anti-inflammatory properties, which calls into question the rationale for employing IL-6 blockade to suppress inflammation-induced tissue injury. Also, studies suggesting a beneficial role for IL-6 in the host response to infection challenge the strategy of using IL-6 blockade to treat COVID-19. In studies of recombinant IL-6 injected into human volunteers, IL-6 levels exceeding those measured in COVID-19 patients have been observed with no pulmonary adverse events or other organ damage. These observations question the role of IL-6 as a contributing factor in COVID-19. Clinical experience with IL-6 receptor antagonists such as tocilizumab demonstrates increase in severe and opportunistic infections, raising concern about using tocilizumab and similar agents to treat COVID-19. Trials of drugs to inhibit IL-6 activity in COVID-19 are ongoing and will shed light on the role of IL-6 in COVID-19 pathogenesis. However, until more information is available, providers should exercise caution in prescribing these therapies given the potential for patient harm.

positive: Features of COVID-19 post-infectious cytokine release syndrome in children presenting to the emergency department The 2019 coronavirus disease (COVID-19) has not appeared to affect children as severely as adults. However, approximately 1 month after the COVID-19 peak in New York City in April 2020, cases of children with prolonged fevers abruptly developing inflammatory shock-like states have been reported in Western Europe and the United States. This case series describes four previously healthy children with COVID-19 infection confirmed by serologic antibody testing, but negative by nasopharyngeal RT-PCR swab, presenting to the Pediatric Emergency Department (PED) with prolonged fever (5 or more days) and abrupt onset of hemodynamic instability with elevated serologic inflammatory markers and cytokine levels (IL-6, IL-8 and TNF-α). Emergency physicians must maintain a high clinical suspicion for this COVID-19 associated post-infectious cytokine release syndrome, with features that overlap with Kawasaki Disease (KD) and Toxic Shock Syndrome (TSS) in children with recent or current COVID-19 infection, as patients can decompensate quickly.

positive: Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19 Background: A recently emerging respiratory disease named coronavirus disease 2019 (COVID-19) has quickly spread across the world. This disease is initiated by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and uncontrolled cytokine storm, but it remains unknown as to whether a robust antibody response is related to clinical deterioration and poor outcome in laboratory-confirmed COVID-19 patients. Methods: Anti-SARS-CoV-2 IgG and IgM antibodies were determined by chemiluminescence analysis (CLIA) in COVID-19 patients from a single center in Wuhan. Median IgG and IgM levels in acute and convalescent-phase sera (within 35 days) for all included patients were calculated and compared among severe and nonsevere patients. Immune response phenotyping based on late IgG levels and neutrophil-to-lymphocyte ratio (NLR) was characterized to stratify patients with different disease severities and outcome. Laboratory parameters in patients with different immune response phenotypes and disease severities were analyzed. Findings: A total of 222 patients were included in this study. IgG was first detected on day 4 of illness, and its peak levels occurred in the fourth week. Severe cases were more frequently found in patients with high IgG levels, compared to those who with low IgG levels (51.8% versus 32.3%; p=0.008). Severity rates for patients with NLRhiIgGhi, NLRhiIgGlo, NLRloIgGhi, and NLRloIgGlo phenotype was 72.3%, 48.5%, 33.3%, and 15.6%, respectively (p<0.0001). Furthermore, severe patients with NLRhiIgGhi, NLRhiIgGlo had higher proinflammatory cytokines levels including IL-2, IL-6 and IL-10, and decreased CD4+ T cell count compared to those with NLRloIgGlo phenotype (p<0.05). Recovery rate for severe patients with NLRhiIgGhi, NLRhiIgGlo, NLRloIgGhi, and NLRloIgGlo phenotype was 58.8% (20/34), 68.8% (11/16), 80.0% (4/5), and 100% (12/12), respectively (p=0.0592). Dead cases only occurred in NLRhiIgGhi and NLRhiIgGlo phenotypes. Interpretation: COVID-19 severity is associated with increased IgG response, and an immune response phenotyping based on late IgG response and NLR could act as a simple complementary tool to discriminate between severe and nonsevere COVID-19 patients, and further predict their clinical outcome.

positive: The Question of Whether to Remain on Therapy for Chronic Rheumatic Diseases in the Setting of the Covid-19 Pandemic We appreciate our Italian colleagues' interest in our editorial denoting the rheumatologist's role in helping to diagnose and treat cytokine storm syndrome (CSS) in the setting of the Covid-19 panemic (1). It is encouraging that none of the 123 pediatric rheumatology patients (primarily juvenile idiopathic arthritis) on background biological disease modifying anti-rheumatic drug (bDMARD) therapies in Milan, Italy surveyed over a 7-week period from February 25 through April 14, 2020 (during which time Covid-19 was hyper-endemic there) had either confirmed or suspected Covid-19 (2).

positive: Circulating Levels of IL‐2, IL‐4, TNF‐α, IFN‐γ and C reactive protein Are Not Associated with Severity of COVID‐19 Symptoms As of May 5, 2020, the total number of coronavirus disease 2019 (COVID‐19) cases had reached over 3.5 million worldwide. The outbreak of COVID‐19 has been officially declared as a pandemic by the World Health Organization because of global spread and severity. Accumulating evidence has been showed that patients with severe COVID‐19 have a cytokine storm syndrome. This article is protected by copyright. All rights reserved.

positive: Tocilizumab in Severe COVID-19 Pneumonia and Concomitant Cytokine Release Syndrome Younger patients with COVID-19 may experience an exaggerated immune response to SARS-CoV-2 infection and develop cytokine release syndrome (CRS), which may be life threatening. There is no proven antiviral therapy for COVID-19 so far, but profound immunosuppression has recently been suggested as a treatment for COVID-19-associated CRS. We present a case of life-threatening CRS caused by COVID-19 infection with a favourable response to immunosuppressive therapy with tocilizumab (TCZ). The rapid clinical and biochemical improvement following TCZ administration suggests that treatment with immunotherapy can be life-saving in selected patients with COVID-19-induced CRS. LEARNING POINTS: Cytokine release syndrome may cause sudden and potentially life-threatening clinical deterioration in COVID-19 pneumonia, particularly in younger patients. Immunosuppressive therapy may provide important additional therapeutic benefit in these patients. Tocilizumab, a specific IL-6 inhibitor, led to dramatic clinical improvement in a young patient with severe COVID-19-associated cytokine release syndrome.

positive: Potential for jaktinib hydrochloride to treat cytokine storms in patients with COVID-19 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become a serious public health threat to the whole world, and the number of infected is still rising dramatically at this moment. Several studies have confirmed that cytokine storms play a critical role in causing a case to worsen from mild to severe or critical. The current treatment for cytokine storms is limited, so the international medical community is focusing on a specific and effective remedy. Jaktinib hydrochloride is a broad spectrum JAK inhibitor. It can inhibit cytokine-induced immune activation by multiple mechanisms and also slow viral proliferation by inhibiting AAK1 without causing unacceptable toxicity. Jaktinib hydrochloride has great potential for the treatment of patients with coronavirus disease 2019 (COVID-19).

positive: Extracellular vesicles from mesenchymal stem cells as a Covid-19 treatment

positive: Tratamiento y evolución del síndrome de tormenta de citoquinas asociados a infección por SARS-CoV-2 en pacientes octogenarios./ [Evolution and treatment of storm cytoquine syndrome associated to SARS-CoV-2 infection among octogenarians] INTRODUCTION: Cytokine storm syndrome (CTS) is a serious complication of patients with SARS-CoV-2 infection. Treatment and evolution in octogenarians are not well defined. Our objective is to describe its clinical characteristics, the treatments and its clinical evolution. PATIENTS AND METHOD: Retrospective observational study of consecutive patients admitted in the period between March 23 and April 12, 2020 with confirmed SARS-CoV-2 infection, with pneumonia by radiological study or chest tomography, whith STC criteria and who received treatment. We classified patients as those who received only glucocorticoid (GC) pulses, or GC and tocilizumab pulses. We determined serum levels of ferritin, CRP and D-dimers. The final variable was survival. RESULTS: 21 patients, (80-88 years). The mean ferritin was 1056 microg/L (317-3,553), CRP 115.8mg/dL (22-306) and D-dimers 2.9m/L (0.45-17.5). All patients received GC pulses and in 2 cases simultaneously tocilizumab. The mean follow-up time was 13.7 days (8-21). The overall mortality was 38.1% (8/21 patients). The 2 patients who received tocilizumab died. The deceased had significantly higher levels of ferritin (1,254 vs. 925microg/L; P=.045) and CRP (197.6 vs. 76mg / dL; P=.007). At the end of the follow-up, a decrease in the biochemical parameters was observed with ferritin of 727microg/L, CRP of 27mg/dl and D-dimers of 1.18mg/L. In 13/21 patients (61.9%), the CTS was controlled without the need to add other treatments. CONCLUSIONS: STC mortality from SARS-CoV-2 is high despite treatment. A greater inflammatory response was associated with a higher mortality. Although it seems that the early use of GC pulses could control it, and the use of other treatments such as tocilizumab shouldo be, with the study design and its limitations, this conclusion cannot be stablished.

positive: Clinical Characteristics of Critically Ill Patients Co-infected with SARS-CoV-2 and the Influenza Virus in Wuhan, China OBJECTIVE: To delineate the clinical characteristics of critically ill COVID-19 patients co-infected with influenza. METHODS: In this study, we included adult patients with laboratory-confirmed COVID-19 form Tongji Hospital (Wuhan, China), with or without influenza, and compared their clinical characteristics. RESULTS: Among 93 patients, 44 died and 49 were discharged. Forty-four (47.3%) were infected with influenza virus A and 2 (2.2%) with influenza virus B. Twenty-two (50.0%) of the non-survivors and 24 (49.0%) of the survivors were infected with the influenza virus. Critically ill COVID-19 patients with influenza were more prone to cardiac injury than those without influenza. For the laboratory indicators at admission, white blood cell counts, neutrophil counts, levels of tumor necrosis factor-α, D-dimer value, and proportion of elevated creatinine were higher in non-survivors with influenza than in those without influenza. CONCLUSION: The results showed a high proportion of COVID-19 patients were co-infected with influenza in Tongji Hospital, with no significant difference in the proportion of co-infection between survivors and non-survivors. The critically ill COVID-19 patients with influenza exhibited more severe inflammation and organ injury, indicating that co-infection with the influenza virus may induce an earlier and more frequently occurring cytokine storm.

positive: Cytokine Storm in COVID-19 patients transforms to a Cytokine Super Cyclone in patients with risk factors The seventh human coronavirus SARS-CoV2 belongs to the cluster of extremely pathogenic coronaviruses like SARS-CoV and MERS-CoV, which are established to cause lower respiratory tract infection. The viral infection can be fatal as the disease advances to pneumonia followed by acute respiratory distress syndrome (ARDS). Increasingly higher cytokine concentration on account of over-stimulated immune response against the virus, or the ‘cytokine storm’, is the reason behind the manifestation of lethal clinical symptoms. In this article, we discuss the immune pathogenesis of cytokine storm and its relation with SARS-CoV2/COVID-19 risk factors. People with underlying risk factors are more susceptible to fatal complications of COVID-19 infection leading to poor clinical outcome. The increased pro-inflammatory immune status in patients with risk factors (diabetes, hypertension, cardiovascular disease, COPD) exacerbates the Cytokine-storm of COVID-19 to a Cytokine Super Cyclone. We also overviewed antiviral immune response provided by BCG vaccine involving the IL-1β, IL-6 and TNF-α secretion via ‘trained monocytes’, which confers early protection against SARS-CoV2.

positive: Can steroids reverse the severe COVID-19 induced 'cytokine storm'? Severe COVID-19 is characterized by an excessive pro-inflammatory cytokine storm, resulting in acute lung injury and development of ARDS. The role of corticosteroids is controversial in severe COVID-19 pneumonia and associated hyper-inflammatory syndrome. We reported a case series of six consecutive COVID-19 patients with severe pneumonia, ARDS and laboratory indices of hyper-inflammatory syndrome. All patients were treated early with a short course of corticosteroids, and clinical outcomes were compared before and after corticosteroids administration. All patients evaded intubation and intensive care admission, ARDS resolved within 11.8 days (median), viral clearance was achieved in 4 patients within 17.2 days (median), and all patients were discharged from the hospital in 16.8 days (median). Early administration of short course corticosteroids improves clinical outcome of patients with severe COVID-19 pneumonia and evidence of immune hyper-reactivity. This article is protected by copyright. All rights reserved.

positive: Covid-19 nephropathy: What could pathologist say? Implication for health policy/practice/research/medical education: The pathogenetic mechanism of renal involvement in coronavirus disease 19 (COVID-19) is still unclear. It is supposed to result from a combination of several contributing factors, such as state of dehydration, leading to pre-renal failure with acute tubular necrosis, toxic tubular damage, induced by cytokine storm or rhabdomyolysis, cytopathic action induced by the virus that invades ACE2- expressing kidney cells and drug-induced nephrotoxicity.

positive: Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response PURPOSE OF REVIEW: Coronavirus disease of 2019 (COVID-19) is a cause of significant morbidity and mortality worldwide. While cardiac injury has been demonstrated in critically ill COVID-19 patients, the mechanism of injury remains unclear. Here, we review our current knowledge of the biology of SARS-CoV-2 and the potential mechanisms of myocardial injury due to viral toxicities and host immune responses. RECENT FINDINGS: A number of studies have reported an epidemiological association between history of cardiac disease and worsened outcome during COVID infection. Development of new onset myocardial injury during COVID-19 also increases mortality. While limited data exist, potential mechanisms of cardiac injury include direct viral entry through the angiotensin-converting enzyme 2 (ACE2) receptor and toxicity in host cells, hypoxia-related myocyte injury, and immune-mediated cytokine release syndrome. Potential treatments for reducing viral infection and excessive immune responses are also discussed. COVID patients with cardiac disease history or acquire new cardiac injury are at an increased risk for in-hospital morbidity and mortality. More studies are needed to address the mechanism of cardiotoxicity and the treatments that can minimize permanent damage to the cardiovascular system.

positive: Tocilizumab, an anti-IL6 receptor antibody, to treat Covid-19-related respiratory failure: a case report

positive: Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? Abstract The emergent outbreak of coronavirus disease 2019 (COVID-19) has caused a global pandemic. Acute respiratory distress syndrome (ARDS) and multiorgan dysfunction are among the leading causes of death in critically ill patients with COVID-19. The elevated inflammatory cytokines suggest that a cytokine storm, also known as cytokine release syndrome (CRS), may play a major role in the pathology of COVID-19. However, the efficacy of corticosteroids, commonly utilized antiinflammatory agents, to treat COVID-19-induced CRS is controversial. There is an urgent need for novel therapies to treat COVID-19-induced CRS. Here, we discuss the pathogenesis of severe acute respiratory syndrome (SARS)-induced CRS, compare the CRS in COVID-19 with that in SARS and Middle East respiratory syndrome (MERS), and summarize the existing therapies for CRS. We propose to utilize interleukin-6 (IL-6) blockade to manage COVID-19-induced CRS and discuss several factors that should be taken into consideration for its clinical application.

positive: Mesenchymal stem cells and management of COVID-19 pneumonia Abstract Human coronavirus, hCoV-19, is highly pathogenic with severe pneumonia associated with rapid virus replication. Arising in Wuhan China December 2019, the current COVID-19 epidemic has rapidly grown with person-to-person infection expanding to become a global health emergency now on pandemic scale. Governments will not be able to minimise both deaths from COVID-19 and the economic impact of viral spread in mitigation of this current COVID-19 pandemic, according to Anderson et al. 2020 [1], Keeping mortality as low as possible will be the highest priority for individuals; hence governments must put in place measures to ameliorate the inevitable economic downturn. The current global picture shows small chains of transmission in many countries and large chains resulting in extensive spread in a few countries, such as Italy, Iran, South Korea, and Japan. Most countries are likely to have spread of COVID-19, at least in the early stages, before any mitigation measures have an impact. The scale of the problem is massive. Here I consider new approaches to improve patient's biological resistance to COVID-19 using stem cells, and how benefit might be scaled and simplified using synthetic stem cells to meet logistical needs within a short time frame.

positive: COVID-19: pathogenesis, genetic polymorphism, clinical features and laboratory findings COVID-19 caused by a novel agent SARS-CoV-2 progressed to a pandemic condition and resulted in a major public health concern worldwide, leading to social and economic issues at the same time. The pathogenesis of COVID-19 starts with the bonding of the virus to ACE2 receptors expressed in many tissues, and the triggered excessive immune response plays a critical role in the course of the disease. The cytokine storm that occurs upon excessive production of pro-inflammatory cytokines is considered responsible for the severe progression of the disease and the organ damage. However, the accurate pathophysiological mechanism of the disease, which progresses with various clinical presentations, is still substantially unknown. While various studies have been conducted on the effect of genetic polymorphism on the course and severity of the disease, the presence of a significant effect has not been proven yet. The clinical course of the disease is variable, with clinical representation ranging from 81% mild course to 14% severe course along with 5% critical course in patients. Asymptomatic course is considered to be higher than expected, although its frequency is not known exactly. Older adults and those with comorbidities are exposed to a more severe disease course. The disease progress with various symptoms, such as fever, cough, dyspnea, malaise, myalgia, taste and smell dysfunctions, diarrhea, and headache. A range of complications (acute respiratory distress syndrome, thromboembolic conditions, arrhythmia and cardiac events, secondary infections) could be seen during the course of the disease. Varied laboratory tests are vital to determine these verity and prognosis of the disease, along with the condition and exposure of the affected systems during thecourse of COVID-19.

positive: On the Alert for Cytokine Storm: Immunopathology in COVID-19 Poor outcomes in COVID-19 correlate with clinical and laboratory features of cytokine storm syndrome. Broad screening for cytokine storm and early, targeted antiinflammatory therapy may prevent immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in cytokine storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID-19.

positive: [Intervention mechanism of Qingwen Baidu Yin on cytokine storm based on network pharmacology]. The aim of this paper was to explore the intervention mechanism of Qingwen Baidu Yin in cytokine storm based on network pharmacology. TCMSP and TCMIP V2.0 server were used to predict all chemical components and action targets of Qingwen Baidu Yin. Diseases that could be treated by Qingwen Baidu Yin were predicted through Enrichr database. A compound target interaction(PPI) network diagram was constructed using STRING 11.0. OmicShare was used to analyzed the gene ontology(GO) enrichment and enrichment of the Kyoto encyclopedia of genes and genomes(KEGG) pathway of core targets. Component-target-path network diagram was constructed with Cytoscape 3.6.0 software. After analysis of the database, 267 compounds were screened for Qingwen Baidu Yin, involving 1 450 targets, and a protein interaction network was constructed. Total 219 core target proteins were predicted, such as NFKB1, STAT1, RAF1, IL2, JAK1, IL6, TNF, BCL2 and other important targets, and 221 core target pathways were enriched, including cancer pathway, Kaposi's sarcoma-associated herpes virus infection, chemokine signal pathway, PI3 K-AKT signal pathway, EB virus infection, virus carcinogenesis and T cell receptor signaling pathways, a collection of which were highly related to cytokine storms. GO annotation analysis suggested that Qingwen Baidu Yin Decoction may exert therapeutic effects by regulating protein phosphorylation, cell response to cytokine stimulation, cell proliferation, inflammatory response, transmembrane receptor protein tyrosine kinase signaling pathway, and cytokine-mediated signaling pathways. This study revealed potential active components of Qingwen Baidu Yin in defending against cytokine storm and its possible mechanism of action, and provided theoretical basis and technical support for further clinical application of this prescription.

positive: The Association between Obesity and Poor Outcome after COVID-19 Indicates a Potential Therapeutic Role for Montelukast It is widely believed that infection with the SARS-CoV2 virus triggers a disproportionate immune response which causes a devastating systemic injury, particularly in individuals with obesity, itself a chronic, multi-organ inflammatory disease. Immune cells accumulate in visceral adipose tissue and together with paracrine adipocytes release a wide range of biologically active cytokines (including IL-1β, IL5, IL6 and IL8) that can result in both local, pulmonary and systemic inflammation. A more intense ‘cytokine storm’ is postulated as the mechanism behind the extreme immune response seen in severe COVID-19. It is striking how dangerous the combination of obesity and COVID-19 is, resulting in a greater risk of ICU admission and a higher mortality. Furthermore, patients from a BAME background appear to have increased mortality after SARS-CoV2 infection; they also have a higher prevalence of central obesity and its metabolic complications. In the absence of an effective vaccine, the therapeutic potential of immune-modulating drugs is a priority, but the development of new drugs is expensive and time-consuming. A more pragmatic solution would be to seek to repurpose existing drugs, particularly those that might suppress the heightened cytokine activity seen in obesity, the major risk factor for a poor prognosis in COVID-19. Montelukast is a cysteinyl leukotriene receptor antagonist licensed to treat asthma and allergic rhinitis. It has been shown to diminish pulmonary response to antigen, tissue eosinophilia and IL-5 expression in inflammatory cells. It has also been shown to decrease elevated levels of IL-1β and IL8 in humans with viral upper respiratory tract infections compared with placebo-treated patients. In addition, in silico studies have demonstrated a high binding affinity of the montelukast molecule to the terminal site of the virus’s main protease enzyme which is needed for virus RNA synthesis and replication. Montelukast, which is cheap, safe and widely available would appear to have the potential to be an ideal candidate drug for clinical trials, particularly in early stage disease before irreparable tissue damage has already occurred. HYPOTHESIS: Through a direct anti-viral effect, or by suppression of heightened cytokine release in response to SARS-CoV2, montelukast will reduce the severity of immune-mediated multiorgan damage resulting from COVID-19, particularly in patients with central obesity and metabolic syndrome.

positive: Enhancement of the infectivity of SARS-CoV in BALB/c mice by IMP dehydrogenase inhibitors, including ribavirin Abstract Because of the conflicting data concerning the SARS-CoV inhibitory efficacy of ribavirin, an inosine monophosphate (IMP) dehydrogenase inhibitor, studies were done to evaluate the efficacy of ribavirin and other IMP dehydrogenase inhibitors (5-ethynyl-1-β-d-ribofuranosylimidazole-4-carboxamide (EICAR), mizoribine, and mycophenolic acid) in preventing viral replication in the lungs of BALB/c mice, a replication model for severe acute respiratory syndrome (SARS) infections (Subbarao, K., McAuliffe, J., Vogel, L., Fahle, G., Fischer, S., Tatti, K., Packard, M., Shieh, W.J., Zaki, S., Murphy, B., 2004. Prior infection and passive transfer of neutralizing antibody prevent replication of severe acute respiratory syndrome coronavirus (SARS-CoV) in the respiratory tract of mice. J. Virol. 78, 3572–3577). Ribavirin given at 75mg/kg 4h prior to virus exposure and then given twice daily for 3 days beginning at day 0 was found to increase virus lung titers and extend the length of time that virus could be detected in the lungs of mice. Other IMP dehydrogenase inhibitors administered near maximum tolerated doses using the same dosing regimen as for ribavirin were found to slightly enhance virus replication in the lungs. In addition, ribavirin treatment seemed also to promote the production of pro-inflammatory cytokines 4 days after cessation of treatment, although after 3 days of treatment ribavirin inhibited pro-inflammatory cytokine production in infected mice, significantly reducing the levels of the cytokines IL-1α, interleukin-5 (IL-5), monocyte chemotactic protein-1 (MCP-1), and granulocyte-macrophage colony stimulating factor (GM-CSF). These findings suggest that ribavirin may actually contribute to the pathogenesis of SARS-CoV by prolonging and/or enhancing viral replication in the lungs. By not inhibiting viral replication in the lungs of infected mice, ribavirin treatment may have provided a continual source of stimulation for the inflammatory response thought to contribute to the pathogenesis of the infection. Our data do not support the use of ribavirin or other IMP dehydrogenase inhibitors for treating SARS infections in humans.

positive: Recovery of COVID-19 acute respiratory distress syndrome with tocilizumab: successful outcome in two critically ill patients Background: Severe pneumonia and acute respiratory distress syndrome (ARDS) due to COVID-19 is a challenge for nowadays medical practice. Although there is no clarity in the principal mechanism of lung damage and ARDS development, it has been suggested that one of the main reasons of this pathology is the hyperactivation of the immune system, better known as cytokine storm syndrome. Tocilizumab has been proposed to treat COVID-19 severe cases associated to ARDS. Results & methodology: Here we present two successful cases of tocilizumab administration in two COVID-19 patients with prior administration of antiviral therapy (hydroxychloroquine, azithromycin, lopinavir and ritonavir) with adequate response and resolution of ARDS, septic shock and severe pneumonia within the first 72 h. Discussion & conclusion: This case supports the usage of tocilizumab as an effective therapy in COVID-19 associated cytokine storm syndrome. Further studies should be done in order to assess its effectiveness and security.

positive: [Exploration on scientific connotation of TCM syndromes and recommended prescriptions against COVID-19 based on TCMTP V2.0] Coronavirus disease 2019(COVID-19) has attracted great attentions from the whole world. Traditional Chinese medicine(TCM) has been widely used and shown satisfying efficacies in treating all stages of COVID-19. In this study, the molecular interaction networks of different stages of COVID-19(the early, severe, critical and recovery stage) were constructed using the links among symptoms-related genes collected from TCMIP V2.0(http://www.tcmip.cn/), an integrated pharmacology network-computing platform for TCM. Following the network topological feature calculation and functional enrichment analysis, we found that the molecular targets and pathways related with the "immune-inflammation system" were involved throughout all the stages of COVID-19. The severe stage and the critical period of COVID-19 were occupied by a large proportion of inflammatory factors and pathways, suggesting that there might be a cytokine storm in these periods, along with respiratory disorders, cardiopulmonary dysfunction, nervous system disorders, etc. Accordingly, the therapeutic targets and pathways hit by the recommended prescriptions against COVID-19 were also aimed to regulate the balance of immune-inflammation system, nutrient absorption and metabolism, abnormal energy metabolism, the cardio-pulmonary function, nerve system function, etc., which may be related to the therapeutic effects of these prescriptions in terms of several clinical symptoms, such as expiratory dyspnea, chest tightness and shortness of breath, abdominal distension and constipation, sweating and limb cold, dizziness, and irritability, etc. The above findings reflect the integrative actions of TCM characterizing by multiple-components, multiple-targets, multiple-pathways, and multiple-effects. This study systematically constructed the molecular networks of different TCM syndromes during the development and progression of COVID-19 and uncovered the biological basis for symptomatic treatment of TCM. Furthermore, our data revealed the pharmacological mechanisms and the scientific connotation of recommended prescriptions, which may provide supports for the prevention and treatment of COVID-19 using TCM.

positive: Successful recovery of severe COVID-19 with cytokine storm treating with extracorporeal blood purification COVID-19 associated cytokine storm could induce ARDS rapidly and the patients would require the support of mechanic ventilation. However, the prognosis was not that optimistic. The outcome might be changed if the intervention of EBP was performed timely. We present a case of severe SARS-CoV-2 infection who recovered from cytokine storm.

positive: Clinical Implications of SARS-Cov2 Interaction with Renin Angiotensin System Abstract SARS-CoV2 host cell infection is mediated by the binding to angiotensin-converting enzyme 2 (ACE2). Systemic dysregulation observed in SARS-CoV was previously postulated to be due to ACE2/Ang1-7/Mas axis downregulation, increased ACE2 activity was shown to mediate disease protection. Since angiotensin II receptor blockers (ARBs), ACE inhibitors, and mineralocorticoid receptor antagonists (MRAs) increase ACE2 receptor expression, it has been tacitly believed that the use of these agents may facilitate viral disease, thus they should not be used in high-risk patients with cardiovascular disease. Based on the anti-inflammatory benefits of the upregulation of the ACE2/Ang1-7/Mas axis and previously demonstrated benefits of lung function improvement in SARS-CoV infections, we hypothesize that the benefits of treatment with renin-angiotensin system inhibitors in SARS-COV2 may outweigh the risks and at the very least should not be withheld.

positive: The Definition and Risks of Cytokine Release Syndrome in 11 COVID-19-Affected Critically Ill Patients with Pneumonia: Analysis of Disease Characteristics Corona Virus Disease 2019(COVID-19)-affected patients with severe immune abnormalities have a risk of cytokine release syndrome. The definition, prevention, and treatment of symptoms of cytokine release syndrome in critically ill patients with COVID-19 are important problems. This was a single-center case series of 11 COVID-19 patients with acute respiratory distress syndrome (ARDS) from The First Affiliated Hospital of Guangzhou Medical University in China from January 26, 2020 to February 18, 2020. The termination date of follow-up was February 19, 2020. In this single-center analysis of 11 critically ill patients with COVID-19, 8 patients were determined to have characteristics of cytokine release syndrome (CRS), including pulmonary inflammation, fever, and dysfunction of non-pulmonary organs; an increase of- Interleukin-6 (IL-6) in peripheral blood was the highest risk factor and an early indicator of CRS in COVID-19.

positive: Could Autism Spectrum Disorders be a Risk Factor for COVID-19? The coronavirus SARS-CoV-2 pandemia is infecting millions of people and some studies relate conditions that might increase the risk of developing a fatal course for the disease, such as diabetes, cardiovascular diseases and obesity. In COVID-19 physiopathology, one of the main inflammation mechanisms is the “cytokine storm”, causing a pro-inflammatory state, related to cardiac and pulmonary damage. There is also a less effective role of lymphocyte B and T in the humoral immunity due to the reduction of their proliferative response. The physiopathology of ASD (Autism Spectrum Disorder) involves several modifications at the genetic and at the immune level, such as the increase of inflammatory cytokines and abnormal immune response in several levels. We hypothesize that ASD could be a risk-factor as the other conditions are.

positive: Molecular mechanism of SARS-CoV-2 components caused ARDS in murine model COVID-19 has become a major challenge to global health, and until now, no efficient antiviral agents have been developed. The SARS-CoV-2 infection is characterized by pulmonary and systemic inflammation in severe patients, and acute respiratory distress syndrome (ARDS) caused respiratory failure contributes to most mortalities. There is an urgent need for developing effective drugs and vaccines against SARS-CoV-2 and COVID-19 caused ARDS. However, most researchers cannot perform SARS-CoV-2 related researches due to lacking P3 or P4 facility. We developed a non-infectious, highly safety, time-saving SARS-CoV-2 components induced murine model to study the SARS-CoV-2 caused ARDS and cytokine storm syndrome (CSS). We also investigated mAbs and inhibitors which potentially neutralize the pro-inflammatory phenotype of COVID-19, and found that anti-IL-1α, anti-IL-6, anti-TNFα, anti-GM-CSF mAbs, p38 inhibitor, and JAK inhibitor partially relieved CSS. Besides, anti-IL-6, anti-TNFα, anti-GM-CSF mAbs and inhibitors of p38, ERK, and MPO somewhat reduced neutrophilic alveolitis in the lung. In all, we established the murine model mimic of COVID-19, opening a biosafety and less time-consuming avenue for clarifying the mechanism of ARDS and CSS in COVID-19 and developing the therapeutic drugs.

positive: In the big picture of COVID-19 pandemic: what can sleep do

positive: Possible Cause of Inflammatory Storm and Septic Shock in Patients Diagnosed with (COVID-19) The novel coronavirus (SARS-CoV-2) infection which has been known as Coronavirus diseases 2019 COVID-19 has become an endemic emergent situation by the World Health Organization. So far, no successful specific treatment has been found for this disease. As has been reported, most of non-survivor patients with COVID-19 (70%) had septic shock which was significantly higher than survived ones. Although the exact pathophysiology of septic shock in these patients is still unclear, it seems to be possible that part of it would be due to the administration of empiric antibiotics with inflammatory properties especially in the absence of bacterial infection. Herein, we have reviewed possible molecular pathways of septic shock in the patients who have received antibiotics with inflammatory properties which mainly is release of interleukin 1ß (IL-1ß), IL-6, and tumor necrosis factor α (TNF- α) through different routes. Altogether, we highly recommend clinicians to look after those antibiotics with anti-inflammatory activity for both empiric antibiotic therapy and reducing the inflammation to prevent septic shock in patients with diagnosed COVID-19.

positive: Is Immuno-modulation the Key to COVID-19 Pandemic?

positive: Mechanism of inflammatory response in associated comorbidities in COVID-19 BACKGROUND AND AIMS: The outbreak of the new coronavirus, SARS-CoV-2, causes a respiratory disease and individuals with pre-existing cardiometabolic disorders display worse prognosis through the infection course. The aim of this minireview is to present epidemiological data related to metabolic comorbidities in association with the SARS-CoV-2. METHODS: This is a narrative mini-review with Pubmed search until April 23, 2020 using the keywords COVID-19, SARS-CoV-2, treatment of coronavirus and following terms: diabetes mellitus, obesity, arterial hypertension, ACE-inhibitors, cytokine storm, immune response and vitamin D. RESULTS: Studies indicate that obese individuals are more likely to develop infections, and that adipose tissue serves as a pathogen reservoir. In diabetic individuals higher rate of inflammatory processes is seen due to constant glucose recognition by C type lectin receptors. Hypertensive individuals, usually grouped with other conditions, are treated with drugs to reduce blood pressure mostly through ACEi and ARB, that leads to increased ACE2 expression, used by SARS-CoV-2 for human's cell entry. Until now, the studies have shown that individuals with those conditions and affected by COVID-19 present an uncontrolled release of pro-inflammatory cytokines and an unbalanced immune response, leading to the cytokine storm phenomenon. Vitamin D is highlighted as a potential therapeutic target, because in addition to acting on the immune system, it plays an important role in the control of cardiometabolic diseases. CONCLUSION: Currently, since there is no proven and effective antiviral therapy for SARS-CoV-2, the efforts should focus on controlling inflammatory response and reduce the risks of associated complications.

positive: Fighting the Host Reaction to SARS-COv-2 in Critically Ill Patients: The Possible Contribution of Off-Label Drugs The severe acute respiratory syndrome coronavirus 2 (SARS-COv-2) is the etiologic agent of the 2019 coronavirus disease (COVID19). The majority of infected people presents flu like symptoms and among them 15–20% develops a severe interstitial pneumonitis (IP) that may eventually evolve in acute respiratory distress syndrome (ARDS). IP is caused by the viral glycoprotein spike (S) binding to the angiotensin converting enzyme 2 (ACE2) expressed on the surface of alveolar pneumocytes. The virus is recognized by the “pattern recognition receptors” (PRR) of the immune cells that release cytokines activating more immune cells that produce a large number of pro-inflammatory cytokines, tissue factors and vasoactive peptides. Affected patients might develop the “cytokine storm syndrome,” a fulminant and fatal hypercytokinaemia with multiorgan failure. In patients infected by SARS-COv-2 increase in T-helper 2 (TH2) cytokines (IL-4 and IL10) are reported in addition to the T-helper 1 (TH1) cytokines (IL1B, IFNγ, IP10, and MCP1) previously detected in other coronavirus infections. Cytokines and other molecules involved in immune response and inflammation are conceivable therapeutic targets for IP and ARDS, improving symptoms and decreasing intensive care unit admissions. To this aim off label drugs may be used taking into consideration the window timing for immunosuppressive drugs in virus infected patients. Some off label therapeutic options and preclinical evidence drugs are herein considered.

positive: SARS-CoV-2–A Tough Opponent for the Immune System Coronaviruses recently returned with a new one, SARS-CoV-2, related to a potentially severe respiratory disease-called the coronavirus disease (COVID-19). Research shows that the SARS-CoV-2 can be clustered with the Bat SARS-like coronavirus. Bats possess an additional, innate ability for antiviral defense, and, on the other hand, the potential to go hand-in-hand with the virus to generate variability. Besides the high potential of the novel coronavirus in compromising the respiratory system, its rapid transmission and ability to engage many hosts in severe forms of infections or immunopathological complications make it a tough opponent for the immune system. The interactions between SARS-CoV2 and the host immune system result in unleashing tremendous amounts of cytokines, and these cytokines make a storm that would determine the outcome (recovery or death) of the lungs of the patient.

positive: Could autism spectrum disorders be a risk factor for COVID-19? The coronavirus SARS-CoV-2 pandemia is infecting millions of people and some studies relate conditions that might increase the risk of developing a fatal course for the disease, such as diabetes, cardiovascular diseases and obesity. In COVID-19 physiopathology, one of the main inflammation mechanisms is the "cytokine storm", causing a pro-inflammatory state, related to cardiac and pulmonary damage. There is also a less effective role of lymphocyte B and T in the humoral immunity due to the reduction of their proliferative response. The physiopathology of ASD (Autism Spectrum Disorder) involves several modifications at the genetic and at the immune level, such as the increase of inflammatory cytokines and abnormal immune response in several levels. We hypothesize that ASD could be a risk-factor as the other conditions are.

positive: The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of “inflame-aging” PURPOSE: Novel Coronavirus disease 2019 (COVID-19), is an acute respiratory distress syndrome (ARDS), which is emerged in Wuhan, and recently become worldwide pandemic. Strangely, ample evidences have been shown that the severity of COVID-19 infections varies widely from children (asymptomatic), adults (mild infection), as well as elderly adults (deadly critical). It has proven that COVID-19 infection in some elderly critical adults leads to a cytokine storm, which is characterized by severe systemic elevation of several pro-inflammatory cytokines. Then, a cytokine storm can induce edematous, ARDS, pneumonia, as well as multiple organ failure in aged patients. It is far from clear till now why cytokine storm induces in only COVID-19 elderly patients, and not in young patients. However, it seems that aging is associated with mild elevated levels of local and systemic pro-inflammatory cytokines, which is characterized by “inflamm-aging”. It is highly likely that “inflamm-aging” is correlated to increased risk of a cytokine storm in some critical elderly patients with COVID-19 infection. METHODS: A systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, as well as Google Scholar pre-print database using all available MeSH terms for COVID-19, Coronavirus, SARS-CoV-2, senescent cell, cytokine storm, inflame-aging, ACE2 receptor, autophagy, and Vitamin D. Electronic database searches combined and duplicates were removed. RESULTS: The aim of the present review was to summarize experimental data and clinical observations that linked the pathophysiology mechanisms of “inflamm-aging”, mild-grade inflammation, and cytokine storm in some elderly adults with severe COVID-19 infection.

positive: COVID-19: risk for cytokine targeting in chronic inflammatory diseases?

positive: Can Hypericum perforatum (SJW) prevent cytokine storm in COVID-19 patients?

positive: Hypercytokinemia and Pathogen–Host Interaction in COVID-19 Severe acute respiratory syndrome (SARS) coronavirus (CoV)-2 (SARS-CoV-2) is a novel coronavirus identified as the cause of coronavirus disease-2019 (COVID-19) that began in Wuhan, China in late 2019 and spread now in 210 countries and territories around the world. Many people are asymptomatic or with mild symptoms. However, in some cases (usually the elderly and those with comorbidities) the disease may progress to pneumonia, acute respiratory distress syndrome and multi-organ dysfunction that can lead to death. Such wide interindividual differences in response to SARS-CoV-2 infection may relate to several pathogen- and host-related factors. These include the different levels of the ubiquitously present human angiotensin I converting enzyme 2 (ACE2) receptors gene expression and its variant alleles, the different binding affinities of ACE2 to the virus spike (S) protein given its L- and S-subtypes and the subsequent extent of innate immunity-related hypercytokinemia. The extensive synthesis of cytokines and chemokines in coronavirus diseases was suggested as a major factor in exacerbating lung damage and other fatal complications. The polymorphisms in genes coding for pro-inflammatory cytokines and chemokines have been associated with mediating the response and susceptibility to a wide range of infections and their severe outcomes. Understanding the nature of pathogen–host interaction in COVID-19 symptomatology together with the role of hypercytokinemia in disease severity may permit developing new avenues of approach for prevention and treatment and can delineate public health measures to control the spread of the disease.

positive: An Update on Current Therapeutic Drugs Treating COVID-19 The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has presented unprecedented challenges to the healthcare systems in almost every country around the world. Currently, there are no proven effective vaccines or therapeutic agents against the virus. Current clinical management includes infection prevention and control measures and supportive care including supplemental oxygen and mechanical ventilatory support. Evolving research and clinical data regarding the virologic SARS-CoV-2 suggest a potential list of repurposed drugs with appropriate pharmacological effects and therapeutic efficacies in treating COVID-19 patients. In this review, we will update and summarize the most common and plausible drugs for the treatment of COVID-19 patients. These drugs and therapeutic agents include antiviral agents (remdesivir, hydroxychloroquine, chloroquine, lopinavir, umifenovir, favipiravir, and oseltamivir), and supporting agents (Ascorbic acid, Azithromycin, Corticosteroids, Nitric oxide, IL-6 antagonists), among others. We hope that this review will provide useful and most updated therapeutic drugs to prevent, control, and treat COVID-19 patients until the approval of vaccines and specific drugs targeting SARS-CoV-2.

positive: The case for Chronotherapy in COVID‐19 induced Acute Respiratory Distress Syndrome (ARDS). COVID‐19, the disease resulting from infection by a novel coronavirus: SARS‐Cov2 that has rapidly spread since November 2019 leading to a global pandemic. SARS‐Cov2 has infected over 4 million people and caused over 290,000 deaths worldwide. Although most cases are mild, a subset of patients develop a severe and atypical presentation of Acute Respiratory Distress Syndrome (ARDS) that is characterised by a cytokine release storm (CRS). Paradoxically, treatment with anti‐inflammatory agents and immune regulators has been associated with worsening of ARDS. We hypothesize that the intrinsic circadian clock of the lung and the immune system may regulate individual components of CRS and thus chronotherapy may be used to effectively manage ARDS in COVID‐19 patients.

positive: Dipeptidyl peptidase-4 (DPP4) inhibition in COVID-19 AIMS: SARS-CoV-2 causes severe respiratory syndrome (COVID-19) with high mortality due to a direct cytotoxic viral effect and a severe systemic inflammation. We are herein discussing a possible novel therapeutic tool for COVID-19. METHODS: Virus binds to the cell surface receptor ACE2; indeed, recent evidences suggested that SARS-CoV-2 may be using as co-receptor, when entering the cells, the same one used by MERS-Co-V, namely the DPP4/CD26 receptor. The aforementioned observation underlined that mechanism of cell entry is supposedly similar among different coronavirus, that the co-expression of ACE2 and DPP4/CD26 could identify those cells targeted by different human coronaviruses and that clinical complications may be similar. RESULTS: The DPP4 family/system was implicated in various physiological processes and diseases of the immune system, and DPP4/CD26 is variously expressed on epithelia and endothelia of the systemic vasculature, lung, kidney, small intestine and heart. In particular, DPP4 distribution in the human respiratory tract may facilitate the entrance of the virus into the airway tract itself and could contribute to the development of cytokine storm and immunopathology in causing fatal COVID-19 pneumonia. CONCLUSIONS: The use of DPP4 inhibitors, such as gliptins, in patients with COVID-19 with, or even without, type 2 diabetes, may offer a simple way to reduce the virus entry and replication into the airways and to hamper the sustained cytokine storm and inflammation within the lung in patients diagnosed with COVID-19 infection.

positive: Coronavirus Disease 2019 and Stroke: Clinical Manifestations and Pathophysiological Insights Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global health threat. Some COVID-19 patients have exhibited widespread neurological manifestations including stroke. Acute ischemic stroke, intracerebral hemorrhage, and cerebral venous sinus thrombosis have been reported in patients with COVID-19. COVID-19-associated coagulopathy is increasingly recognized as a result of acute infection and is likely caused by inflammation, including inflammatory cytokine storm. Recent studies suggest axonal transport of SARS-CoV-2 to the brain can occur via the cribriform plate adjacent to the olfactory bulb that may lead to symptomatic anosmia. The internalization of SARS-CoV-2 is mediated by the binding of the spike glycoprotein of the virus to the angiotensin-converting enzyme 2 (ACE2) on cellular membranes. ACE2 is expressed in several tissues including lung alveolar cells, gastrointestinal tissue, and brain. The aim of this review is to provide insights into the pathophysiological stroke mechanisms in COVID-19 patients. SARS-CoV-2 can down-regulate ACE2 and, in turn, over-activate the classical renin-angiotensin system (RAS) axis and decrease the activation of the alternative RAS pathway in the brain. The consequent imbalance in vasodilation, neuroinflammation, oxidative stress, and thrombotic response may contribute to the pathophysiology of stroke during SARS-CoV-2 infection.

positive: COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs In the Wuhan Province of China, in December 2019, the novel coronavirus 2019 (COVID-19) has caused a severe involvement of the lower respiratory tract leading to an acute respiratory syndrome. Subsequently, coronavirus 2 (SARS-CoV-2) provoked a pandemic which is considered a life-threatening disease. The SARS-CoV-2, a family member of betacoronaviruses, possesses single-stranded positive-sense RNA with typical structural proteins, involving the envelope, membrane, nucleocapsid and spike proteins that are responsible for the viral infectivity, and nonstructural proteins. The effectual host immune response including innate and adaptive immunity against SARS-Cov-2 seems crucial to control and resolve the viral infection. However, the severity and outcome of the COVID-19 might be associated with the excessive production of proinflammatory cytokines “cytokine storm” leading to an acute respiratory distress syndrome. Regretfully, the exact pathophysiology and treatment, especially for the severe COVID-19, is still uncertain. The results of preliminary studies have shown that immune-modulatory or immune-suppressive treatments such as hydroxychloroquine, interleukin (IL)-6 and IL-1 antagonists, commonly used in rheumatology, might be considered as treatment choices for COVID-19, particularly in severe disease. In this review, to gain better information about appropriate anti-inflammatory treatments, mostly used in rheumatology for COVID-19, we have focused the attention on the structural features of SARS-CoV-2, the host immune response against SARS-CoV-2 and its association with the cytokine storm.

positive: Adjunct Immunotherapies for the Management of Severely Ill COVID-19 Patients Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has infected millions, with more than 275,000 fatal cases as of May 8, 2020. Currently, there are no specific COVID-19 therapies. Most patients depend on mechanical ventilation. Current COVID-19 data clearly highlight that cytokine storm and activated immune cell migration to the lungs characterize the early immune response to COVID-19 that causes severe lung damage and development of acute respiratory distress syndrome. In view of uncertainty associated with immunosuppressive treatments, such as corticosteroids and their possible secondary effects, including risks of secondary infections, we suggest immunotherapies as an adjunct therapy in severe COVID-19 cases. Such immunotherapies based on inflammatory cytokine neutralization, immunomodulation, and passive viral neutralization not only reduce inflammation, inflammation-associated lung damage, or viral load but could also prevent intensive care unit hospitalization and dependency on mechanical ventilation, both of which are limited resources.

positive: [Exploration on scientific connotation of TCM syndromes and recommended prescriptions against COVID-19 based on TCMTP V2.0]. Coronavirus disease 2019(COVID-19) has attracted great attentions from the whole world. Traditional Chinese medicine(TCM) has been widely used and shown satisfying efficacies in treating all stages of COVID-19. In this study, the molecular interaction networks of different stages of COVID-19(the early, severe, critical and recovery stage) were constructed using the links among symptoms-related genes collected from TCMIP V2.0(http://www.tcmip.cn/), an integrated pharmacology network-computing platform for TCM. Following the network topological feature calculation and functional enrichment analysis, we found that the molecular targets and pathways related with the "immune-inflammation system" were involved throughout all the stages of COVID-19. The severe stage and the critical period of COVID-19 were occupied by a large proportion of inflammatory factors and pathways, suggesting that there might be a cytokine storm in these periods, along with respiratory disorders, cardiopulmonary dysfunction, nervous system disorders, etc. Accordingly, the therapeutic targets and pathways hit by the recommended prescriptions against COVID-19 were also aimed to regulate the balance of immune-inflammation system, nutrient absorption and metabolism, abnormal energy metabolism, the cardio-pulmonary function, nerve system function, etc., which may be related to the therapeutic effects of these prescriptions in terms of several clinical symptoms, such as expiratory dyspnea, chest tightness and shortness of breath, abdominal distension and constipation, sweating and limb cold, dizziness, and irritability, etc. The above findings reflect the integrative actions of TCM characterizing by multiple-components, multiple-targets, multiple-pathways, and multiple-effects. This study systematically constructed the molecular networks of different TCM syndromes during the development and progression of COVID-19 and uncovered the biological basis for symptomatic treatment of TCM. Furthermore, our data revealed the pharmacological mechanisms and the scientific connotation of recommended prescriptions, which may provide supports for the prevention and treatment of COVID-19 using TCM.

positive: β-Glucan extracts from the same edible shiitake mushroom Lentinus edodes produce differential in-vitro immunomodulatory and pulmonary cytoprotective effects — Implications for coronavirus disease (COVID-19) immunotherapies Abstract Coronavirus pneumonia is accompanied by rapid virus replication, where a large number of inflammatory cell infiltration and cytokine storm may lead to acute lung injury, acute respiratory distress syndrome (ARDS) and death. The uncontrolled release of pro-inflammatory cytokines, including interleukin (IL)-1β and IL-6, is associated with ARDS. This constituted the first study to report on the variability in physicochemical properties of β-glucans extracts from the same edible mushroom Lentinus edodes on reduction of these pro-inflammatory cytokines and oxidative stress. Specifically, the impact on the immunomodulatory and cytoprotective properties of our novel ‘in house’ (IH-Lentinan, IHL) and a commercial (Carbosynth-Lentinan, CL) Lentinan extract were investigated using in vitro models of lung injury and macrophage phagocytosis. CL comprised higher amounts of α-glucans and correspondingly less β-glucans. The two lentinan extracts demonstrated varying immunomodulatory activities. Both Lentinan extracts reduced cytokine induced NF-κB activation in human alveolar epithelial A549 cells, with the IHL extract proving more effective at lower doses. In contract, in activated THP-1 derived macrophages, the CL extract more effectively attenuated pro-inflammatory cytokine production (TNF-α, IL-8, IL-2, IL-6, IL-22) as well as TGF-β and IL-10. The CL extract attenuated oxidative stress induced early apoptosis, while the IHL extract attenuated late apoptosis. Our findings demonstrate significant physicochemical differences between Lentinan extracts, which produce differential in vitro immunomodulatory and pulmonary cytoprotective effects that may also have positive relevance to candidate COVID-19 therapeutics targeting cytokine storm.

positive: Platelet‐to‐lymphocyte ratio is associated with prognosis in patients with coronavirus disease‐19 Since December 2019, novel coronavirus infected pneumonia emerged in Wuhan city and rapidly spread throughout China. In severe novel coronavirus pneumonia cases, the number of platelets, their dynamic changes during the treatment, platelet‐to‐lymphocyte ratio (PLR) were a concern. We sought to describe the platelet feature of these cases. Single‐center case series of the 30 hospitalized patients with confirmed coronavirus disease (COVID)‐19 in Huizhou municipal central hospital from January 2020 to February 2020 were retrospectively analyzed. Demographic, clinical, blood routine results, other laboratory results, and treatment data were collected and analyzed. Outcomes of severe patients and nonsevere patients were compared. Univariate analysis showed that: age, platelet peaks, and PLR at peak platelet were the influencing factors in severe patients, multivariate analysis showed that the PLR value at peak platelet during treatment was an independent influencing factor in severe patients. The average hospitalization day of patients with platelet peaks during treatment was longer than those without platelet peaks (P < .05). The average age of patients with platelet peaks during treatment was older than those without platelet peaks (P < .05). The patients with significantly elevated platelets during treatment had longer average hospitalization days. And the higher PLR of patients during treatment had longer average hospitalization days. Single‐center case series of the 30 hospitalized patients with confirmed COVID‐19 in Huizhou Municipal Central Hospital, presumed that the number of platelets and their dynamic changes during the treatment may have a suggestion on the severity and prognosis of the disease. The patient with markedly elevated platelets and longer average hospitalization days may be related to the cytokine storm. The PLR of patients means the degree of cytokine storm, which might provide a new indicator in the monitoring in patients with COVID‐19.

positive: Chronic conventional disease-modifying anti-rheumatic drugs masking severe SARS-CoV-2 manifestations in an elderly rheumatic patient

positive: [Novel coronavirus infection (COVID-19) and cytokine storms - treatment options based on inflammatory processes]

positive: Curcumin suppression of cytokine release and cytokine storm. A potential therapy for patients with Ebola and other severe viral infections. BACKGROUND The terminal stage of Ebola and other viral diseases is often the onset of a cytokine storm, the massive overproduction of cytokines by the body's immune system. MATERIALS AND METHODS The actions of curcumin in suppressing cytokine release and cytokine storm are discussed. RESULTS Curcumin blocks cytokine release, most importantly the key pro-inflammatory cytokines, interleukin-1, interleukin-6 and tumor necrosis factor-α. The suppression of cytokine release by curcumin correlates with clinical improvement in experimental models of disease conditions where a cytokine storm plays a significant role in mortality. CONCLUSION The use of curcumin should be investigated in patients with Ebola and cytokine storm. Intravenous formulations may allow achievement of therapeutic blood levels of curcumin.

positive: Comparative Survival Analysis of Immunomodulatory Therapy for COVID-19 'Cytokine Storm': A Retrospective Observational Cohort Study Background: Cytokine storm is a marker of COVID-19 illness severity and increased mortality. Immunomodulatory treatments have been repurposed to improve mortality outcomes. Methods: We conducted a retrospective analysis of electronic health records across the Northwell Health system. COVID-19 patients hospitalized between March 1, 2020 and April 15, 2020, were included. Cytokine storm was defined by inflammatory markers: ferritin >700ng/mL, C-reactive protein >30mg/dL, or lactate dehydrogenase >300U/L. Patients were subdivided into six groups -no immunomodulatory treatment (standard of care) and five groups that received either corticosteroids, anti-interleukin 6 (IL-6) antibody (tocilizumab) or anti-IL-1 therapy (anakinra) alone or in combination with corticosteroids. The primary outcome was hospital mortality. Results: There were 3,098 patients who met inclusion criteria. The most common comorbidities were hypertension (40-56%), diabetes (32-43%) and cardiovascular disease (2-15%). Patients most frequently met criteria with high lactate dehydrogenase (74.8%) alone, or in combination, followed by ferritin (71.4%) and C-reactive protein (9.4%). More than 80% of patients had an elevated D-dimer. Patients treated with a combination of tocilizumab and corticosteroids (Hazard Ratio [HR]: 0.459, 95% Confidence Interval [CI]: 0.295-0.714; p<0.0001) or corticosteroids alone (HR: 0.696, 95% CI: 0.512-0.946; p=0.01) had improved hospital survival compared to standard of care. Corticosteroids and tocilizumab was associated with increased survival when compared to corticosteroids and anakinra (HR: 0.612, 95% CI: 0.391-0.958; p-value=0.02). Conclusions: When compared to standard of care, corticosteroid and tocilizumab used in combination, or corticosteroids alone, was associated with reduced hospital mortality for patients with COVID-19 cytokine storm.

positive: An update on SARS-CoV-2/COVID-19 with particular reference to its clinical pathology, pathogenesis, immunopathology and mitigation strategies Coronavirus Disease 2019 (COVID-19), emerged in early December 2019 in China and became a pandemic situation worldwide by its rapid spread to nearly 190 countries. Bats are considered as the reservoir host, and the search of a probable intermediate host is still going on. The severe form of the infection is associated with death is mainly reported in older and immune-compromised patients with pre-existing disease history. Death in severe cases is attributed to respiratory failure associated with hyperinflammation. Cytokine storm syndrome associated with inflammation in response to SARS-CoV-2 infection is considered as the leading cause of mortality in COVID-19 patients. COVID-19 patients have thus higher levels of many proinflammatory cytokines and chemokines. The blood lab profile of the COVID-19 patients exhibits lymphopenia, leukopenia, thrombocytopenia, and RNAaemia, along with increased levels of aspartate aminotransferase. SARS-CoV-2 infection in pregnant women does not lead to fetus mortality, unlike other zoonotic coronaviruses such as SARS-CoV and MERS-CoV, and there is, to date, no evidence of intrauterine transmission to neonates. Rapid diagnostics have been developed, and significant efforts are being made to develop effective vaccines and therapeutics. In the absence of any virus-specific therapy, internationally, health care authorities are recommending the adoption of effective community mitigation measures to counter and contain this pandemic virus. This paper is an overview of this virus and the disease with a particular focus on SARS-CoV-2/COVID-19 clinical pathology, pathogenesis, and immunopathology, along with recent research developments.

positive: The vascular endothelium: the cornerstone of organ dysfunction in severe SARS-CoV-2 infection In severe SARS-CoV-2 infections, emerging data including recent histopathological studies have emphasized the crucial role of endothelial cells (ECs) in vascular dysfunction, immunothrombosis, and inflammation. Histopathological studies have evidenced direct viral infection of ECs, endotheliitis with diffuse endothelial inflammation, and micro- and macrovascular thrombosis both in the venous and arterial circulations. Venous thrombotic events, particularly pulmonary embolism, with elevated D-dimer and coagulation activation are highly prevalent in COVID-19 patients. The pro-inflammatory cytokine storm, with elevated levels of interleukin-6 (IL-6), IL-2 receptor, and tumor necrosis factor-α, could also participate in endothelial dysfunction and leukocyte recruitment in the microvasculature. COVID-19-induced endotheliitis may explain the systemic impaired microcirculatory function in different organs in COVID-19 patients. Ongoing trials directly and indirectly target COVID-19-related endothelial dysfunctions: i.e., a virus-cell entry using recombinant angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS-2) blockade, coagulation activation, and immunomodulatory therapies, such as anti-IL-6 strategies. Studies focusing on endothelial dysfunction in COVID-19 patients are warranted as to decipher their precise role in severe SARS-CoV-2 infection and organ dysfunction and to identify targets for further interventions.

positive: Immunotherapies for COVID-19: lessons learned from sepsis

positive: A pilot study on primary cultures of human respiratory tract epithelial cells to predict patients’ responses to H7N9 infection Avian influenza A(H7N9) virus infections frequently lead to acute respiratory distress syndrome and death in humans. We aimed to investigate whether primary cultures of human respiratory tract epithelial cells are helpful to understand H7N9 virus pathogenesis and tissue tropism, and to evaluate how patient-related characteristics can affect the host's response to infection. Normal human bronchial epithelial cells (isolated from two different donors) and primary epithelial cells (harvested from 27 patients undergoing airway surgery) were experimentally infected with H7N9 and/or H1N1pdm for 72 h. After virus infection, the culture media were collected for viral RNA quantitation and cytokine detection. Both H7N9 and H1N1pdm viruses replicated and induced a cytokine response differently for each donor in the normal human bronchial epithelial model. H7N9 replicated equivalently in epithelial cells harvested from the inferior turbinate and paranasal sinus, and those from the larynx and bronchus, at 72 h post-infection. Viral RNA quantity at 72 h was significantly higher in patients aged 21–64 years than in patients aged ≥ 65 years; however, no effects of sex, medical comorbidities, and obesity were noted. H7N9-infected cultured cells released multiple cytokines within 72 h. Levels of interleukin-1β, interleukin-6, interleukin-8, interferon-γ, and tumor necrosis factor-α were associated differently with patient-related characteristics (such as age, sex, obesity, and medical comorbidities). In the era of precision medicine, these findings illustrate the potential utility of this primary culture approach to predict a host's response to H7N9 infection or to future infection by newly emerging viral infections, and to dissect viral pathogenesis.

positive: Consider TLR5 for new therapeutic development against COVID‐19 TLR5, a member of Toll-like receptors (TLRs), has a significant role to recognize the flagellin or same kind of molecule. After reorganization, it can modulate innate immune responses. In this article, we urge for the development of new therapeutic molecule by targeting TLR5 modulation against SARS-CoV-2. This article is protected by copyright. All rights reserved.

positive: Endothelial progenitor cells and mesenchymal stem cells to overcome vascular deterioration and cytokine storm in critical patients with COVID-19

positive: COVID-19 cytokine storm: The anger of inflammation Patients with COVID-19 who require ICU admission might have the cytokine storm. It is a state of out-of-control release of a variety of inflammatory cytokines. The molecular mechanism of the cytokine storm has not been explored extensively yet. The attachment of SARS-CoV-2 spike glycoprotein with angiotensin-converting enzyme 2 (ACE2), as its cellular receptor, triggers complex molecular events that leads to hyperinflammation. Four molecular axes that may be involved in SARS-CoV-2 driven inflammatory cytokine overproduction are addressed in this work. The virus-mediated down-regulation of ACE2 causes a burst of inflammatory cytokine release through dysregulation of the renin-angiotensin-aldosterone system (ACE/angiotensin II/AT1R axis), attenuation of Mas receptor (ACE2/MasR axis), increased activation of [des-Arg9]-bradykinin (ACE2/bradykinin B1R/DABK axis), and activation of the complement system including C5a and C5b-9 components. The molecular clarification of these axes will elucidate an array of therapeutic strategies to confront the cytokine storm in order to prevent and treat COVID-19 associated acute respiratory distress syndrome.

positive: Steroid-responsive severe encephalopathy in SARS-CoV-2 infection SARS-CoV-2 infection has the potential for targeting central nervous system and several neurological symptoms have been described in patients with severe respiratory distress. Here we described the case of an otherwise healthy 60-year old subject with SARS-CoV-2 infection but only mild respiratory abnormalities who developed severe progressive encephalopathy associated with mild pleocytosis and hyperproteinorrachia. MRI was negative whereas EEG showed theta waves on the anterior brain regions. Serum and CSF analyses excluded other known infectious or autoimmune disorders. The patient dramatically improved after high-doses steroid treatment suggesting an inflammatory-mediated brain involvement related to SARS-CoV-2 infection

positive: Insights into the Use of C-Reactive Protein as a Diagnostic Index of Disease Severity in COVID-19 Infections Approximately 20% of patients infected with SARS-CoV-2 (COVID-19) develop potentially life-threatening pathologies involving hyperinflammation, cytokine storm, septic shock complications, coagulation dysfunction, and multiple organ failure. Blood levels of the prototypic acute phase reactant, C-reactive protein (CRP), which is hepatically synthesized and released in response to interleukin-6 stimulation, is markedly elevated in patients with COVID-19. Markedly high CRP levels correlate with poor prognosis for survival. Insights into CRP structure-function relationships have uncovered both pro- and anti-inflammatory isoforms that may be used to monitor the extent of tissue damage associated with COVID-19 pathologies and prognoses. Herein, rationale is given for interpretation of CRP blood levels as a simple, rapid, and cost-effective way to assess disease severity and help guide therapeutic options in COVID-19 patients.

positive: The ACE2‐deficient mouse: A model for a cytokine storm‐driven inflammation Angiotensin converting enzyme 2 (ACE2) plays an important role in inflammation, which is attributable at least, in part, to the conversion of the pro‐inflammatory angiotensin (Ang) II peptide into angiotensin 1‐7 (Ang 1‐7), a peptide which opposes the actions of AngII. ACE2 and AngII are present in many tissues but information on the cornea is lacking. We observed that mice deficient in the Ace2 gene (Ace2(−/−)), developed a cloudy cornea phenotype as they aged. Haze occupied the central cornea, accompanied by corneal edema and neovascularization. In severe cases with marked chronic inflammation, a cell‐fate switch from a transparent corneal epithelium to a keratinized, stratified squamous, psoriasiform‐like epidermis was observed. The stroma contained a large number of CD11c, CD68, and CD3 positive cells. Corneal epithelial debridement experiments in young ACE2‐deficient mice showed normal appearing corneas, devoid of haze. We hypothesized, however, that these mice are “primed” for a corneal inflammatory response, which once initiated, would persist. In vitro studies reveal that interleukins (IL‐1a, IL‐1b), chemokines (CCL2, CXCL8), and TNF‐α, are all significantly elevated, resulting in a cytokine storm‐like phenotype. This phenotype could be partially rescued by treatment with the AngII type 1 receptor (AT1R) antagonist, losartan, suggesting that the observed effect was mediated by AngII acting on its main receptor. Since the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) utilizes human ACE2 as the receptor for entry with subsequent downregulation of ACE2, corneal inflammation in Ace2(−/−) mice may have a similar mechanism with that in COVID‐19 patients. Thus the Ace2(−/−) cornea, because of easy accessibility, may provide an attractive model to explore the molecular mechanisms, immunological changes, and treatment modalities in patients with COVID‐19.

positive: Weathering the Cytokine Storm in Susceptible Patients with Severe SARS-CoV-2 Infection

positive: Cytokine storm intervention in the early stages of COVID-19 pneumonia Clinical intervention in patients with corona virus disease 2019 (COVID-19) has demonstrated a strong upregulation of cytokine production in patients who are critically ill with SARS-CoV2-induced pneumonia. In a retrospective study of 41 patients with COVID-19, most patients with SARS-CoV-2 infection developed mild symptoms, whereas some patients later developed aggravated disease symptoms, and eventually passed away because of multiple organ dysfunction syndrome (MODS), as a consequence of a severe cytokine storm. Guidelines for the diagnosis and treatment of SARS-CoV-2 infected pneumonia were first published January 30th, 2020; these guidelines recommended for the first time that cytokine monitoring should be applied in severely ill patients to reduce pneumonia related mortality. The cytokine storm observed in COVID-19 illness is also an important component of mortality in other viral diseases, including SARS, MERS and influenza. In view of the severe morbidity and mortality of COVID-19 pneumonia, we review the current understanding of treatment of human coronavirus infections from the perspective of a dysregulated cytokine and immune response.

positive: Immune Cell Profiling of COVID-19 Patients in the Recovery Stage by Single-Cell Sequencing COVID-19 caused by SARS-CoV-2 has recently affected over 200,000 people and killed more than 8000. Immune system dysregulation such as lymphopenia and inflammatory cytokine storm has been observed in COVID-19 patients, but it remains unclear for the change of key immune cell subsets and their states during COVID-19. Here, we applied single-cell technology to comprehensively characterize transcriptional changes of peripheral blood mononuclear cells in ten patients recovered from COVID-19. Compared with healthy control, COVID-19 induced a unique signature of immune cells in humans, especially in the early recovery stage (ERS). In ERS patients, T cells were decreased remarkably, while monocytes were increased. A detailed analysis of monocytes showed that there was an increased ratio of classical CD14++ monocytes with highly inflammatory genes expression, as well as a greater abundance of CD14++IL1B+ monocytes. For nature killer (NK) cells and T cells, CD4+ T cells were significantly decreased and expressed high level of inflammatory markers, while NK cells were increased. In addition, T cells were highly expanded clone, especially in CD4+ T memory cells and CD8+ T cells. Among B cells, plasma cells were increased remarkably, and naïve B cells were reduced. Our study also identified several novel B cell receptor (BCR) changes (such as IGHV1-8 and IGHV3-7), and confirmed isotypes (IGKV3-11 and IGHV3-21) previously used for virus vaccine development. The strongest pairing frequencies, IGHV3-23+IGHJ4, indicated a monoclonal state associated with SARS-CoV-2 specificity. Furthermore, integrated analysis predicated that IL-1B and M-CSF may be novel candidate target gene for inflammatory storm, and TNFSF13, IL-18 and IL-4 may be benefit for the recovery of COVID-19 patients. Our study provides the first evidence of inflammatory immune signature in early recovery stage, suggesting that the COVID-19 patients are still vulnerable after hospital discharge. Our identification of novel BCR signaling may lead to the development of vaccine and antibodies for the treatment of COVID-19.

positive: Is Hesperidin Essential for Prophylaxis and Treatment of COVID-19 Infection? SARS-CoV-2 or COVID-19 is representing the major global burden that implicated more than 4.7 million infected cases and 310 thousand deaths worldwide in less than 6 months. The prevalence of this pandemic disease is expected to rise every day. The challenge is to control its rapid spread meanwhile looking for a specific treatment to improve patient outcomes. Hesperidin is a classical herbal medicine used worldwide for a long time with an excellent safety profile. Hesperidin is a well-known herbal medication used as an antioxidant and anti-inflammatory agent. Available shreds of evidence support the promising use of hesperidin in prophylaxis and treatment of COVID 19. Herein, we discuss the possible prophylactic and treatment mechanisms of hesperidin based on previous and recent findings. Hesperidin can block coronavirus from entering host cells through ACE2 receptors which can prevent the infection. Anti-viral activity of hesperidin might constitute a treatment option for COVID- 19 through improving host cellular immunity against infection and its good anti-inflammatory activity may help in controlling cytokine storm. Hesperidin mixture with diosmin co-administrated with heparin protect against venous thromboembolism which may prevent disease progression. Based on that, hesperidin might be used as a meaningful prophylactic agent and a promising adjuvant treatment option against SARS-CoV-2 infection.

positive: [Comparison of clinical and pathological features between severe acute respiratory syndrome and coronavirus disease 2019]. Severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19) shared similar pathogenetic, clinical and pathological features. Fever and cough were the most common symptoms of both diseases, while myalgia and diarrhea were less common in patients with COVID-19. Acute respiratory distress syndrome (ARDS) was the most severe pulmonary complication that caused high mortality rate. Histologically, diffuse alveolar damage (DAD) was the most characteristic finding in non-survivors with either SARS or COVID-19. Cases of patients died less than 10~14 days of disease duration demonstrated acute-phase DAD, while cases beyond 10~14 days of disease duration exhibited organizing-phase DAD in SARS. Meanwhile, organization and fibrosis were usually accompanied by exudation. Coronavirus was mostly detected in pneumocytes, while less in macrophages and bronchiolar epithelial cells. Hemorrhagic necrosis and lymphocytes depletion were found in lymph nodes and spleen in both SARS and COVID-19, indicating a pathological basis of lymphocytopenia. Thrombosis was commonly observed in small vessels and microvascular in lungs accompanying DAD. Microthrombosis was also found in extrapulmonary organs in COVID-19, that was less reported in SARS. Damages in multiple extrapulmonary organs were observed, but coronavirus was not detected in some of those organs, might indicating an alternative mechanism beyond viral infection, such as hypoxemia, ischemia and cytokine storm induced immunological injury. Diffuse alveolar damage due to viral infection and immunological injury, as well as multi-organ dysfunction and extensive microthrombus formation, brought huge challenge to the management of patients with severe SARS or COVID-19.

positive: TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor Fedratinib Abstract COVID-19 emerges as a pandemic disease with high mortality. Development of effective prevention and treatment is an urgent need. We reviewed TH17 responses in patients with SARS-CoV-2 and proposed an FDA approved JAK2 inhibitor Fedratinib for reducing mortality of patients with TH17 type immune profiles.

positive: Clinical value of immune-inflammatory parameters to assess the severity of coronavirus disease 2019 Abstract Objective To explore the clinical value of immune-inflammatory markers to assess the severity of coronavirus disease 2019 (COVID-19). Methods 127 consecutive hospitalized patients with confirmed COVID-19 were enrolled in this study, and classified into non-severe and severe groups. Demographics, symptoms, underlying diseases and laboratory data were collected and assessed for predictive value. Results Of 127 COVID-19 patients, 16 cases (12.60%) were classified into the severe group. High level of interleukin-6 (IL-6), C-reaction protein (CRP) and hypertension were independent risk factors for the severity of COVID-19. The risk model based on IL-6, CRP and hypertension had the highest area under the receiver operator characteristic curve (AUROC). Additionally, the baseline IL-6 was positively correlated with other immune-inflammatory parameters and the dynamic change of IL-6 in the severe cases were parallel to the amelioration of the disease. Conclusion Our study showed that high level of IL-6, CRP and hypertension were independent risk factors for assessing the severity of COVID-19. The risk model established upon IL-6, CRP and hypertension had the highest predictability in this study. Besides, IL-6 played a pivotal role in the severity of COVID-19 and had a potential value for monitoring the process of severe cases.

positive: Pharmacological (or Synthetic) and Nutritional Agonists of PPAR-Î³ as Candidates for Cytokine Storm Modulation in COVID-19 Disease The cytokine storm is an abnormal production of inflammatory cytokines, due to the over-activation of the innate immune response. This mechanism has been recognized as a critical mediator of influenza-induced lung disease, and it could be pivotal for COVID-19 infections. Thus, an immunomodulatory approach targeting the over-production of cytokines could be proposed for viral aggressive pulmonary disease treatment. In this regard, the peroxisome proliferator-activated receptor (PPAR)-Î³, a member of the PPAR transcription factor family, could represent a potential target. Beside the well-known regulatory role on lipid and glucose metabolism, PPAR-Î³ also represses the inflammatory process. Similarly, the PPAR-Î³ agonist thiazolidinediones (TZDs), like pioglitazone, are anti-inflammatory drugs with ameliorating effects on severe viral pneumonia. In addition to the pharmacological agonists, also nutritional ligands of PPAR-Î³, like curcuma, lemongrass, and pomegranate, possess anti-inflammatory properties through PPAR-Î³ activation. Here, we review the main synthetic and nutritional PPAR-Î³ ligands, proposing a dual approach based on the strengthening of the immune system using pharmacological and dietary strategies as an attempt to prevent/treat cytokine storm in the case of coronavirus infection.

positive: Potential mechanisms of cardiac injury and common pathways of inflammation in patients with COVID-19 Due to the lack of prospective, randomized, controlled clinical studies on inflammation and cardiovascular involvement, the exact mechanism of cardiac injury among patients with COVID-19 still remains uncertain. It was demonstrated that there is a high and significantly positive linear correlation between troponin T and plasma high-sensitivity C-reactive protein levels, biomarkers of cardiac injury and systemic inflammation, respectively. Cardiac injury and inflammation is a relatively common association among patients hospitalized with COVID-19, and it is related to higher risk of in-hospital mortality. In our literature search, we identified several potential mechanisms of myocardial tissue damage, namely, coronavirus-associated acute myocarditis, angiotensin-converting enzyme 2 receptor binding affinity to the virus Spike protein, increased cytokine secretion, and hypoxia induced cardiac myocyte apoptosis. Elucidation of the disease pathogenesis and prospective histopathological studies are crucial for future proper treatment in case of renewed outbreaks. Of interest is that with hundred of thousands of bodies available for autopsy studies, no prospective investigation has been reported so far. Strong efforts and continued research of the cardiovascular complications and identification of risk factors for poor prognosis in COVID-19 are steadily needed. The high morbidity and mortality of COVID-19, its monumental economic burden and social impact, the despair of a new pandemic outbreak, and the thread of potential utilization of novel SARS-CoV2 as biologic weapons make it a preponderant necessity to better comprehend the therapeutic management of this lethal disease. Emerging as an acute infectious disease, COVID-19 may become a chronic epidemic because of genetic recombination. Therefore, we should be ready for the reemergence of COVID-19 or other coronaviruses.

positive: Role of inflammatory markers in corona virus disease (COVID-19) patients: A review. IMPACT STATEMENT In late 2019, a novel virus called SARS-CoV-2, expanded globally from Wuhan, China and was declared a pandemic on 11 March 2020 by the WHO. The mechanism of virus entry inside the host cell depends upon the cellular proteases including cathepsins, HAT, and TMPRSS2, which splits up the spike protein and causes further penetration. MERS coronavirus uses DPP4, while coronavirus HCoV-NL63 and SARS-CoV and SARS-CoV-2 employ ACE-2 as the key receptor. Cytokine storm syndrome was analyzed in critically ill nCOVID-19 patients and it is presented with high inflammatory mediators, systemic inflammation, and multiple organ failure. Among various inflammatory mediators, the level of interleukins (IL-2, IL-7, IL-10), G-CSF, MIP1A, MCP1, and TNF-α was reported to be higher in critically ill patients. Understanding this molecular mechanism of ILs, T cells, and dendritic cells will be helpful to design immunotherapy and novel drugs for the treatment of nCOVID-19 infection.

positive: The bio-mission of interleukin-6 in the pathogenesis of COVID-19: A brief look at potential therapeutic tactics Interleukin-6 (IL-6), known as an inflammatory cytokine, can be involved in many innate and adaptive immune responses. The role of IL-6 in the pathogenesis of the novel coronavirus disease 2019 (COVID-19) has recently received much more attention due to the spread of the virus and its pandemic potential. Cytokine storm is among the most critical pathological events in patients affected with coronaviruses (CoVs), i.e., severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and COVID-19, causing inflammation-induced lung injury and also occurring as a result of dysregulation of immune responses to the mentioned viruses. IL-6, along with some other inflammatory cytokines, including IL-1 beta (β), IL-8, and tumor necrosis factor-alpha (TNF-α), as well as inflammatory chemokines, can significantly contribute to, fever, lymphopenia, coagulation, lung injury, and multi-organ failure (MOF). Therefore, researchers are to explore novel approaches to treat the disease through targeting of IL-6 and its receptors based on prior experience of other disorders. In this review article, the latest findings on the role of IL-6 in the pathogenesis of COVID-19, as well as therapeutic perspectives, were summarized and discussed.

positive: Baricitinib, a drug with potential effect to prevent SARS-COV-2 from entering target cells and control cytokine storm induced by COVID-19 In December 2019, a novel coronavirus pneumonia (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suddenly broke out in China and rapidly spread all over the world. Recently, a cell surface protein, known as angiotensin-converting enzyme II (ACE2), has been identified to be involved in receptor-mediated endocytosis for SARS-CoV-2 entry to the cells. Many studies have reported the clinical characteristics of COVID-19: sudden deterioration of disease around 1-2 weeks after onset; much lower level of lymphocytes, especially natural killer (NK) cells in peripheral blood; extremely high pro-inflammatory cytokines and C reactive protein (CRP). About 15.7% of patients develop severe pneumonia, and cytokine storm is an important factor leading to rapid disease progression. Currently, there are no specific drugs for COVID-19 and the cytokine storm it causes. Baricitinib intracellularly inhibits the proinflammatory signal of several cytokines by suppressing Janus kinase (JAK) JAK1/JAK2. It has been demonstrated clinical benefits for the patients with rheumatoid arthritis (RA), active systemic lupus erythematosus and atopic dermatitis with good efficacy and safety records. Baricitinib is expected to interrupt the passage and intracellular assembly of SARS-CoV-2 into the target cells mediated by ACE2 receptor, and treat cytokine storm caused by COVID-19. Several clinical trials are currently investigating the drug, and one of which has been completed with encouraging results. In this paper, we will elaborate the role of cytokine storm mediated by JAK-STAT pathway in severe COVID-19, the possible mechanisms of baricitinib on reducing the viral entry into the target cells and cytokine storm, the key points of pharmaceutical care based on the latest research reports, clinical trials progress and drug instruction from the US FDA, so as to provide reference for the treatment of severe COVID-19.

positive: First case of drug‐induced liver injury associated with the use of tocilizumab in a patient with COVID‐19 BACKGROUND AND AIMS: Tocilizumab (TCZ; interleukine‐6 receptor antagonist) has been proposed to treat severe forms of Coronavirus disease‐19 (COVID‐19) because interleukine‐6 plays an important role in COVID‐19‐induced cytokine storm. Several clinical studies have shown very good effects of TCZ in patients with COVID‐19, with a few minor side effects reported. Only eight serious liver injuries caused by TCZ were reported before being used in the treatment of patients with COVID‐19. Considering the significantly increased use of TCZ for the treatment of COVID‐19, we would like to warn of its rare but possible serious hepatotoxicity, especially when used together with other hepatotoxic drugs. METHODS: We describe a patient with COVID‐19‐induced cytokine storm who developed drug‐induced liver injury associated with the use of TCZ. RESULTS: One day after TCZ administration, serum transaminase levels increased 40‐fold. Nevertheless, TCZ had a positive effect on clinical and laboratory parameters in cytokine storm, with transaminases values normalizing in 10 days. CONCLUSIONS: This is the first reported case of DILI caused by TCZ in a COVID‐19 patient. Intensive liver function monitoring is imperative in COVID‐19 patients, because of frequent polypharmacy with potentially hepatotoxic drugs.

positive: Cytokine Release Syndrome (CRS) and Nicotine in COVID-19 Patients: Trying to Calm the Storm SARS-CoV-2 is a new coronavirus that has caused a worldwide pandemic. It causes severe acute respiratory syndrome (COVID-19), which is fatal in many cases, and is characterized by a cytokine release syndrome (CRS). Great efforts are currently being made to block the signal transduction pathway of pro-inflammatory cytokines in order to control this "cytokine storm" and rescue severely affected patients. Consequently, possible treatments for cytokine-mediated hyperinflammation, preferably within approved safe therapies, are urgently being researched to reduce rising mortality. One approach to inhibit proinflammatory cytokine release is to activate the cholinergic anti-inflammatory pathway through nicotinic acetylcholine receptors (α7nAchR). Nicotine, an exogenous α7nAchR agonist, is clinically used in ulcerative colitis to counteract inflammation. We have found epidemiological evidence, based on recent clinical SARS-CoV-2 studies in China, that suggest that smokers are statistically less likely to be hospitalized. In conclusion, our hypothesis proposes that nicotine could constitute a novel potential CRS therapy in severe SARS-CoV-2 patients.

positive: Battling COVID-19 Pandemic: Sphingosine-1-Phosphate Analogs as an Adjunctive Therapy? With the sudden outbreak of COVID-19 patient worldwide and associated mortality, it is critical to come up with an effective treatment against SARS-CoV-2. Studies suggest that mortality due to COVID 19 is mainly attributed to the hyper inflammatory response leading to cytokine storm and ARDS in infected patients. Sphingosine-1-phosphate receptor 1 (S1PR1) analogs, AAL-R and RP-002, have earlier provided in-vivo protection from the pathophysiological response during H1N1 influenza infection and improved mortality. Recently, it was shown that the treatment with sphingosine-1-phosphate receptor 1 analog, CYM5442, resulted in the significant dampening of the immune response upon H1N1 challenge in mice and improved survival of H1N1 infected mice in combination with an antiviral drug, oseltamivir. Hence, here we suggest to investigate the possible utility of using S1P analogs to treat COVID-19.

positive: Inflammation: A bridge between Diabetes and COVID-19, and possible management with sitagliptin Patients with SARS-CoV-2 infections experience lymphopenia and inflammatory cytokine storms in the severe stage of the disease, leading to multi-organ damage. The exact pattern of immune system changes and their condition during the disease process is unclear. The available knowledge has indicated that the NF-kappa-B pathway, which is induced by several mediators, has a significant role in cytokine storm through the various mechanisms. Therefore, identifying the state of the immune cells and the dominant mechanisms for the production of cytokines incorporated in the cytokine storm can be a critical step in the therapeutic approach. On the other hand, some studies identified a higher risk for diabetic patients. Diabetes mellitus exhibits a close association with inflammation and increases the chance of developing COVID-19. Patients with diabetes mellitus have shown to have more virus entry, impaired immunity response, less viral elimination, and dysregulated inflammatory cytokines. The parallel analysis of COVID-19 and diabetes mellitus pathogenesis has proposed that the control of the inflammation through the interfering with the critical points of major signaling pathways may provide the new therapeutic approaches. In recent years, the role of Dipeptidyl Peptidase 4 (DPP4) in chronic inflammation has been proved. Numerous immune cells express the DPP4 protein. DPP4 regulates antibody production, cytokine secretion, and immunoglobulin class switching. DPP4 inhibitors like sitagliptin reduce inflammation intensity in different states. Following the accumulating data, we hypothesize that sitagliptin might reduce COVID-19 severity. Sitagliptin, an available DPP4 inhibitor drug, showed multidimensional anti-inflammatory effects among diabetic patients. It reduces the inflammation mostly by affecting on NF-kappa-B signaling pathway. Under the fact that inflammatory mediators are active in individuals with COVID-19, blocking the predominant pathway could be helpful.

positive: Decreased T cell populations contribute to the increased severity of COVID-19 BACKGROUND: We observe changes of the main lymphocyte subsets (CD16(+)CD56、CD19、CD3、CD4、and CD8) in COVID-19-infected patients and explore whether the changes are associated with disease severity. METHODS: One-hundred fifty-four cases of COVID-19-infected patients were selected and divided into 3 groups (moderate group, severe group and critical group). The flow cytometry assay was performed to examine the numbers of lymphocyte subsets. RESULTS: CD3(+), CD4(+) and CD8+ T lymphocyte subsets were decreased in COVID-19-infected patients. Compared with the moderate group and the sever group, CD3(+), CD4(+) and CD8(+) T cells in the critical group decreased greatly (P < 0.001, P= 0.005 or P = 0.001). CONCLUSIONS: Reduced CD3(+), CD4(+), CD8(+) T lymphocyte counts may reflect the severity of the COVID-19. Monitoring T cell changes has important implications for the diagnosis and treatment of severe patients who may become critically ill.

positive: COVID-19 and Asthma: Reflection During the Pandemic Coronavirus disease 2019 (COVID-19) is a global pandemic infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and abnormal, overactivated innate immunity and "cytokine storms" have been proposed as potential pathological mechanisms for rapid COVID-19 progression. Theoretically, asthmatic patients should have increased susceptibility and severity for SARS-CoV-2 infection due to a deficient antiviral immune response and the tendency for exacerbation elicited by common respiratory viruses. However, existing studies have not shown an expected prevalence of asthmatic individuals among COVID-19 patients. Certain aspects of type 2 immune response, including type 2 cytokines (IL-4, IL-13, etc.) and accumulation of eosinophils, might provide potential protective effects against COVID-19. Furthermore, conventional therapeutics for asthma, including inhaled corticosteroids, allergen immunotherapy (AIT), and anti-IgE monoclonal antibody, might also reduce the risks of asthmatics suffering infection of the virus through alleviating inflammation or enhancing antiviral defense. The interactions between COVID-19 and asthma deserve further attention and clarification.

positive: Successful treatment of plasma exchange followed by intravenous immunogloblin in a critically ill patient with 2019 novel coronavirus infection Abstract We report a case of a laboratory-confirmed 2019 novel coronavirus infected (known as COVID-19) patient who developed respiratory failure and shock accompanied by persistent diarrhoea despite conventional therapeutic interventions. The patient avoided mechanical ventilation and acquired an immediate clinical and radiological improvement, after treatment of intensive plasma exchange (PE) followed by intravenous immunogloblin (IVIG). Successful therapeutic strategies in our case suggest timely initiating PE treatment followed by IVIG in critically ill patients with COVID-19 may prevent the disease from worsening and help to reduce the requirements for mechanical ventilation and intensive supportive care. What's more, it may improve poor clinical outcomes of these patients.

positive: Imatinib might constitute a treatment option for lung involvement in COVID-19

positive: SARS-CoV-2 infection: the role of cytokines in COVID-19 disease COVID-19 disease, caused by infection with SARS-CoV-2, is related to a series of physiopathological mechanisms that mobilize a wide variety of biomolecules, mainly immunological in nature. In the most severe cases, the prognosis can be markedly worsened by the hyperproduction of mainly proinflammatory cytokines, such as IL-1, IL-6, IL-12, IFN-γ, and TNF-α, preferentially targeting lung tissue. This study reviews published data on alterations in the expression of different cytokines in patients with COVID-19 who require admission to an intensive care unit. Data on the implication of cytokines in this disease and their effect on outcomes will support the design of more effective approaches to the management of COVID-19.

positive: Protective role of ACE2 and its downregulation in SARS-CoV-2 infection leading to Macrophage Activation Syndrome: Therapeutic implications. In light of the outbreak of the 2019 novel coronavirus disease (COVID-19), the international scientific community has joined forces to develop effective treatment strategies. The Angiotensin-Converting Enzyme (ACE) 2, is an essential receptor for cell fusion and engulfs the SARS coronavirus infections. ACE2 plays an important physiological role, practically in all the organs and systems. Also, ACE2 exerts protective functions in various models of pathologies with acute and chronic inflammation. While ACE2 downregulation by SARS-CoV-2 spike protein leads to an overactivation of Angiotensin (Ang) II/AT1R axis and the deleterious effects of Ang II may explain the multiorgan dysfunction seen in patients. Specifically, the role of Ang II leading to the appearance of Macrophage Activation Syndrome (MAS) and the cytokine storm in COVID-19 is discussed below. In this review, we summarized the latest research progress in the strategies of treatments that mainly focus on reducing the Ang II-induced deleterious effects rather than attenuating the virus replication.

positive: Nrf2 Activator PB125® as a Potential Therapeutic Agent Against COVID-19 Nrf2 is a transcription factor that regulates cellular redox balance and the expression of a wide array of genes involved in immunity and inflammation, including antiviral actions. Nrf2 activity declines with age, making the elderly more susceptible to oxidative stress-mediated diseases, which include type 2 diabetes, chronic inflammation, and viral infections. Published evidence suggests that Nrf2 activity may regulate important mechanisms affecting viral susceptibility and replication. We examined gene expression levels by GeneChip microarray and by RNA-seq assays. We found that the potent Nrf2 activating composition PB125® downregulates ACE2 and TMPRSS2 mRNA expression in human liver-derived HepG2 cells. ACE2 is a surface receptor and TMPRSS2 activates the spike protein for SARS-Cov-2 entry into host cells. Furthermore, in endotoxin-stimulated primary human pulmonary artery endothelial cells we report the marked downregulation by PB125 of 36 genes encoding cytokines. These include IL1-beta, IL6, TNF-α the cell adhesion molecules ICAM1, VCAM1, and E-selectin, and a group of IFN-γ-induced genes. Many of these cytokines have been specifically identified in the “cytokine storm” observed in fatal cases of COVID-19, suggesting that Nrf2 activation may significantly decrease the intensity of the storm.

positive: COVID-19-associated Hemophagocytic Lymphohistiocytosis and Coagulopathy: Targeting the Duumvirate. CONTEXT Preliminary data on coexistence of secondary hemophagocytic lymphohistiocytosis syndrome (HLH) and disseminated intravascular coagulation (DIC) in critically ill children with novel coronavirus disease (COVID-19) are emerging. Herein, we summarize the available literature and fill-in the gaps in this regard. EVIDENCE ACQUISITION We have performed a literature search for articles in PubMed, EMBASE and Google Scholar databases till May 12, 2020, with following keywords: "COVID-19", "SARS-CoV-2", "HLH", "HScore", "coagulopathy", "D-dimer", "cytokine storm", "children" and "pediatrics" with interposition of Boolean operator "AND". RESULTS Children presenting with moderate-severe COVID-19 and Kawasaki disease shock-like syndrome exhibit peripheral blood picture analogous to HLH. HScore, a validated tool to diagnose HLH, has been suggested to screen severe COVID-19 patients for cytokine storm. However, HScore faces certain limitations in this scenario. It may be more pragmatic to use 'high D-dimer' (> 3 µg/mL) instead of 'low fibrinogen' to facilitate early detection of cytokine storm. COVID-19 associated coagulopathy resembles hypercoagulable form of DIC with bleeding being rarely reported. Although the International Society on Thrombosis and Haemostasis (ISTH) interim guidance recommends low molecular weight heparin in all hospitalized patients, data is lacking in population below 14 years of age. However, in the presence of life-threatening thromboembolic event or symptomatic acro-ischemia, unfractionated heparin (UFH) should be used with caution. CONCLUSION HScore can be used as a complement to clinical decision for initiating immunosuppression. Children with moderate-to-severe COVID-19, especially those with documented thrombocytopenia or chilblains, should be regularly monitored for coagulopathy.

positive: COVID 19: a clue from innate immunity The recent COVID-19 pandemic has had a significant impact on our lives and has rapidly expanded to reach more than 4 million cases worldwide by May 2020. These cases are characterized by extreme variability, from a mild or asymptomatic form lasting for a few days up to severe forms of interstitial pneumonia that may require ventilatory therapy and can lead to patient death.Several hypotheses have been drawn up to understand the role of the interaction between the infectious agent and the immune system in the development of the disease and the most severe forms; the role of the cytokine storm seems important.Innate immunity, as one of the first elements of guest interaction with different infectious agents, could play an important role in the development of the cytokine storm and be responsible for boosting more severe forms. Therefore, it seems important to study also this important arm of the immune system to adequately understand the pathogenesis of the disease. Research on this topic is also needed to develop therapeutic strategies for treatment of this disease.

positive: Tocilizumab in the treatment of a critical COVID-19 patient: a case report. In December 2019, Coronavirus disease 2019 (COVID-19) emerged in Wuhan and rapidly spread throughout China and the rest of the world. COVID-19 is currently a global pandemic. There are cytokine storms in severe COVID-19 patients. Interleukin-6 plays an important role in cytokine storm. Tocilizumab is a blocker of interleukin-6 receptor, which is likely to become an effective drug for patients with severe COVID-19. Here, we reported a case in which tocilizumab was effective for a critical COVID-19 patient.

positive: The Imperfect Cytokine Storm: Severe COVID-19 with ARDS in Patient on Durable LVAD Support Abstract As health systems worldwide grapple with the COVID-19 pandemic, patients on durable LVAD support represent a unique population at risk for the disease. We outline such a patient who developed COVID-19 complicated by “cytokine storm” with severe ARDS and myocardial injury; and describe the challenges that arose during management.

positive: Weathering the COVID-19 storm: Lessons from hematologic cytokine syndromes A subset of patients with severe COVID-19 develop profound inflammation and multi-organ dysfunction consistent with a “Cytokine Storm Syndrome” (CSS). In this review we compare the clinical features, diagnosis, and pathogenesis of COVID-CSS with other hematological CSS, namely secondary hemophagocytic lymphohistiocytosis (sHLH), idiopathic multicentric Castleman disease (iMCD), and CAR-T cell therapy associated Cytokine Release Syndrome (CRS). Novel therapeutics targeting cytokines or inhibiting cell signaling pathways have now become the mainstay of treatment in these CSS. We review the evidence for cytokine blockade and attenuation in these known CSS as well as the emerging literature and clinical trials pertaining to COVID-CSS. Established markers of inflammation as well as cytokine levels are compared and contrasted between these four entities in order to establish a foundation for future diagnostic criteria of COVID-CSS.

positive: Preventing cytokine storm syndrome in COVID-19 using α-1 adrenergic receptor antagonists. Medications that target catecholamine-associated inflammation may prevent cytokine storm syndrome associated with COVID-19 and other diseases.

positive: A fatal case of COVID-19 due to metabolic acidosis following dysregulate inflammatory response (cytokine storm) The ongoing outbreak of COVID-19 has been expanding worldwide. As of 17 April 2020, the death toll stands at a sobering 147,027 and over two million cases, this has been straining the health care systems all over. Respiratory failure has been cited as the major cause of death but here we present a case about a patient who instead succumbed to severe metabolic acidosis with multiple organ failure.

positive: Phenotype of SARS-CoV-2-specific T-cells in COVID-19 patients with acute respiratory distress syndrome COVID-19 is associated with lymphopenia and cytokine storm, but no information is available on specific cellular immune responses to SARS-CoV-2. Here, we characterized SARS-CoV-2-specific CD4+ and CD8+ T-cells in patients with acute respiratory distress syndrome. The spike protein (S) proved a potent T-cell antigen and specific T-cells predominantly produced Th1 cytokines. These novel data are important in vaccine design and will facilitate evaluation of vaccine candidate immunogenicity.

positive: Retinal outcomes of COVID-19: possible role of CD147 and cytokine storm in infected patients with diabetes mellitus

positive: May the Central Nervous System Be Fogged by the Cytokine Storm in COVID-19?: an Appraisal

positive: The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system In 2019-2020 a new coronavirus named SARS-CoV-2 was identified as the causative agent of a several acute respiratory infection named COVID-19, which is causing a worldwide pandemic. There are still many unresolved questions regarding the pathogenesis of this disease and especially the reasons underlying the extremely different clinical course, ranging from asymptomatic forms to severe manifestations, including the Acute Respiratory Distress Syndrome (ARDS). SARS-CoV-2 showed phylogenetic similarities to both SARS-CoV and MERS-CoV viruses, and some of the clinical features are shared between COVID-19 and previously identified beta-coronavirus infections. Available evidence indicate that the so called "cytokine storm" an uncontrolled over-production of soluble markers of inflammation which, in turn, sustain an aberrant systemic inflammatory response, is a major responsible for the occurrence of ARDS. Chemokines are low molecular weight proteins with powerful chemoattractant activity which play a role in the immune cell recruitment during inflammation. This review will be aimed at providing an overview of the current knowledge on the involvement of the chemokine/chemokine-receptor system in the cytokine storm related to SARS-CoV-2 infection. Basic and clinical evidences obtained from previous SARS and MERS epidemics and available data from COVID-19 will be taken into account.

positive: Influence of COVID-19 on Cerebrovascular Disease and its Possible Mechanism The global spread of COVID-19 has caused a substantial societal burden and become a major global public health issue. The COVID-19 elderly population with hypertension, diabetes, cardiovascular, and cerebrovascular diseases are at risk. Mortality rates are highest in these individuals if infected with COVID-19. Although the lungs are the main organs involved in acute respiratory distress syndrome caused by COVID-19 infection, COVID-19 triggers inflammatory and immune mechanisms, inducing a “cytokine storm” that aggravates disease progression and may lead to death. Presently, effective drugs are lacking, although current studies have confirmed that drugs with therapeutic potential include redaciclovir, lopinavir/ritonavir combined with interferon-β, convalescent plasma, and monoclonal antibodies. Currently, the most reasonable and effective way to prevent COVID-19 is to control the source of infection, terminate routes of transmission, and protect susceptible populations. With the rise of COVID-19 in China and worldwide, further prevention, diagnosis, and treatment measures are a critical unmet need. Cerebrovascular disease has high incidence, disability rate, and fatality rate. COVID-19 patient outcomes may also be complicated with acute stroke. This paper summarizes the influence of COVID-19 on cerebrovascular disease and discusses possible pathophysiological mechanisms to provide new angles for the prevention and diagnosis of this disease.

positive: COVID-19: Melatonin as a potential adjuvant treatment This article summarizes the likely benefits of melatonin in the attenuation of COVID-19 based on its putative pathogenesis. The recent outbreak of COVID-19 has become a pandemic with tens of thousands of infected patients. Based on clinical features, pathology, the pathogenesis of acute respiratory disorder induced by either highly homogenous coronaviruses or other pathogens, the evidence suggests that excessive inflammation, oxidation, and an exaggerated immune response very likely contribute to COVID-19 pathology. This leads to a cytokine storm and subsequent progression to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and often death. Melatonin, a well-known anti-inflammatory and anti-oxidative molecule, is protective against ALI/ARDS caused by viral and other pathogens. Melatonin is effective in critical care patients by reducing vessel permeability, anxiety, sedation use, and improving sleeping quality, which might also be beneficial for better clinical outcomes for COVID-19 patients. Notably, melatonin has a high safety profile. There is significant data showing that melatonin limits virus-related diseases and would also likely be beneficial in COVID-19 patients. Additional experiments and clinical studies are required to confirm this speculation.

positive: Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial INTRODUCTION: The rapid worldwide spread of COVID-19 has caused a global health crisis. To date, symptomatic supportive care has been the most common treatment. It has been reported that the mechanism of COVID-19 is related to cytokine storms and subsequent immunogenic damage, especially damage to the endothelium and alveolar membrane. Vitamin C (VC), also known as L-ascorbic acid, has been shown to have antimicrobial and immunomodulatory properties. A high dose of intravenous VC (HIVC) was proven to block several key components of cytokine storms, and HIVC showed safety and varying degrees of efficacy in clinical trials conducted on patients with bacterial-induced sepsis and acute respiratory distress syndrome (ARDS). Therefore, we hypothesise that HIVC could be added to the treatment of ARDS and multiorgan dysfunction related to COVID-19. METHODS AND ANALYSIS: The investigators designed a multicentre prospective randomised placebo-controlled trial that is planned to recruit 308 adults diagnosed with COVID-19 and transferred into the intensive care unit. Participants will randomly receive HIVC diluted in sterile water or placebo for 7 days once enrolled. Patients with a history of VC allergy, end-stage pulmonary disease, advanced malignancy or glucose-6-phosphate dehydrogenase deficiency will be excluded. The primary outcome is ventilation-free days within 28 observational days. This is one of the first clinical trials applying HIVC to treat COVID-19, and it will provide credible efficacy and safety data. We predict that HIVC could suppress cytokine storms caused by COVID-19, help improve pulmonary function and reduce the risk of ARDS of COVID-19. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of Zhongnan Hospital of Wuhan University (identifiers: Clinical Ethical Approval No. 2020001). Findings of the trial will be disseminated through peer-reviewed journals and scientific conferences. TRIAL REGISTRATION NUMBER: NCT04264533.

positive: Targeting JAK-STAT Signaling to Control Cytokine Release Syndrome in COVID-19 Recent advances in the pathophysiologic understanding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has indicated that patients with severe coronavirus disease 2019 (COVID-19) might experience cytokine release syndrome (CRS), characterized by increased interleukin (IL)-6, IL-2, IL-7, IL-10, etc. Therefore, the treatment of cytokine storm has been proposed as a critical part of rescuing severe COVID-19. Several of the cytokines involved in COVID-19 employ a distinct intracellular signaling pathway mediated by Janus kinases (JAKs). JAK inhibition, therefore, presents an attractive therapeutic strategy for CRS, which is a common cause of adverse clinical outcomes in COVID-19. Below, we review the possibilities and challenges of targeting the pathway in COVID-19.

positive: Pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 – implications for microvascular inflammation and hypercoagulopathy in COVID-19 patients Accumulating clinical observations suggest pathogenesis beyond viral pneumonia and its secondary consequences in COVID-19 patients. In particular, many patients develop profound hyperinflammation and hypercoagulopathy with disseminated thrombogenesis and thromboembolism, which we observe also in a Swedish COVID-19 intensive care patient cohort. To understand these vascular manifestations, it is important to establish the potential vascular entry point(s) of the SARS-CoV-2 virus, i.e. which vascular cell types express the SARS-CoV-2 receptor ACE2. We present data that ACE2 is specifically and highly expressed in microvascular pericytes, but absent from endothelial cells, perivascular macrophages and fibroblasts. Mice with pericyte ablation show increased expression and release of Von Willebrand Factor from microvascular endothelial cells, suggesting that pericytes orchestrate thrombogenic responses in neighboring endothelial cells. Identifying pericytes rather than endothelial cells as the ACE2-expressing cells in the vasculature may explain why hypertension, diabetes and obesity are risk factors for severe COVID-19 patients, as these conditions are characterized by an impaired endothelial barrier function, allowing SARS-CoV-2 to reach and infect the pericytes that are normally shielded from the blood behind an intact endothelial barrier. This novel COVID-19-pericyte hypothesis is testable, offers explanations for some of the most enigmatic and lethal aspects of COVID-19 and calls for further investigations into the possible benefits of preventive anticoagulant therapy.

positive: A Mathematical Model of Cytokine Dynamics During a Cytokine Storm Cytokine storms are a potentially fatal exaggerated immune response consisting of an uncontrolled positive feedback loop between immune cells and cytokines. The dynamics of cytokines are highly complex and little is known about specific interactions. Researchers at the Ontario Veterinary College have encountered cytokine storms during virotherapy. Multiple mouse trials were conducted where a virus was injected into mice whose leukocytes lacked expression of the type I interferon receptor. In each case a rapid, fatal cytokine storm occurred. A nonlinear differential equation model of the recorded cytokine amounts was produced to obtain some information on their mutual interactions. Results provide insight into the complex mechanism that drives the storm and possible ways to prevent such immune responses.

positive: Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients Abstract Introduction. No therapy has yet proven effective in COVID-19. Tocilizumab (TCZ) in patients with severe COVID-19 could be an effective treatment. Method. We conducted a retrospective case-control study in the Nord Franche-Comté Hospital, France. We compared the outcome of patients treated with TCZ and patients without TCZ considering a combined primary endpoint: death and/or ICU admissions. Results. Patients with TCZ (n=20) had a higher Charlson comorbidity index (5.3 [±2.4] vs 3.4 [±2.6], p=0.014), presented with more severe forms (higher level of oxygen therapy at 13 L/min vs 6 L/min, p<0.001), and had poorer biological findings (severe lymphopenia: 676/mm3 vs 914/mm3, p=0.037 and higher CRP level: 158 mg/l vs 105 mg/l, p=0.017) than patients without TCZ (n=25). However, death and/or ICU admissions were higher in patients without TCZ than in the TCZ group (72% vs 25%, p=0.002). Conclusion. Despite the small sample size and retrospective nature of the work, this result strongly suggests that TCZ may reduce the number of ICU admissions and/or mortality in patients with severe SARS-CoV-2 pneumonia.

positive: Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19 Coronavirus disease 2019 (COVID-19) is a pandemic with no specific drugs and high fatality. The most urgent need is to find effective treatments. We sought to determine whether hydroxychloroquine (HCQ) application may reduce the death risk of critically ill COVID-19 patients. In this retrospective study, we included 550 critically ill COVID-19 patients who need mechanical ventilation in Tongji Hospital, Wuhan, from February 1, 2020 to April 4, 2020. All 550 patients received comparable basic treatments including antiviral drugs and antibiotics, and 48 of them were treated with oral HCQ treatment (200 mg twice a day for 7–10 days) in addition to the basic treatments. Primary endpoint is fatality of patients, and inflammatory cytokine levels were compared between HCQ and non-hydroxychloroquine (NHCQ) treatments. We found that fatalities are 18.8% (9/48) in HCQ group, which is significantly lower than 47.4% (238/502) in the NHCQ group (P<0.001). The time of hospital stay before patient death is 15 (10–21) days and 8 (4–14) days for the HCQ and NHCQ groups, respectively (P<0.05). The levels of inflammatory cytokine IL-6 were significantly reduced from 22.2 (8.3-118.9) pg mL(–1) at the beginning of the treatment to 5.2 (3.0–23.4) pg mL(–1) (P<0.05) at the end of the treatment in the HCQ group but there is no change in the NHCQ group. These data demonstrate that addition of HCQ on top of the basic treatments is highly effective in reducing the fatality of critically ill patients of COVID-19 through attenuation of inflammatory cytokine storm. Therefore, HCQ should be prescribed as a part of treatment for critically ill COVID-19 patients, with possible outcome of saving lives. hydroxychloroquine, IL-6, mortalities, COVID-19

positive: IL-1β is a key cytokine that induces trypsin upregulation in the influenza virus–cytokine–trypsin cycle Severe influenza is characterized by a cytokine storm, and the influenza virus–cytokine–trypsin cycle is one of the important mechanisms of viral multiplication and multiple organ failure. The aim of this study was to define the key cytokine(s) responsible for trypsin upregulation. Mice were infected with influenza virus strain A/Puerto Rico/8/34 (H1N1) or treated individually or with a combination of interleukin-1β, interleukin-6, and tumor necrosis factor α. The levels of these cytokines and trypsin in the lungs were monitored. The neutralizing effects of anti-IL-1β antibodies on cytokine and trypsin expression in human A549 cells and lung inflammation in the infected mice were examined. Infection induced interleukin-1β, interleukin-6, tumor necrosis factor α, and ectopic trypsin in mouse lungs in a dose- and time-dependent manner. Intraperitoneal administration of interleukin-1β combined with other cytokines tended to upregulate trypsin and cytokine expression in the lungs, but the combination without interleukin-1β did not induce trypsin. In contrast, incubation of A549 cells with interleukin-1β alone induced both cytokines and trypsin, and anti-interleukin-1β antibody treatment abrogated these effects. Administration of the antibody in the infected mice reduced lung inflammation area. These findings suggest that IL-1β plays a key role in trypsin upregulation and has a pathological role in multiple organ failure.

positive: Treat 2019 novel coronavirus (COVID-19) with IL-6 inhibitor: Are we already that far? The world is in the midst of the coronavirus disease 2019 (COVID-19) pandemic. Interleukin 6 (IL-6) inhibitor (tocilizumab) had been suggested for the treatment of acute respiratory distress syndrome (ARDS) patients based on the concept of "cytokine storm" in COVID-19. However, we still lack reliable studies to verify "cytokine storm" in COVID-19 pneumonia. Furthermore, IL-6 inhibitor has potential hazards of inducing infectious diseases. The efficacy of IL-6 monoclonal antibody-directed therapy remains to be fully evaluated.

positive: Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors Since the outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China, it has rapidly spread across many other countries. While the majority of patients were considered mild, critically ill patients involving respiratory failure and multiple organ dysfunction syndrome are not uncommon, which could result death. We hypothesized that cytokine storm is associated with severe outcome. We enrolled 102 COVID-19 patients who were admitted to Renmin Hospital (Wuhan, China). All patients were classified into moderate, severe and critical groups according to their symptoms. 45 control samples of healthy volunteers were also included. Inflammatory cytokines and C-Reactive Protein (CRP) profiles of serum samples were analyzed by specific immunoassays. Results showed that COVID-19 patients have higher serum level of cytokines (TNF-α, IFN-Î³, IL-2, IL-4, IL-6 and IL-10) and CRP than control individuals. Within COVID-19 patients, serum IL-6 and IL-10 levels are significantly higher in critical group (n = 17) than in moderate (n = 42) and severe (n = 43) group. The levels of IL-10 is positively correlated with CRP amount (r = 0.41, P < 0.01). Using univariate logistic regression analysis, IL-6 and IL-10 are found to be predictive of disease severity and receiver operating curve analysis could further confirm this result (AUC = 0.841, 0.822 respectively). Our result indicated higher levels of cytokine storm is associated with more severe disease development. Among them, IL-6 and IL-10 can be used as predictors for fast diagnosis of patients with higher risk of disease deterioration. Given the high levels of cytokines induced by SARS-CoV-2, treatment to reduce inflammation-related lung damage is critical.

positive: COVID-19 and NSAIDS: A Narrative Review of Knowns and Unknowns Concern about the appropriate role of nonsteroidal anti-inflammatory drugs (NSAIDs) in COVID-19 speculate that NSAIDs, in particular ibuprofen, may upregulate the entry point for the virus, the angiotensin-converting enzyme (ACE) 2 receptors and increase susceptibility to the virus or worsen symptoms in existing disease. Adverse outcomes with COVID-19 have been linked to cytokine storm but the most effective way to address exaggerated inflammatory response is complex and unclear. The Expert Working Group on the Commission of Human Medicines in the UK and other organizations have stated that there is insufficient evidence to establish a link between ibuprofen and susceptibility to or exacerbation of COVID-19. NSAID use must also be categorized by whether the drugs are relatively low-dose over-the-counter oral products taken occasionally versus higher-dose or parenteral NSAIDs. Even if evidence emerged arguing for or against NSAIDs in this setting, it is unclear if this evidence would apply to all NSAIDs at all doses in all dosing regimens. Paracetamol (acetaminophen) has been proposed as an alternative to NSAIDs but there are issues with liver toxicity at high doses. There are clearly COVID-19 cases where NSAIDs should not be used, but there is no strong evidence that NSAIDs must be avoided in all patients with COVID-19; clinicians must weigh these choices on an individual basis.

positive: An inflammatory cytokine signature helps predict COVID-19 severity and death The COVID-19 pandemic caused by infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to more than 100,000 deaths in the United States. Several studies have revealed that the hyper-inflammatory response induced by SARS-CoV-2 is a major cause of disease severity and death in infected patients. However, predictive biomarkers of pathogenic inflammation to help guide targetable immune pathways are critically lacking. We implemented a rapid multiplex cytokine assay to measure serum IL-6, IL-8, TNF-, and IL-1{beta} in hospitalized COVID-19 patients upon admission to the Mount Sinai Health System in New York. Patients (n=1484) were followed up to 41 days (median 8 days) and clinical information, laboratory test results and patient outcomes were collected. In 244 patients, cytokine measurements were repeated over time, and effect of drugs could be assessed. Kaplan-Meier methods were used to compare survival by cytokine strata, followed by Cox regression models to evaluate the independent predictive value of baseline cytokines. We found that high serum IL-6, IL-8, and TNF- levels at the time of hospitalization were strong and independent predictors of patient survival. Importantly, when adjusting for disease severity score, common laboratory inflammation markers, hypoxia and other vitals, demographics, and a range of comorbidities, IL-6 and TNF- serum levels remained independent and significant predictors of disease severity and death. We propose that serum IL-6 and TNF- levels should be considered in the management and treatment of COVID-19 patients to stratify prospective clinical trials, guide resource allocation and inform therapeutic options. We also propose that patients with high IL-6 and TNF- levels should be assessed for combinatorial blockade of pathogenic inflammation in this disease.

positive: Accelerating drug repurposing for COVID-19 via modeling drug mechanism of action with large scale gene-expression profiles The novel coronavirus disease, named COVID-19, emerged in China in December 2019, and has rapidly spread around the world. It is clearly urgent to fight COVID-19 at global scale. The development of methods for identifying drug uses based on phenotypic data can improve the efficiency of drug development. However, there are still many difficulties in identifying drug applications based on cell picture data. This work reported one state-of-the-art machine learning method to identify drug uses based on the cell image features of 1024 drugs generated in the LINCS program. Because the multi-dimensional features of the image are affected by non-experimental factors, the characteristics of similar drugs vary greatly, and the current sample number is not enough to use deep learning and other methods are used for learning optimization. As a consequence, this study is based on the supervised ITML algorithm to convert the characteristics of drugs. The results show that the characteristics of ITML conversion are more conducive to the recognition of drug functions. The analysis of feature conversion shows that different features play important roles in identifying different drug functions. For the current COVID-19, Chloroquine and Hydroxychloroquine achieve antiviral effects by inhibiting endocytosis, etc., and were classified to the same community. And Clomiphene in the same community inibited the entry of Ebola Virus, indicated a similar MoAs that could be reflected by cell image.

positive: Reduced expression of COVID-19 host receptor, ACE2 is associated with small bowel inflammation, more severe disease, and response to anti-TNF therapy in Crohn’s disease Angiotensin-Converting Enzyme 2 (ACE2) has been identified as the host receptor for SARS-coronavirus 2 (SARS-CoV-2) which has infected millions world-wide and likely caused hundreds of thousands of deaths. Utilizing transcriptomic data from four cohorts taken from Crohn’s disease (CD) and non-inflammatory bowel disease (IBD) subjects, we observed evidence of increased ACE2 mRNA in ileum with demographic features that have been associated with poor outcomes in COVID-19 including age and raised BMI. ACE2 was downregulated in CD compared to controls in independent cohorts. Within CD, ACE2 expression was reduced in inflamed ileal tissue and also remarkably, from un-involved tissue in patients with a worse prognosis in both adult and pediatric cohorts. In active CD, small bowel ACE2 expression was restored by anti-TNF therapy particularly in anti-TNF responders. Collectively our data suggest that ACE2 downregulation is associated with inflammation and worse outcomes in CD.

positive: Combating COVID-19 with Mesenchymal Stem Cell therapy The COVID-19 disease is caused by a positive stranded RNA virus called SARS-CoV-2. The virus mainly targets the pulmonary epithelial cells as it’s initial site of infection by letting its surface spike protein interact and bind to the host ACE2 receptor. The internalization and gradual replication of the virus results in an exaggerated immune response triggering release of many pro-inflammatory cytokines and chemokines. This immune storm is responsible for multiple health hazards in the host ultimately leading to multiple organ failure. Mesenchymal stem cell therapy offers a promising approach towards mitigating the delirious effects of the infection in the COVID-19 patients. This therapy has shown to reduce the expression of pro-inflammatory cytokines as well as repair of damaged tissues in COVID-19 patients. This review has been organized to put forward the positive aruments and implications in support of mesenchymal stem cell therapy as a necessary approach for treating COVID-19 patients.

positive: Immunologic aspects of characteristics, diagnosis, and treatment of coronavirus disease 2019 (COVID-19) On March 11, 2020, the World Health Organization declared the worldwide spread of the infectious disease COVID-19, caused by a new strain of coronavirus, SARS-CoV-2, as a pandemic. Like in all other infectious diseases, the host immune system plays a key role in our defense against SARS-CoV-2 infection. However, viruses are able to evade the immune attack and proliferate and, in susceptible individuals, cause severe inflammatory response known as cytokine storm, particularly in the lungs. The advancement in our understanding of the mechanisms underlying the host immune responses promises to facilitate the development of approaches for prevention or treatment of diseases. Components of immune system, such as antibodies, can also be used to develop sensitive and specific diagnostic methods as well as novel therapeutic agents. In this review, we summarize our knowledge about how the host mounts immune responses to infection by SARS-CoV-2. We also describe the diagnostic methods being used for COVID-19 identification and summarize the current status of various therapeutic strategies, including vaccination, being considered for treatment of the disease.

positive: Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients Background: The dynamic changes of lymphocyte subsets and cytokines profiles of patients with novel coronavirus disease (COVID-19) and their correlation with the disease severity remain unclear. Method: Peripheral blood samples were longitudinally collected from 40 confirmed COVID-19 patients and examined for lymphocyte subsets by flow cytometry and cytokine profiles by specific immunoassays. Findings: Of the 40 COVID-19 patients enrolled, 13 severe cases showed significant and sustained decreases in lymphocyte counts but increases in neutrophil counts than 27 mild cases. Further analysis demonstrated significant decreases in the counts of T cells, especially CD8 + T cells, as well as increases in IL-6, IL-10, IL-2 and IFN-γ levels in the peripheral blood in the severe cases compared to those in the mild cases. T cell counts and cytokine levels in severe COVID-19 patients who survived the disease gradually recovered at later time points to levels that were comparable to those of the mild cases. Moreover, the neutrophil-to-CD8+ T cell ratio (N8R) were identified as the most powerful prognostic factor affecting the prognosis for severe COVID-19. Conclusion: The degree of lymphopenia and a proinflammatory cytokine storm is higher in severe COVID-19 patients than in mild cases, and is associated with the disease severity. N8R may serve as a useful prognostic factor for early identification of severe COVID-19 cases.

positive: Model based approach for estimating the dosage regimen of indomethacin a potential antiviral treatment of patients infected with SARS CoV-2 To face SARS-CoV-2 pandemic various attempts are made to identify potential effective treatments by repurposing available drugs. Among them, indomethacin, an anti-inflammatory drug, was shown to have potent in-vitro antiviral properties on human SARS-CoV-1, canine CCoV, and more recently on human SARS-CoV-2 at low micromolar range. Our objective was to show that indomethacin could be considered as a promising candidate for the treatment of SARS-CoV-2 and to provide criteria for comparing benefits of alternative dosage regimens using a model-based approach. A multi-stage model-based approach was developed to characterize % of recovery and viral load in CCoV-infected dogs, to estimate the PK of indomethacin in dog and human using published data after administration of immediate (IR) and sustained-release (SR) formulations, and to estimate the expected antiviral activity as a function of different assumptions on the effective exposure in human. Different dosage regimens were evaluated for IR formulation (25 mg and 50 mg three-times-a-day, and 25 mg four-times-a-day), and SR formulation (75 mg once and twice-a-day). The best performing dosing regimens were: 50 mg three-times-a-day for the IR formulation, and 75 mg twice-a-day for the SR formulation. The treatment with the SR formulation at the dose of 75 mg twice-a-day is expected to achieve a complete response in three days for the treatment in patients infected by the SARS-CoV-2 coronavirus. These results suggest that indomethacin could be considered as a promising candidate for the treatment of SARS-CoV-2 whose potential therapeutic effect need to be further assessed in a prospective clinical trial. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10928-020-09690-4) contains supplementary material, which is available to authorized users.

positive: Potential for jaktinib hydrochloride to treat cytokine storms in patients with COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become a serious public health threat to the whole world, and the number of infected is still rising dramatically at this moment. Several studies have confirmed that cytokine storms play a critical role in causing a case to worsen from mild to severe or critical. The current treatment for cytokine storms is limited, so the international medical community is focusing on a specific and effective remedy. Jaktinib hydrochloride is a broad spectrum JAK inhibitor. It can inhibit cytokine-induced immune activation by multiple mechanisms and also slow viral proliferation by inhibiting AAK1 without causing unacceptable toxicity. Jaktinib hydrochloride has great potential for the treatment of patients with coronavirus disease 2019 (COVID-19).

positive: mTORC inhibitor Sirolimus deprograms monocytes in “cytokine storm” in SARS-CoV2 secondary hemophagocytic lymphohistiocytosis- like syndrome

positive: Impact of COVID-19 pandemic on SLE: beyond the risk of infection

positive: TNFα inhibitor may be effective for severe COVID-19: learning from toxic epidermal necrolysis Increased inflammatory cytokines [such as tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6)] are observed in COVID-19 patients, especially in the severe group. The phenomenon of a cytokine storm may be the central inducer of apoptosis of alveolar epithelial cells, which leads to rapid progression in severe group patients. Given the similarities of clinical features and pathogenesis between toxic epidermal necrolysis (TEN) and COVID-19, we hypothesize that the application of etanercept, an inhibitor of TNFα, could attenuate disease progression in severe group COVID-19 patients by suppressing systemic auto-inflammatory responses. The reviews of this paper are available via the supplemental material section.

positive: Perspectives on therapeutic neutralizing antibodies against the Novel Coronavirus SARS-CoV-2 A newly identified novel coronavirus (SARS-CoV-2) is causing pneumonia-associated respiratory syndrome across the world. Epidemiology, genomics, and pathogenesis of the SARS-CoV-2 show high homology with that of SARS-CoV. Current efforts are focusing on development of specific antiviral drugs. Therapeutic neutralizing antibodies (NAbs) against SARS-CoV-2 will be greatly important therapeutic agents for the treatment of coronavirus disease 2019 (COVID-19). Herein, the host immune responses against SARS-CoV discussed in this review provide implications for developing NAbs and understanding clinical interventions against SARS-CoV-2. Further, we describe the benefits, challenges and considerations of NAbs against SARS-CoV-2. Although many challenges exist, NAbs still offer a therapeutic option to control the current pandemic and the possible re-emergence of the virus in the future, and their development therefore remains a high priority.

positive: Weather the Cytokine Storm: A Report of Successful Management of a Colon Cancer Survivor and a Critically Ill Patient with COVID-19 Patients with novel corona virus infection (COVID-19) can develop acute respiratory failure secondary to acute respiratory distress syndrome. Cytokine storm is suggested as one of underlying mechanisms for the rapid clinical decline. Immunocompromised patients and cancer patients are at particular risk for poor outcomes due to COVID-19 infection. This case report describes the presentation and clinical course of a cancer survivor who became critically ill and required mechanical ventilation. The patient was treated with hydroxychloroquine, azithromycin, and ceftriaxone; however, he remained febrile, hypoxemic, continued to require full mechanical ventilator support and his chest X-ray showed increased bilateral infiltrates. The patient was treated with tocilizumab, after which he improved and was successfully extubated. This report illustrates a possible role of tocilizumab in management of cytokine storm in critically ill patients with COVID-19 infection.

positive: Clinical aspects and cytokine response in severe H1N1 influenza A virus infection INTRODUCTION: The immune responses in patients with novel A(H1N1) virus infection (nvA(H1N1)) are incompletely characterized. We investigated the profile of Th1 and Th17 mediators and interferon-inducible protein-10 (IP-10) in groups with severe and mild nvA(H1N1) disease and correlated them with clinical aspects. METHODS: Thirty-two patients hospitalized with confirmed nvA(H1N1) infection were enrolled in the study: 21 patients with nvA(H1N1)-acute respiratory distress syndrome (ARDS) and 11 patients with mild disease. One group of 20 patients with bacterial sepsis-ARDS and another group of 15 healthy volunteers were added to compare their cytokine levels with pandemic influenza groups. In the nvA(H1N1)-ARDS group, the serum cytokine samples were obtained on admission and 3 days later. The clinical aspects were recorded prospectively. RESULTS: In the nvA(H1N1)-ARDS group, obesity and lymphocytopenia were more common and IP-10, interleukin (IL)-12, IL-15, tumor necrosis factor (TNF)α, IL-6, IL-8 and IL-9 were significantly increased versus control. When comparing mild with severe nvA(H1N1) groups, IL-6, IL-8, IL-15 and TNFα were significantly higher in the severe group. In nonsurvivors versus survivors, IL-6 and IL-15 were increased on admission and remained higher 3 days later. A positive correlation of IL-6, IL-8 and IL-15 levels with C-reactive protein and with > 5-day interval between symptom onset and admission, and a negative correlation with the PaO(2):FiO(2 )ratio, were found in nvA(H1N1) groups. In obese patients with influenza disease, a significant increased level of IL-8 was found. When comparing viral ARDS with bacterial ARDS, the level of IL-8, IL-17 and TNFα was significantly higher in bacterial ARDS and IL-12 was increased only in viral ARDS. CONCLUSIONS: In our critically ill patients with novel influenza A(H1N1) virus infection, the hallmarks of the severity of disease were IL-6, IL-15, IL-8 and TNFα. These cytokines, except TNFα, had a positive correlation with the admission delay and C-reactive protein, and a negative correlation with the PaO(2):FiO(2 )ratio. Obese patients with nvA(H1N1) disease have a significant level of IL-8. There are significant differences in the level of cytokines when comparing viral ARDS with bacterial ARDS.

positive: Is Inhaled Furosemide a Potential Therapeutic for COVID-19? The potentially lethal infection caused by the novel Severe Acute Respiratory Disease Coronavirus-2 (SARS-CoV-2) has evolved into a global crisis. Following the initial viral infection is the host inflammatory response that frequently results in excessive secretion of inflammatory cytokines (e.g., IL-6 and TNFα), developing into a self-targeting, toxic "cytokine storm" causing critical pulmonary tissue damage. The need for a therapeutic that is available immediately is growing daily but the de novo development of a vaccine may take years. Therefore, repurposing of approved drugs offers a promising approach to address this urgent need. Inhaled furosemide, a small molecule capable of inhibiting IL-6 and TNFα, may be an agent capable of treating the Coronavirus Disease 2019 cytokine storm in both resource-rich and developing countries. Furosemide is a "repurpose-able" small molecule therapeutics, that is safe, easily synthesized, handled, and stored, and is available in reasonable quantities worldwide.

positive: Survival of covid-19 patients requires precise immune regulation: the hypothetical immunoprotective role of nicotinic agonists Summary recent studies have provided novel evidence regarding the effect of nicotine agonists on the prevention or modulation of cytokines storm and reduction of infection. In this study we tried to attempt to address these issues from a therapeutic perspective of nicotine agonists in this manner and we describe one of the most challenging theories of immunotherapy in coronavirus-19 (COV-19). The analysis of the proposed mechanism goes beyond the physiological consequences of a way to design new strategies to provide anti-inflammatory drugs.

positive: Cerebrovascular events in COVID-19 patients Neurological manifestations in patients with COVID-19 are more frequently being reported. Cerebrovascular events have been reported in around 3% of patients. In this review we summarize the published literature on cerebrovascular events in patients with COVID-19 as available on the PubMed database. So far, 3 studies have reported cerebrovascular events. Cerebrovascular events were identified on screening patients with decreased consciousness or in the presence of focal neurological deficits. These events were common in elderly, critically ill patients and in patients with prior cardio-cerebrovascular comorbidities. The diagnosis of cerebrovascular events was confirmed with computed tomography of the brain in most studies reporting neurological events. Multiple pathological mechanisms have been postulated regarding the process of neurological and vascular injury among which cytokine storm is shown to correlate with mortality. Patients with severe illness are found to have a higher cardio- cerebrovascular comorbidity. With an increasing number of cases and future prospective studies, the exact mechanism by which these cerebrovascular events occur and attribute to the poor outcome will be better understood.

positive: Current targeted therapeutics against COVID-19: based on first-line experience in china Abstract SARS-CoV-2 is a novel strain, causing a global pandemic since the end of 2019. The majority of patients showed nonspecific symptoms such as fever, dry cough, and fatigue. Most patients have a good prognosis while some with severe conditions could rapidly progress to acute respiratory distress syndrome, septic shock, metabolic acidosis, coagulation dysfunction, and even die. The exacerbation of the patient's condition may be due to a cytokine storm in the body. Effective targeted therapies including antiviral and immunization are urgently needed. Although many clinical trials are already underway and the majority of patients have received antiviral therapy based on medication experience with severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), and preliminary results from some clinical trials, there are no antiviral drugs proven to be effective currently. We summarize the current therapeutic medicines used in the clinic, hope to be able to provide some implications for clinical medication.

positive: Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory support COVID-19 is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SAR-CoV-2), resulting in symptoms, such as fever, cough, and shortness of breath. The SARS-CoV-2 virus has also been suggested to initiate a cytokine storm in patients with COVID-19 evidenced by elevated cytokines, such as interleukin-6 (IL-6) and C-reactive protein (CRP). We report preliminary data from 21 patients with COVID-19 who developed pneumonia/acute respiratory distress syndrome (ARDS) and participated in a compassionate-use program at Papa Giovanni XXIII hospital in Bergamo, Italy. All 21 patients received intravenous siltuximab, a chimeric mAb that binds to and blocks the effect of IL-6, at a dose ranging between 700 to 1,200 mg (median 900 mg). The median age of patients treated was 64 years, and all patients were followed for a median of eight days. Serum CRP levels reduced in all 16 patients with available data following treatment. An improvement in the clinical condition was observed in 33% (7/21) of patients, 43% (9/21) of patients stabilized as evidenced by no clinically relevant change in their condition, and 24% (5/21) experienced a worsening in their condition. Of those patients who experienced a worsening in their condition, one patient died, and one patient experienced a cerebrovascular event. This analysis is presented to inform the medical community of the potential role of siltuximab in treating patients with ARDS secondary to SARS-CoV-2 infection, and a cohort study with patients treated with standard therapy in our hospital is ongoing, and will report the 30-day mortality rates upon completion.

positive: Severe Acute Lung Injury Related to COVID‐19 Infection: A Review and the Possible Role for Escin Acute lung injury (ALI) represents the most severe form of the viral infection sustained by coronavirus disease 2019 (COVID‐19). Today, it is a pandemic infection, and even if several compounds are used as curative or supportive treatment, there is not a definitive treatment. In particular, antiviral treatment used for the treatment of several viral infections (eg, hepatitis C, HIV, Ebola, severe acute respiratory syndrome–coronavirus) are today used with a mild or moderate effect on the lung injury. In fact, ALI seems to be related to the inflammatory burst and release of proinflammatory mediators that induce intra‐alveolar fibrin accumulation that reduces the gas exchange. Therefore, an add‐on therapy with drugs able to reduce inflammation, edema, and cell activation has been proposed as well as a treatment with interferon, corticosteroids or monoclonal antibodies (eg, tocilizumab). In this article reviewing literature data related to the use of escin, an agent having potent anti‐inflammatory and anti‐viral effects in lung injury, we suggest that it could represent a therapeutic opportunity as add‐on therapy in ALI related to COVID‐19 infection.

positive: Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus Pathogenic human coronavirus infections, such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV), cause high morbidity and mortality 1,2. Recently, a severe pneumonia-associated respiratory syndrome caused by a new coronavirus was reported at December 2019 (2019-nCoV) in the city Wuhan, Hubei province, China3–5, which was also named as pneumonia-associated respiratory syndrome (PARS)6. Up to 9th of February 2020, at least 37, 251 cases have been reported with 812 fatal cases according to the report from China CDC. However, the immune mechanism that potential orchestrated acute mortality from patients of 2019-nCoV is still unknown. Here we show that after the 2019-nCoV infection, CD4+T lymphocytes are rapidly activated to become pathogenic T helper (Th) 1 cells and generate GM-CSF etc. The cytokines environment induces inflammatory CD14+CD16+ monocytes with high expression of IL-6 and accelerates the inflammation. These aberrant and excessive immune cells may enter the pulmonary circulation in huge numbers and play an immune damaging role to causing lung functional disability and quick mortality. Our results demonstrate that excessive non-effective host immune responses by pathogenic T cells and inflammatory monocytes may associate with severe lung pathology. Therefore, we suggest that monoclonal antibody that targets the GM-CSF or interleukin 6 receptor may potentially curb immunopathology caused by 2019-nCoV and consequently win more time for virus clearance.

positive: COVID-19 revisiting inflammatory pathways of arthritis Coronavirus disease 2019 (COVID-19) is an infectious disease, caused by severe acute respiratory syndrome coronavirus 2, which predominantly affects the lungs and, under certain circumstances, leads to an excessive or uncontrolled immune activation and cytokine response in alveolar structures. The pattern of pro-inflammatory cytokines induced in COVID-19 has similarities to those targeted in the treatment of rheumatoid arthritis. Several clinical studies are underway that test the effects of inhibiting IL-6, IL-1β or TNF or targeting cytokine signalling via Janus kinase inhibition in the treatment of COVID-19. Despite these similarities, COVID-19 and other zoonotic coronavirus-mediated diseases do not induce clinical arthritis, suggesting that a local inflammatory niche develops in alveolar structures and drives the disease process. COVID-19 constitutes a challenge for patients with inflammatory arthritis for several reasons, in particular, the safety of immune interventions during the pandemic. Preliminary data, however, do not suggest that patients with inflammatory arthritis are at increased risk of COVID-19.

positive: Targeting the Linear Ubiquitin Assembly Complex to Modulate the Host Response and Improve Influenza A Virus Induced Lung Injury Influenza virus infection is characterized by symptoms ranging from mild congestion and body aches to severe pulmonary edema and respiratory failure. While the majority of those exposed have minor symptoms and recover with little morbidity, an estimated 500,000 people succumb to IAV-related complications each year worldwide. In these severe cases, an exaggerated inflammatory response, known as "cytokine storm", occurs which results in damage to the respiratory epithelial barrier and development of acute respiratory distress syndrome (ARDS). Data from retrospective human studies as well as experimental animal models of influenza virus infection highlight the fine line between an excessive and an inadequate immune response, where the host response must balance viral clearance with exuberant inflammation. Current pharmacological modulators of inflammation, including corticosteroids and statins, have not been successful in improving outcomes during influenza virus infection. We have reported that the amplitude of the inflammatory response is regulated by Linear Ubiquitin Assembly Complex (LUBAC) activity and that dampening of LUBAC activity is protective during severe influenza virus infection. Therapeutic modulation of LUBAC activity may be crucial to improve outcomes during severe influenza virus infection, as it functions as a molecular rheostat of the host response. Here we review the evidence for modulating inflammation to ameliorate influenza virus infection-induced lung injury, data on current anti-inflammatory strategies, and potential new avenues to target viral inflammation and improve outcomes.

positive: Expanded Umbilical Cord Mesenchymal Stem Cells (UC-MSCs) as a Therapeutic Strategy in Managing Critically Ill COVID-19 Patients: The Case for Compassionate Use COVID-19 has affected the United States leading to a national emergency with health care and economic impact, propelling the country into a recession with disrupted lifestyles not seen in recent history. COVID-19 is a serious illness leading to multiple deaths in various countries including the United States. Several million Americans satisfy the Center for Disease Control and Prevention (CDC) criteria for being high risk. Unfortunately, the available supply of medical beds and equipment for mechanical ventilation are much less than is projected to be needed. The World Health Organization (WHO) and multiple agencies led by the CDC in the United States have attempted to organize intensive outbreak investigation programs utilizing appropriate preventive measures, evaluation, and treatment. The clinical spectrum of COVID-19 varies from asymptomatic forms to conditions encompassing multiorgan and systemic manifestations in terms of septic shock, and multiple organ dysfunction (MOD) syndromes. The presently approved treatments are supportive but not curative for the disease. There are multiple treatments being studied. These include vaccines, medications Remdesivir and hydroxychloroquine and potentially combination therapy. Finally, expanded umbilical cord mesenchymal stem cells or (UC-MSCs) may have a role and are being studied. The cure of COVID-19 is essentially dependent on the patients' own immune system. When the immune system is over activated in an attempt to kill the virus, this can lead to the production of a large number of inflammatory factors, resulting in severe cytokine storm. The cytokine storm may induce organ damage followed by the edema, dysfunction of air exchange, acute respiratory distress syndrome (ARDS), acute cardiac injury, and secondary infection, which may lead to death. Thus, at this point, the avoidance of the cytokine storm may be the key for the treatment of HCOV-19 infected patients.In China, where there was limited availability of effective modalities to manage COVID-19 several patients were treated with expanded UC-MSCs. Additionally, the Italian College of Anesthesia, Analgesia, Resuscitation and Intensive Care have reported guidelines to treat coronavirus patients with stem cells in the hope of decreasing the number of patients going to the ICU, and, also relatively quickly getting them out of ICU. In this manuscript, we describe the urgent need for various solutions, pathogenesis of coronavirus and the clinical evidence for treatment of COVID-19 with stem cells. The limited but emerging evidence regarding UC MSC in managing COVID-19 suggests that it might be considered for compassionate use in critically ill patients to reduce morbidity and mortality in the United States. The administration and Coronavirus Task Force might wish to approach the potential of expanded UC-MSCs as an evolutionary therapeutic strategy in managing COVID-19 illness with a 3-pronged approach: If proven safe and effective on a specific and limited basis 1. Minimize regulatory burden by all agencies so that critically ill COVID-19 patients will have access regardless of their financial circumstance.2. Institute appropriate safeguards to avoid negative consequences from unscrupulous actors.3. With proper informed consent from patients or proxy when necessary, and subject to accumulation of data in that cohort, allow the procedure to be initiated in critically ill patients who are not responding to conventional therapies.KEY WORDS: Coronavirus, COVID-19, cytokine storm, multiorgan failure, expanded umbilical cord mesenchymal stem cells.

positive: Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19) Background: The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed great threat to human health. T cells play a critical role in antiviral immunity but their numbers and functional state in COVID-19 patients remain largely unclear. Methods: We retrospectively reviewed the counts of T cells and serum cytokine concentration from data of 522 patients with laboratory-confirmed COVID-19 and 40 healthy controls. In addition, the expression of T cell exhaustion markers were measured in 14 COVID-19 cases. Results: The number of total T cells, CD4(+) and CD8(+) T cells were dramatically reduced in COVID-19 patients, especially in patients requiring Intensive Care Unit (ICU) care. Counts of total T cells, CD8(+) T cells or CD4(+) T cells lower than 800, 300, or 400/μL, respectively, were negatively correlated with patient survival. T cell numbers were negatively correlated to serum IL-6, IL-10, and TNF-α concentration, with patients in the disease resolution period showing reduced IL-6, IL-10, and TNF-α concentrations and restored T cell counts. T cells from COVID-19 patients had significantly higher levels of the exhausted marker PD-1. Increasing PD-1 and Tim-3 expression on T cells was seen as patients progressed from prodromal to overtly symptomatic stages. Conclusions: T cell counts are reduced significantly in COVID-19 patients, and the surviving T cells appear functionally exhausted. Non-ICU patients with total T cells counts lower than 800/μL may still require urgent intervention, even in the immediate absence of more severe symptoms due to a high risk for further deterioration in condition.

positive: The Inhibitory Effect of Curcumin on Virus-Induced Cytokine Storm and Its Potential Use in the Associated Severe Pneumonia Coronavirus infection, including SARS-CoV, MERS-CoV, and SARS-CoV2, causes daunting diseases that can be fatal because of lung failure and systemic cytokine storm. The development of coronavirus-evoked pneumonia is associated with excessive inflammatory responses in the lung, known as “cytokine storms,” which results in pulmonary edema, atelectasis, and acute lung injury (ALI) or fatal acute respiratory distress syndrome (ARDS). No drugs are available to suppress overly immune response-mediated lung injury effectively. In light of the low toxicity and its antioxidant, anti-inflammatory, and antiviral activity, it is plausible to speculate that curcumin could be used as a therapeutic drug for viral pneumonia and ALI/ARDS. Therefore, in this review, we summarize the mounting evidence obtained from preclinical studies using animal models of lethal pneumonia where curcumin exerts protective effects by regulating the expression of both pro- and anti-inflammatory factors such as IL-6, IL-8, IL-10, and COX-2, promoting the apoptosis of PMN cells, and scavenging the reactive oxygen species (ROS), which exacerbates the inflammatory response. These studies provide a rationale that curcumin can be used as a therapeutic agent against pneumonia and ALI/ARDS in humans resulting from coronaviral infection.

positive: Could SARS-CoV-2-Induced Hyperinflammation Magnify the Severity of Coronavirus Disease (CoViD-19) Leading to Acute Respiratory Distress Syndrome?

positive: Hyperbaric oxygen therapy in preventing mechanical ventilation in COVID-19 patients: a retrospective case series OBJECTIVE: A pandemic afflicts the entire world. The highly contagious SARS-CoV-2 virus originated in Wuhan, China in late 2019 and rapidly spread across the entire globe. According to the World Health Organization (WHO), the novel Coronavirus (COVID-19)has infected more than two million people worldwide, causing over 160,000 deaths. Patients with COVID-19 disease present with a wide array of symptoms, ranging from mild flu-like complaints to life threatening pulmonary and cardiac complications. Older people and patients with underlying disease have an increased risk of developing severe acute respiratory syndrome (SARS) requiring mechanical ventilation. Once intubated, mortality increases exponentially. A number of pharmacologic regimens, including hydroxychloroquine-azithromycin, antiviral therapy (eg, remdesevir), and anti-IL-6 agents (e.g., toclizumab), have been highlighted by investigators over the course of the pandemic, based on the therapy's potential to interrupt the viral life-cycle of SARS-CoV-2 or preventing cytokine storm. At present, there have been no conclusive series of reproducible randomised clinical trials demonstrating the efficacy of any one drug or therapy for COVID-19. CASES: COVID-19 positive patients (n=5) at a single institution received hyperbaric oxygen therapy (HBOT) between 13 and 20 April 2020. All the patients had tachypnoea and low oxygen saturation despite receiving high FiO2. HBOT was added to prevent the need for mechanical ventilation. A standard dive profile of 2.0ATA for 90 minutes was employed. Patients received between one and six treatments in one of two dedicated monoplace hyperbaric chambers. RESULTS: All the patients recovered without the need for mechanical ventilation. Following HBOT, oxygen saturation increased, tachypnoea resolved and inflammatory markers fell. At the time of writing, three of the five patients have been discharged from the hospital and two remain in stable condition. CONCLUSION: This small sample of patients exhibited dramatic improvement with HBOT. Most importantly, HBOT potentially prevented the need for mechanical ventilation. Larger studies are likely to define the role of HBOT in the treatment of this novel disease.

positive: Hemophagocytic lymphohistiocytosis: a review inspired by the COVID-19 pandemic Hemophagocytic syndrome (HPS) or hemophagocytic lymphohistiocytosis (HLH) is an acute and rapidly progressive systemic inflammatory disorder characterized by cytopenia, excessive cytokine production, and hyperferritinemia. Common clinical manifestations of HLH are acute unremitting fever, lymphadenopathy, hepatosplenomegaly, and multiorgan failure. Due to a massive cytokine release, this clinical condition is considered as a cytokine storm syndrome. HPS has primary and acquired (secondary, reactive) forms. Its primary form is mostly seen in childhood and caused by various mutations with genetic inheritance and, therefore, is called familial HLH. Secondary HLH may be caused in the presence of an underlying disorder, that is, secondary to a malignant, infectious, or autoimmune/autoinflammatory stimulus. This paper aims to review the pathogenesis and the clinical picture of HLH, and its severe complication, the cytokine storm, with a special emphasis on the developed classification criteria sets for rheumatologists, since COVID-19 infection has clinical symptoms resembling those of the common rheumatologic conditions and possibly triggers HLH. MED-LINE/Pubmed was searched from inception to April 2020, and the following terms were used for data searching: "hemophagocytic syndrome" OR "macrophage activation syndrome" OR "hemophagocytic lymphohistiocytosis", OR "cytokine storm". Finally, AND "COVID-19" was included in this algorithm. The selection is restricted to the past 5 years and limited numbers of earlier key references were manually selected. Only full-text manuscripts, published in an English language peer-reviewed journal were included. Manuscript selection procedure and numbers are given in Fig. 2. Briefly, the database search with the following terms of "Hemophagocytic syndrome" OR "Macrophage activation syndrome" OR "Hemophagocytic lymphohistiocytosis" OR "Cytokine storm" yielded 6744 results from inception to April 2020. The selection is restricted to the past 5 years and only limited numbers of earlier key references were selected, and this algorithm resulted in 3080 manuscripts. The addition of (AND "COVID-19") resulted in 115 publications of which 47 studies, together with four sections of an online book were used in the final review. No statistical method was used. HLH is triggered by genetic conditions, infections, malignancies, autoimmune-autoinflammatory diseases, and some drugs. In COVID-19 patients, secondary HLH and cytokine storm may be responsible for unexplained progressive fever, cytopenia, ARDS, neurological and renal impairment. Differentiation between the primary and secondary forms of HLH is utterly important, since primary form of HLH requires complicated treatments such as hematopoietic stem cell transplantation. Further studies addressing the performance of HScore and other recommendations in the classification of these patients is necessary.

positive: Zinc and respiratory tract infections: Perspectives for COVID-19 (Review) In view of the emerging COVID-19 pandemic caused by SARS-CoV-2 virus, the search for potential protective and therapeutic antiviral strategies is of particular and urgent interest. Zinc is known to modulate antiviral and antibacterial immunity and regulate inflammatory response. Despite the lack of clinical data, certain indications suggest that modulation of zinc status may be beneficial in COVID-19. In vitro experiments demonstrate that Zn(2+) possesses antiviral activity through inhibition of SARS-CoV RNA polymerase. This effect may underlie therapeutic efficiency of chloroquine known to act as zinc ionophore. Indirect evidence also indicates that Zn(2+) may decrease the activity of angiotensin-converting enzyme 2 (ACE2), known to be the receptor for SARS-CoV-2. Improved antiviral immunity by zinc may also occur through up-regulation of interferon α production and increasing its antiviral activity. Zinc possesses anti-inflammatory activity by inhibiting NF-κB signaling and modulation of regulatory T-cell functions that may limit the cytokine storm in COVID-19. Improved Zn status may also reduce the risk of bacterial co-infection by improving mucociliary clearance and barrier function of the respiratory epithelium, as well as direct antibacterial effects against S. pneumoniae. Zinc status is also tightly associated with risk factors for severe COVID-19 including ageing, immune deficiency, obesity, diabetes, and atherosclerosis, since these are known risk groups for zinc deficiency. Therefore, Zn may possess protective effect as preventive and adjuvant therapy of COVID-19 through reducing inflammation, improvement of mucociliary clearance, prevention of ventilator-induced lung injury, modulation of antiviral and antibacterial immunity. However, further clinical and experimental studies are required.

positive: N-acetyl-cysteine may prevent COVID-19-associated cytokine storm and acute respiratory distress syndrome

positive: Cytokine storm in COVID-19 and parthenolide: Preclinical evidence A group of patients with pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were reported from China in December 2019. Although several antiviral drugs are widely tested, none of them has been approved as specific antiviral therapy for coronavirus disease 2019 (COVID-19). Accumulating evidence established a hyperinflammatory states or cytokine storm in COVID-19. Among these cytokines, IL-6 plays a key role in cytokine storm and can predict the adverse clinical outcomes and fatality in these patients. Based on the evidence of the significant role of IL-6 in cytokine storm, diabetes mellitus, and cardiovascular diseases as principal comorbidities, it seems that anti-cytokine therapy may be useful in patients with severe COVID-19 to reduce mortality. Recent studies demonstrated that herbal-derived natural products had immunosuppressive and anti-inflammatory properties and exhibited exceptional act on mediators of inflammation. Parthenolide is the principal sesquiterpene lactones and the main biologically active constituent Tanacetum parthenium (commonly known as feverfew) which has could significantly reduce IL-1, IL-2, IL-6, IL-8, and TNF-α production pathways established in several human cell line models in vitro and in vivo studies. Therefore, parthenolide may be one of the herbal candidates for clinical evaluation.

positive: Inhibiting influenza's immunopathology Although a host of companies are pursuing sphingosine 1-phosphate as a target in cancer and autoimmune diseases, researchers at Scripps may have found new therapeutic real estate for S1P's receptor: lowering cytokine-related pulmonary tissue damage in influenza.

positive: COVID‐19: Consider IL6 receptor antagonist for the therapy of cytokine storm syndrome in SARS‐CoV‐2 infected patients COVID‐19 leads to mortality of several patients and the cytokine storm is reportedly critical in the patients. In order to reduce the cytokine storm, we would like to propose the IL6 receptor antagonist therapy for the COVID‐19 patients. Two humanized monoclonal antibodies are in clinical trial following IL6R antagonist therapies namely tocilizumab and sarilumab. However, researchers and physicians should look for more IL6 receptor antagonists for the therapy of cytokine storm syndrome SARS‐CoV‐2 infected persons to enhance the therapeutic options for cytokine storm. This article is protected by copyright. All rights reserved.

positive: Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients Abstract Background The dynamic changes of lymphocyte subsets and cytokines profiles of patients with novel coronavirus disease (COVID-19) and their correlation with the disease severity remain unclear. Methods Peripheral blood samples were longitudinally collected from 40 confirmed COVID-19 patients and examined for lymphocyte subsets by flow cytometry and cytokine profiles by specific immunoassays. Findings Of the 40 COVID-19 patients enrolled, 13 severe cases showed significant and sustained decreases in lymphocyte counts [0•6 (0•6-0•8)] but increases in neutrophil counts [4•7 (3•6-5•8)] than 27 mild cases [1.1 (0•8-1•4); 2•0 (1•5-2•9)]. Further analysis demonstrated significant decreases in the counts of T cells, especially CD8+ T cells, as well as increases in IL-6, IL-10, IL-2 and IFN-γ levels in the peripheral blood in the severe cases compared to those in the mild cases. T cell counts and cytokine levels in severe COVID-19 patients who survived the disease gradually recovered at later time points to levels that were comparable to those of the mild cases. Moreover, the neutrophil-to-lymphocyte ratio (NLR) (AUC=0•93) and neutrophil-to-CD8+ T cell ratio (N8R) (AUC =0•94) were identified as powerful prognostic factors affecting the prognosis for severe COVID-19. Interpretation The degree of lymphopenia and a proinflammatory cytokine storm is higher in severe COVID-19 patients than in mild cases, and is associated with the disease severity. N8R and NLR may serve as a useful prognostic factor for early identification of severe COVID-19 cases. Funding The National Natural Science Foundation of China, the National Science and Technology Major Project, the Health Commission of Hubei Province, Huazhong University of Science and Technology, and the Medical Faculty of the University Hospital Essen, Germany.

positive: Multiple expression assessments of ACE2 and TMPRSS2 SARS-CoV-2 entry molecules in the urinary tract and their associations with clinical manifestations of COVID-19 Background Since December 2019, the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first spread quickly in Wuhan, China, then globally. From previously published evidence, ACE2 and TMPRSS2, are both pivotal entry molecules that enable cellular infection by SARS-CoV-2. Meanwhile, increased expression of pro-inflammatory cytokines, or a “cytokine storm,” is associated with multiple organ dysfunction syndrome that is often observed in critically ill patients. Methods We investigated the expression pattern of ACE2 and TMPRSS2 in major organs in the human body, especially under specific disease conditions. Multiple sequence alignment of ACE2 in different species was used to explain animal susceptibility. Moreover, the cell-specific expression patterns of ACE2 and cytokine receptors in the urinary tract were assessed using single-cell RNA sequencing (scRNA-seq). Additional biological relevance was determined through Gene Set Enrichment Analysis (GSEA) using an ACE2 specific signature. Results Our results revealed that ACE2 and TMPRSS2 were highly expressed in genitourinary organs. ACE2 was highly and significantly expressed in the kidney among individuals with chronic kidney diseases or diabetic nephropathy. In single cells, ACE2 was primarily enriched in gametocytes in the testis, and renal proximal tubules. The receptors for pro-inflammatory cytokines, especially IL6ST, were remarkably concentrated in endothelial cells, macrophages, and spermatogonial stem cells in the testis, and renal endothelial cells, which suggested the occurrence of alternative damaging mechanisms via autoimmune attacks. Conclusions This study provided new insights into the pathogenicity mechanisms of SARS-CoV-2 that underlie the clinical manifestations observed in the human testis and kidney. These observations might substantially facilitate the development of effective treatments for this rapidly spreading disease.

positive: COVID-19: Melatonin as a potential adjuvant treatment Abstract This article summarizes the likely benefits of melatonin in the attenuation of COVID-19 based on its putative pathogenesis. The recent outbreak of COVID-19 has become a pandemic with tens of thousands of infected patients. Based on clinical features, pathology, the pathogenesis of acute respiratory disorder induced by either highly homogenous coronaviruses or other pathogens, the evidence suggests that excessive inflammation, oxidation, and an exaggerated immune response very likely contribute to COVID-19 pathology. This leads to a cytokine storm and subsequent progression to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and often death. Melatonin, a well-known anti-inflammatory and anti-oxidative molecule, is protective against ALI/ARDS caused by viral and other pathogens. Melatonin is effective in critical care patients by reducing vessel permeability, anxiety, sedation use, and improving sleeping quality, which might also be beneficial for better clinical outcomes for COVID-19 patients. Notably, melatonin has a high safety profile. There is significant data showing that melatonin limits virus-related diseases and would also likely be beneficial in COVID-19 patients. Additional experiments and clinical studies are required to confirm this speculation.

positive: Qiangzhi Decoction (羌跖汤) protects mice from influenza A pneumonia through inhibition of inflammatory cytokine storm OBJECTIVE: To investigate the preventive effects of Qiangzhi Decoction (羌跖汤, QZD) on influenza A pneumonia through inhibition of inflammatory cytokine storm in vivo and in vitro. METHODS: One hundred ICR mice were randomly divided into the virus control, the Tamiflu control and the QZD high-, medium-, and low-dose groups. Mice were infected intranasally with influenza virus (H1N1) at 10 median lethal dose (LD(50)). QZD and Tamiflu were administered intragastrically twice daily from day 0 to day 7 after infection. The virus control group was treated with distilled water alone under the same condition. The number of surviving mice was recorded daily for 14 days after viral infection. The histological damage and viral replication and the expression of inflammatory cytokines were monitored. Additionally, the suppression capacity on the secretion of regulated on activation normal T cells expressed and secreted (RANTES) and tumor necrosis factor-α (TNF-α) in epithelial and macrophage cell-lines were evaluated. RESULTS: Compared with the virus control group, the survival rate of the QZD groups signifificantly improved in a dose-dependent manner (P<0.05), the viral titers in lung tissue was inhibited (P<0.05), and the production of inflammatory cytokines interferon-γ (IFN-γ), interleukin-6 (IL-6), TNF-α, and intercellular adhesion molecule-1 (ICAM-1) were suppressed (P<0.05). Meanwhile, the secretion of RANTETS and TNF-α by epithelial and macrophage cell-lines was inhibited with the treatment of QZD respectively in vitro (p<0.05) CONCLUSIONS: The preventive effects of QZD on influenza virus infection might be due to its unique cytokine inhibition mechanism. QZD may have significant therapeutic potential in combination with antiviral drugs.

positive: African American children are at higher risk for COVID‐19 infection Infection by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the viral etiology of the novel coronavirus disease 2019 (COVID‐19), was first reported in Wuhan, China in late 2019. Peculiarly, the virus has not caused significant impact on pediatric populations, unlike other coronaviruses (1). Children comprise only 1.7% of COVID‐19 positive cases in the United States (2). Furthermore, children are noted to have a milder disease course (3, 4). However, much is unknown about the age, gender and race risk factors of COVID‐19 among children. There has been recent evidence suggestive of higher rates of COVID‐19 and related fatality rates in African American adult communities around the United States(5). However, there is limited data, to our knowledge, whether any race or ethnicity group is at higher risk for COVID‐19 infection in children.

positive: Lethal concentration of perfluoroisobutylene induces acute lung injury in mice mediated via cytokine storm, oxidative stress and apoptosis. Perfluoroisobutylene (PFIB) is a highly toxic gas that targets the lungs. Low-level inhalation of the gas can lead to acute lung injury (ALI), pulmonary edema and even death. No specific anti-PFIB drugs are currently available and the pathogenesis of PFIB-induced ALI is not fully understood. Early direct oxidative injury and a secondary hyper-inflammatory response are recognized as the primary mechanisms of PFIB-induced ALI. In the present study, our data demonstrate for the first time that a cytokine storm is associated with PFIB-induced ALI. Levels of 10 pro-inflammatory cytokines and one anti-inflammatory cytokine were significantly increased in lung tissues of PFIB-exposed mice. PFIB inhalation additionally led to significant oxidative stress in lung tissue. Inflammation-associated CD11b+Ly6G+Ly6Cint neutrophils and CD11b+Ly6G-Ly6Chi monocytes were significantly increased in blood in association with PFIB-induced ALI. Bcl-2/Bax-mediated lung cell apoptosis was significantly increased at 1 h, followed by a sustained decrease after 1 h, which was significant at 4-8 h in PFIB-exposed mice. This suppression of apoptosis is possibly associated with the Akt-signaling pathway.

positive: “Toxic erythema” and eosinophilia associated to tocilizumab therapy in a COVID‐19 patient Since the new fatal pneumonia was identified in December 2019 in Wuhan, China, the WHO declared the infection a health emergency of international concern. The novel ss‐RNA ß‐coronavirus (SARS‐CoV‐2) spreads through airborne and direct contagion; virulence is high in the elderly and in patients with diabetes, chronic pulmonary, cardiovascular and neoplastic diseases. SARS‐CoV‐2 ssRNA is recognized by intracellular Pattern Recognition Receptors (PRRs), which trigger NF‐kB – the master regulator of inflammation – and Interferon Regulatory Factors (IRFs)(1).

positive: The modelling of COVID19 pathways sheds light on mechanisms, opportunities and on controversial interpretations of medical treatments. v2 The new coronavirus (2019-nCoV or SARS-CoV2), inducing the current pandemic disease (COVID-19) and causing pneumoniae in humans, is dramatically increasing in epidemic scale since its first appearance in Wuhan, China, in December 2019. The first infection from epidemic coronaviruses in 2003 fostered the spread of an overwhelming amount of related scientific efforts. The manifold aspects that have been raised, as well as their redundancy offer precious information that has been underexploited and needs to be critically re-evaluated, appropriately used and offered to the whole community, from scientists, to medical doctors, stakeholders and common people. These efforts will favour a holistic view on the comprehension, prevention and development of strategies (pharmacological, clinical etc) as well as common intervention against the new coronavirus spreading. Here we describe a model that emerged from our analysis that was focused on the Renin Angiotensin System (RAS) and the possible routes linking it to the viral infection. because the infection is mediated by the viral receptor on human cell membranes Angiotensin Converting Enzyme (ACE2), which is a key component in RAS signalling. The model depicts the main pathways determining the disease and the molecular framework for its establishment, and can help to shed light on mechanisms involved in the infection. It promptly gives an answer to some of the controversial, and still open, issues concerning predisposing conditions and medical treatments that protect from or favour the severity of the disease (such as the use of ACE inhibitors or ARBs/sartans), or to the sex related biases in the affected population. The model highlights novel opportunities for further investigations, diagnosis and appropriate intervention to understand and fight COVID19.

positive: Free DNA, a reason for severe COVID-19 infection? Abstract The fast-growing outbreak of 2019 novel coronaviruses (SARS-CoV-2) reached all continents except the Antarctica in merely three months. Severe SARS-CoV-2 infection (COVID-19) has a bad clinical outcome, and some reports emphasized the role of cytokine storm and dysfunctions of multiple organs. However, the etiology of severe COVID-19 has been largely unknown. Similar as SARS-CoV and MERS-CoV, SARS-CoV-2 is also thought derived from bat coronaviruses. However, it is not pathogenic for bat at all, because free DNA in cytoplasm or blood cannot bring up violent immune response in bat; but it can produce severe inflammations in human. I hypothesized that the damage induced by free DNA is a reason for severe COVID-19, which can explain many symptoms of this disease, such as cytokine storm, ARDS and muscus plug, acute injuries of heart, liver and kidney, and some special symptoms of COVID-19. My hypothesis will be helpful for better understand the etiology of severe COVID-19.

positive: Cytokine storm and the prospects for immunotherapy with COVID-19 Knowledge about the pathobiology of SARS-CoV-2 as it interacts with immune defenses is limited. SARS-CoV-2 is spread by droplets that come into contact with mucous membranes. COVID-19 is characterized by 2 or 3 stages: most patients who recover experience 2 stages of illness commencing with an asymptomatic or paucisymptomatic incubation period, followed by a nonsevere symptomatic illness lasting for several weeks, occurring in about 80% of those infected. In the remainder, a third phase marked by a severe respiratory illness, often accompanied by multisystem dysfunction, coagulopathy, and shock is observed. This phase of the illness is characterized by hypercytokinemic inflammation and is often referred to as "cytokine storm." While the immunopathogenesis remains unclear, prospects of treating this severe phase of the illness with immunotherapy are evolving, with some treatments showing promise.

positive: Diffuse pneumonitis from coronavirus HKU1 on checkpoint inhibitor therapy BACKGROUND: Immune checkpoint inhibitors (ICIs) can produce specific immune-related adverse events including pneumonitis. The impact of ICI therapy on the severity of acute coronavirus infection symptomatology warrants further exploration. CASE PRESENTATION: We report a 65-year-old man diagnosed with stage IV melanoma who developed pulmonary and brain metastases and was treated with bilateral craniotomies followed by combined nivolumab and ipilimumab immunotherapy. He developed early-onset severe dyspnea associated with acute coronavirus HKU1 (non-COVID-19) infection, with diffuse pneumonitis evidenced by ground glass opacification on CT scan. He was treated with steroids leading to resolution of pneumonitis on repeat imaging, suggesting an exacerbated immune-mediated toxicity. CONCLUSION: We report the first case of a patient with melanoma with severe and reversible diffuse pneumonitis in association with coronavirus HKU1 following combined nivolumab and ipilimumab immunotherapy. Although we do not have data on the impact of ICI therapy on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) symptomatology, a possible interaction should be considered when deciding on dosing in patients with possible SARS-CoV-2 exposure or when evaluating patients with presumed ICI-related pneumonitis during the COVID-19 pandemic.

positive: Down Syndrome and COVID-19: A Perfect Storm? People with Down syndrome show signs of chronic immune dysregulation, including a higher prevalence of autoimmune disorders, increased rates of hospitalization during respiratory viral infections, and higher mortality rates from pneumonia and sepsis. At the molecular and cellular levels, they show markers of chronic autoinflammation, including interferon hyperactivity, elevated levels of many inflammatory cytokines and chemokines, and changes in diverse immune cell types reminiscent of inflammatory conditions observed in the general population. However, the impact of this immune dysregulation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and CoV disease of 2019 (COVID-19) remains unknown. This Perspective outlines why individuals with Down syndrome should be considered an at-risk population for severe COVID-19. Specifically, the immune dysregulation caused by trisomy 21 may result in an exacerbated cytokine release syndrome relative to that observed in the euploid population, thus justifying additional monitoring and specialized care for this vulnerable population.

positive: COVID-19: an update on diagnostic and therapeutic approaches The unexpected pandemic set off by the novel coronavirus 2019 (COVID-19) has caused severe panic among people worldwide. COVID-19 has created havoc, and scientists and physicians are urged to test the efficiency and safety of drugs used to treat this disease. In such a pandemic situation, various steps have been taken by the government to control and prevent the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). This pandemic situation has forced scientists to rework strategies to combat infectious diseases through drugs, treatment, and control measures. COVID-19 treatment requires both limiting viral multiplication and neutralizing tissue damage induced by an inappropriate immune reaction. Currently, various diagnostic kits to test for COVID-19 are available, and repurposing therapeutics for COVID-19 has shown to be clinically effective. As the global demand for diagnostics and therapeutics continues to rise, it is essential to rapidly develop various algorithms to successfully identify and contain the virus. This review discusses the updates on specimens/samples, recent efficient diagnostics, and therapeutic approaches to control the disease and repurposed drugs mainly focusing on chloroquine/hydroxychloroquine and convalescent plasma (CP). More research is required for further understanding of the influence of diagnostics and therapeutic approaches to develop vaccines and drugs for COVID-19.

positive: Interleukin-6 as prognosticator in patients with COVID-19: IL-6 and Covid-19

positive: Adrenal Insufficiency and Glucocorticoid Use During the COVID-19 Pandemic The coronavirus disease 2019 (COVID-19) is an emerging pandemic challenge. Acute respiratory distress syndrome (ARDS) in COVID-19 is characterized by a severe cytokine storm. Patients undergoing glucocorticoid (GC) replacement therapy for adrenal insufficiency (AI) represent a highly vulnerable group that could develop severe complications due to the SARS-CoV-2 infection. In this review, we highlight the strategies to avoid an adrenal crisis in patients with AI and COVID-19. Adrenal crisis is a medical emergency and an important cause of death. Once patients with AI present symptoms of COVID-19, the dose of GC replacement therapy should be immediately doubled. In the presence of any emergency warning signs or inability to administer oral GC doses, we recommend that patients should immediately seek Emergency services to evaluate COVID-19 symptoms and receive 100 mg hydrocortisone by intravenous injection, followed by 50 mg hydrocortisone intravenously every 6 h or 200 mg/day by continuous intravenous infusion.

positive: Against Ebola: type I interferon guard risk and mesenchymal stromal cell combat sepsis The 2014 Ebola outbreak in West Africa triggered a global crisis. Nine countries have reported more than 20 000 infection cases in total and nearly 8000 lives have been lost. The actual death toll is likely much higher than this figure; the death rate is as high as 70%, considering confirmed cases. The Ebola virus launches its destruction by shutting down the host’s innate and adaptive immune systems. The virus then replicates itself out of control and causes a cytokine storm in the host. Consequently, the host’s overdriven immune system attacks its own endothelial cells and this leads to multiple organ hemorrhagic damage, the host dies of septic shock finally. Under current circumstances where no specific interventions have shown effectiveness against the virus, our opinions are justified in applying a non-specific anti-viral approach during the incubation period of virus infection as an essential protection to put the host’s immune system into an alert state and henceforth to slow down the viral replication. When the viral infection proceeds to the terminal stage, the key factor would be applying a non-specific immune modulation approach to suppress the cytokine storm that causes multiple organ failure, in an attempt to open a time window for the host’s immune system to recover.

positive: A Comprehensive Review of Manifestations of Novel Coronaviruses in the Context of Deadly COVID-19 Global Pandemic Since December 2019, the global pandemic caused by the highly infectious novel coronavirus 2019-nCoV (COVID-19) has been rapidly spreading. As of April 2020, the outbreak has spread to over 210 countries, with over 2,400,000 confirmed cases and over 170,000 deaths [1]. COVID-19 causes a severe pneumonia characterized by fever, cough, and shortness of breath. Similar coronavirus outbreaks have occurred in the past causing severe pneumonia like COVID-19, most recently, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). However, over time, SARS-CoV and MERS-CoV were shown to cause extra-pulmonary signs and symptoms including hepatitis, acute renal failure, encephalitis, myositis, and gastroenteritis. Similarly, sporadic reports of COVID-19 related extrapulmonary manifestations emerge. Unfortunately, there is no comprehensive summary of the multi-organ manifestations of COVID-19, making it difficult for clinicians to quickly educate themselves about this highly contagious and deadly pathogen. What's more, is that SARS-CoV and MERS-CoV are the closest humanity has come to combating something similar to COVID-19, however, there exists no comparison between the manifestations of any of these novel coronaviruses. In this review, we summarize the current knowledge of the manifestations of the novel coronaviruses SARS-CoV, MERS-CoV, and COVID-19, with a particular focus on the latter, and highlight their differences and similarities.

positive: Cytokine Levels in the Body Fluids of a Patient With COVID-19 and Acute Respiratory Distress Syndrome: A Case Report

positive: COVID‐19—Associated dyslipidemia: Implications for mechanism of impaired resolution and novel therapeutic approaches The current coronavirus disease 2019 (COVID‐19) pandemic presents a global challenge for managing acutely ill patients and complications from viral infection. Systemic inflammation accompanied by a “cytokine storm,” hemostasis alterations and severe vasculitis have all been reported to occur with COVID‐19, and emerging evidence suggests that dysregulation of lipid transport may contribute to some of these complications. Here, we aim to summarize the current understanding of the potential mechanisms related to COVID‐19 dyslipidemia and propose possible adjunctive type therapeutic approaches that modulate lipids and lipoproteins. Specifically, we hypothesize that changes in the quantity and composition of high‐density lipoprotein (HDL) that occurs with COVID‐19 can significantly decrease the anti‐inflammatory and anti‐oxidative functions of HDL and could contribute to pulmonary inflammation. Furthermore, we propose that lipoproteins with oxidized phospholipids and fatty acids could lead to virus‐associated organ damage via overactivation of innate immune scavenger receptors. Restoring lipoprotein function with ApoA‐I raising agents or blocking relevant scavenger receptors with neutralizing antibodies could, therefore, be of value in the treatment of COVID‐19. Finally, we discuss the role of omega‐3 fatty acids transported by lipoproteins in generating specialized proresolving mediators and how together with anti‐inflammatory drugs, they could decrease inflammation and thrombotic complications associated with COVID‐19.

positive: Effectiveness of corticoid pulses in patients with cytokine storm syndrome induced by SARS-CoV-2 infection Abstract Introduction Cytokine storm syndrome (CSS) is a serious complication of COVID-19 patients. Treatment is tocilizumab. The use of glucocorticoids (GC) is controversial. In other very similar CSS, such as macrophage activation syndrome (MAS) and hemophagocytic syndrome (HFS), the main treatment are corticosteroids. Our objective is to evaluate the efficacy of GC in the CSS by COVID-19. Patients We included 92 patients with CSS associated to COVID-19 who received GC, GC, and tocilizumab and only tocilizumab. We determine CSS markers. We evaluated mortality, intubation, and a combined variable. Results In all cases the percentages of events were lower in the group of patients with GC was administered. The hazard ratio of the final variables with GC versus the group in which only tocilizumab was administered was lower as CGs were considered, with statistical significance for survival. Discussion The early use of GC pulses could control SLC, with a lower requirement to use tocilizumab and a decrease in events such as intubation and death.

positive: Role of Interleukin-6 in Lung Complications in Patients With COVID-19: Therapeutic Implications COVID-19 is viral respiratory infection with frequently fatal lung complications in the elderly or in people with serious comorbidities. Lung destruction appears to be associated with a cytokine storm related to an increased level of interleukin-6 (IL6). Therapeutic targeting of the interleukin-6 signaling pathway can attenuate such a cytokine storm and can be beneficial for patients with COVID-19 in danger of pulmonary failure. This article demonstrates the importance of IL6 in progression of disease and the possibility of inhibition of IL6 signaling in COVID-19 therapy.

positive: The association between obesity and poor outcome after COVID-19 indicates a potential therapeutic role for montelukast It is widely believed that infection with the SARS-CoV-2 virus triggers a disproportionate immune response which causes a devastating systemic injury, particularly in individuals with obesity, itself a chronic, multi-organ inflammatory disease. Immune cells accumulate in visceral adipose tissue and together with paracrine adipocytes release a wide range of biologically active cytokines (including IL-1ß, IL5, IL6 and IL8) that can result in both local, pulmonary and systemic inflammation. A more intense 'cytokine storm' is postulated as the mechanism behind the extreme immune response seen in severe COVID-19. It is striking how dangerous the combination of obesity and COVID-19 is, resulting in a greater risk of ICU admission and a higher mortality. Furthermore, patients from a BAME background appear to have increased mortality after SARS-CoV-2 infection; they also have a higher prevalence of central obesity and its metabolic complications. In the absence of an effective vaccine, the therapeutic potential of immune-modulating drugs is a priority, but the development of new drugs is expensive and time-consuming. A more pragmatic solution would be to seek to repurpose existing drugs, particularly those that might suppress the heightened cytokine activity seen in obesity, the major risk factor for a poor prognosis in COVID-19. Montelukast is a cysteinyl leukotriene receptor antagonist licensed to treat asthma and allergic rhinitis. It has been shown to diminish pulmonary response to antigen, tissue eosinophilia and IL-5 expression in inflammatory cells. It has also been shown to decrease elevated levels of IL-1ß and IL8 in humans with viral upper respiratory tract infections compared with placebo-treated patients. In addition, in silico studies have demonstrated a high binding affinity of the montelukast molecule to the terminal site of the virus's main protease enzyme which is needed for virus RNA synthesis and replication. Montelukast, which is cheap, safe and widely available would appear to have the potential to be an ideal candidate drug for clinical trials, particularly in early stage disease before irreparable tissue damage has already occurred. HYPOTHESIS: Through a direct anti-viral effect, or by suppression of heightened cytokine release in response to SARS-CoV-2, montelukast will reduce the severity of immune-mediated multiorgan damage resulting from COVID-19, particularly in patients with central obesity and metabolic syndrome.

positive: Commentary: Phosphodiesterase 4 inhibitors as potential adjunct treatment targeting the cytokine storm in COVID-19 The most severe presentation of COVID-19 is characterized by a hyperinflammatory state attributed to the massive pro-inflammatory cytokine release, called “cytokine storm”. Several specific anti-inflammatory/immunosuppressive agents are being evaluated by ongoing clinical trials; however, there is currently insufficient evidence for their efficacy and safety in COVID-19 treatment. Given the role of phosphodiesterase 4 (PDE) 4 and cyclic adenosine monophosphate in the inflammatory response, we hypothesize that selective PDE4 inhibition may attenuate the cytokine storm in COVID-19, through the upstream inhibition of pro-inflammatory molecules, particularly TNF-α, and the regulation of the pro-inflammatory/anti-inflammatory balance. Conversely, other anti-cytokine agents lead to the downstream inhibition of specific targets, such as IL-1, IL-6 or TNF-α, and may not be efficient in blocking the cytokine storm, once it has been triggered. Due to their mechanism of action targeting an early stage of the inflammatory response and ameliorating lung inflammation, we believe that selective PDE4 inhibitors may represent a promising treatment option for the early phase of COVID-19 pneumonia before the cytokine storm and severe multiorgan dysfunction take place. Furthermore, PDE4 inhibitors present several advantages including an excellent safety profile; the oral route of administration; the convenient dosing; and beneficial metabolic properties. Interestingly, obesity and diabetes mellitus type 2 have been reported to be risk factors for the severity of COVID-19. Therefore, randomized clinical trials of PDE4 inhibitors are necessary to explore their potential therapeutic effect as an adjunct to supportive measures and other therapeutic regiments.

positive: Dynamics of a Cytokine Storm Six volunteers experienced severe inflammatory response during the Phase I clinical trial of a monoclonal antibody that was designed to stimulate a regulatory T cell response. Soon after the trial began, each volunteer experienced a “cytokine storm”, a dramatic increase in cytokine concentrations. The monoclonal antibody, TGN1412, raised serum concentrations of both pro- and anti-inflammatory cytokines το very hiγh values during the first day, while lymphocyte and monocyte concentrations plummeted. Because the subjects were healthy and had no prior indications of immune deficiency, this event provided an unusual opportunity to study the dynamic interactions of cytokines and other measured parameters. Here, the response histories of nine cytokines have been modeled by a set of linear ordinary differential equations. A general search procedure identifies parameters of the model, whose response fits the data well during the five-day measurement period. The eighteenth-order model reveals plausible cause-and-effect relationships among the cytokines, showing how each cytokine induces or inhibits other cytokines. It suggests that perturbations in IL2, IL8, and IL10 have the most significant inductive effect, while IFN-γ and IL12 have the greatest inhibiting effect on other cytokine concentrations. Although TNF-α is a major pro-inflammatory factor, IFN-γ and three other cytokines have faster initial and median response to TGN1412 infusion. Principal-component analysis of the data reveals three clusters of similar cytokine responses: [TNF-α, IL1, IL10], [IFN-γ, IL2, IL4, IL8, and IL12], and [IL6]. IL1, IL6, IL10, and TNF-α have the highest degree of variability in response to uncertain initial conditions, exogenous effects, and parameter estimates. This study illuminates details of a cytokine storm event, and it demonstrates the value of linear modeling for interpreting complex, coupled biological system dynamics from empirical data.

positive: A review of cardiac manifestations and predictors of outcome in patients with COVID - 19 Coronavirus disease (COVID-19) pandemic has so far involved 184 countries and more than 2.79 million patients worldwide. Over the past three months, it has attributed to more than 196,000 deaths, with more than 50,000 deaths in the United States alone. Pulmonary manifestations are predominant and have been well identified. Cardiac involvement is also common. Acute cardiac injury, the most common cardiac manifestation of this disease can be seen in patients even without prior cardiac comorbidities. Established cardiovascular risk factors such as diabetes mellitus, hypertension, and coronary artery disease predispose to cardiac injury, the severity of illness and mortality. Non-ischemic myocardial injury secondary to cytokine storm is thought to be the predominant mechanism of acute cardiac injury associated with COVID-19. Multiple mechanisms and processes contribute to cardiac injury resulting in a poor outcome. Some of these are not clearly understood. Clinical and diagnostic details of cardiovascular involvement in these patients are mostly limited to biochemical markers. Multiple therapeutic agents have been tried with questionable efficacy and without clinical evidence. Interactions of comorbidities, cardiovascular drugs, the cardiac effect of therapeutic agents on the illness continue to be under investigation. With an increasing number of patients, newer promising therapies, and ongoing clinical trials, the exact mechanisms and extent to which these risk factors contribute to outcomes will be clearer in the future.

positive: Potential Therapeutic Targets and Promising Drugs for Combating SARS‐CoV‐2 As of April 9, 2020, a novel coronavirus (SARS‐CoV‐2) had caused 89,931 deaths and 1,503,900 confirmed cases worldwide, which indicates an increasingly severe and uncontrollable situation. Initially, little was known about the virus. As research continues, we have learned the genome structure, epidemiological and clinical characteristics and pathogenic mechanisms of SARS‐CoV‐2. Based on these discoveries, identifying potential targets involved in the processes of virus pathogenesis is urgently needed, and discovering or developing promising drugs based on potential targets is the most pressing need. Therefore, we summarize the potential therapeutic targets involved in virus pathogenesis and discuss the advancements, possibilities and significance of promising drugs based on these targets for treating SARS‐CoV‐2. This review will facilitate the identification of potential targets and provide promising clues for drug development that can be translated into clinical applications for combating SARS‐CoV‐2.

positive: Dual-Histamine Blockade with Cetirizine - Famotidine Reduces Pulmonary Symptoms in COVID-19 Patients Background: The COVID-19 pandemic due to SARS-CoV-2 infection can produce Acute Respiratory Distress Syndrome as a result of a pulmonary cytokine storm. Antihistamines are safe and effective treatments for reducing inflammation and cytokine release. Combinations of Histamine-1 and Histamine-2 receptor antagonists have been effective in urticaria, and might reduce the histamine-mediated pulmonary cytokine storm in COVID-19. Can a combination of Histamine-1 and Histamine-2 blockers improve COVID-19 inpatient outcomes? Methods: A physician-sponsored cohort study of cetirizine and famotidine was performed in hospitalized patients with severe to critical pulmonary symptoms. Pulmonologists led the inpatient care in a single medical center of 110 high-acuity patients that were treated with cetirizine 10 mg and famotidine 20 mg b.i.d. plus standard-of-care. Results: Of all patients, including those with Do Not Resuscitate directives, receiving the dual-histamine blockade for at least 48 hours, the combination drug treatment resulted in a 16.4% rate of intubation, a 7.3% rate of intubation after a minimum of 48 hours of treatment, a 15.5% rate of inpatient mortality, and 11.0 days duration of hospitalization. The drug combination exhibited reductions in symptom progression when compared to published reports of COVID-19 patients. Concomitant medications were assessed and hydroxychloroquine was correlated with worse outcomes. Conclusions: This physician-sponsored cohort study of cetirizine and famotidine provides proof-of-concept of a new safe and effective method to reduce the progression in symptom severity, presumably by minimizing the histamine-mediated cytokine storm. Further clinical studies in COVID-19 are warranted of the repurposed off-label combination of two historically-safe histamine blockers.

positive: Host Immune Response and Immunobiology of Human SARS-CoV-2 Infection One of the most serious viral outbreaks of the decade, infecting humans, originated from the city of Wuhan, China, by the end of December 2019, has left the world shaken up. It is the successor infection of severe acute respiratory syndrome coronavirus (SARS-CoV) named as SARS-CoV-2 causing a disease called as COVID-19 (Coronavirus disease-19). Being one of the most severe diseases in terms of transmission, this disease agitates the immune system of an individual quite disturbingly which at times leads to death, which is why it has become the need of the hour to step forward to extensively involve in understanding the genetics, pathogenesis, and immunopathology of SARS-CoV-2 in order to design drugs to treat or to design a vaccine to prevent. In this chapter, we have tried to review and summarize the studies done so far to understand the host–pathogen relationship and the host immune response during COVID-19 infection. One of the recent developments regarding the understanding of SARS-CoV-2 infection is the mechanism of immune evasion involved during the pathogenesis and cytokine storm syndrome during infection in the patient against which a drug called as Hydroxychloroquine has been designed. Comprehensively, we have tried to give an immunological insight into the SARS-CoV-2 infection in order to understand the possible outcome for any therapeutic advancement.

positive: Cytokine storm induced by SARS-CoV-2 Coronavirus disease 2019 (COVID-19), caused by the virus designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread widely throughout the world. Despite the strict global outbreak management and quarantine measures that have been implemented, the incidence of COVID-19 continues to rise, resulting in more than 290,000 deaths and representing an extremely serious threat to human life and health. The clinical symptoms of the affected patients are heterogeneous, ranging from mild upper respiratory symptoms to severe pneumonitis and even acute respiratory distress syndrome (ARDS) or death. Systemic immune over activation due to SARS-CoV-2 infection causes the cytokine storm, which is especially noteworthy in severely ill patients with COVID-19. Pieces of evidence from current studies have shown that the cytokine storm may be an important factor in disease progression, even leading to multiple organ failure and death. This review provides an overview of the knowledge on the COVID-19 epidemiological profile, the molecular mechanisms of the SARS-CoV-2-induced cytokine storm and immune responses, the pathophysiological changes that occur during infection, the main antiviral compounds used in treatment strategies and the potential drugs for targeting cytokines, this information is presented to provide valuable guidance for further studies and for a therapeutic reduction of this excessive immune response.

positive: Network pharmacological analysis and mechanism prediction of Xiaochaihu Decoction in treatment of COVID-19 with syndrome of pathogenic heat lingering in lung and obstructive cardinalate/ 小柴胡汤治疗早期新型冠状病毒肺炎（COVID-19）邪热郁肺、枢机不利证功效网络分析与机制预测 Objective: To study the efficacy network and potential mechanism of Xiaochaihu Decoction (XCHD) in the treatment of coronavirus disease 2019 (COVID-19) with syndrome of pathogenic heat lingering in the lung and obstructive cardinalat, and analyze the active ingredients of XCHD with anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) efficacy. Methods: The correspondence between COVID-19 and XCHD was analyzed by literature consulting. Based on network pharmacology, Cytoscape 3.6.0 and other software were then used to construct XCHD efficacy network of “Chinese medicine prescription-active ingredient-key target” for pneumonia and immune regulation, in order to confirm anti-SARS-CoV-2 active ingredients in the prescription. Some softwares were used to analyze XCHD for COVID-19 treatment in multiple aspects. Results: A total of 48 active ingredients with potential anti-SARS-CoV-2 effect in herbs were collected; 140 active ingredients in XCHD for pneumonia treatment and immune regulation were analyzed, of which 12 ingredients had direct anti-SARS-CoV-2 activity including baicalein, formononetin, quercetin, etc. The active ingredients in XCHD exerted efficacy for pneumonia treatment and immunoregulation through 95 key targets such as IL-6, NOS2, and ESR1, involving multiple pathways such as the TNF signaling pathway, IL-17 signaling pathway, and influenza A. Analysis of gene co-expression and PPI interaction analysis found that ACE2 only co-expressed with NOS2 in the above targets, and also interacted with only five targets in the PPI interaction network. It is speculated that the ACE2 target only plays an important role when SARS-CoV-2 invaded the human body, and had little effect in the treatment of pneumonia after viral infection. Conclusion: The active ingredients in XCHD play a role in treating COVID-19 by inhibiting SARS-CoV-2 activity, blocking the SARS-CoV-2 invasion pathway, inhibiting cytokine storm, and regulating immunity. It is worth noting that drugs designed for the ACE2 target can block virus invasion, but may not be effective for diseases such as alveolar inflammation, Therefore, this study also provides a multi-target and multi-directional space for XCHD for early COVID-19 treatment. In addition, when XCHD is used in the early treatment of COVID-19, we should pay attention to the precise use of drugs based on syndrome accurate identification, one is to avoid adverse reactions, the other is to avoid cytokine damage caused by re-crown disease.

positive: Redox Biology of Respiratory Viral Infections Respiratory viruses cause infections of the upper or lower respiratory tract and they are responsible for the common cold—the most prevalent disease in the world. In many cases the common cold results in severe illness due to complications, such as fever or pneumonia. Children, old people, and immunosuppressed patients are at the highest risk and require fast diagnosis and therapeutic intervention. However, the availability and efficiencies of existing therapeutic approaches vary depending on the virus. Investigation of the pathologies that are associated with infection by respiratory viruses will be paramount for diagnosis, treatment modalities, and the development of new therapies. Changes in redox homeostasis in infected cells are one of the key events that is linked to infection with respiratory viruses and linked to inflammation and subsequent tissue damage. Our review summarizes current knowledge on changes to redox homeostasis, as induced by the different respiratory viruses.

positive: Repositioning PARP inhibitors for SARS-CoV-2 infection(COVID-19); a new multi-pronged therapy for acute respiratory distress syndrome? Clinically approved PARP inhibitors (PARPi) have a mild adverse effect profile and are well tolerated as continuous daily oral therapy. We review the evidence that justifies the repurposing of PARPi to block the proliferation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and combat the life-threatening sequelae of coronavirus disease 2019 (COVID-19) by several mechanisms. PARPi can effectively decrease IL-6, IL-1 and TNF-α levels (key interleukins in SARS-CoV-2-induced cytokine storm) and can alleviate subsequent lung fibrosis, as demonstrated in murine experiments and clinical trials. PARPi can tune macrophages towards a tolerogenic phenotype. PARPi may also counteract SARS-CoV-2-induced and inflammation-induced cell death and support cell survival. PARPi is effective in animal models of acute respiratory distress syndrome (ARDS), asthma and ventilator-induced lung injury. PARPi may potentiate the effectiveness of tocilizumab, anakinra, sarilumab, adalimumab, canakinumab or siltuximab therapy. The evidence suggests that PARPi would benefit COVID-19 patients and trials should be undertaken.

positive: Could Sars-coronavirus-2 trigger autoimmune and/or autoinflammatory mechanisms in genetically predisposed subjects?

positive: Successful treatment with plasma exchange followed by intravenous immunoglobulin in a critically ill patient with COVID-19 Here we report a case of a laboratory-confirmed 2019 novel coronavirus (2019-nCoV)-infected patient with COVID-19 (coronavirus disease 2019) who developed respiratory failure and shock accompanied by persistent diarrhoea despite conventional therapeutic interventions. The patient avoided mechanical ventilation and showed an immediate clinical and radiological improvement following treatment with intensive plasma exchange (PE) followed by intravenous immunoglobulin (IVIG). Successful therapeutic strategies in this case suggest that timely initiation of PE treatment followed by IVIG in critically ill patients with COVID-19 may prevent the disease from worsening and help to reduce the requirement for mechanical ventilation and intensive supportive care. Moreover, it may improve poor clinical outcomes of these patients.

positive: Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome The outbreak of Coronavirus Disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, December 2019, and continuously poses a serious threat to public health. Our previous study has shown that cytokine storm occurred during SARS-CoV-2 infection, while the detailed role of cytokines in the disease severity and progression remained unclear due to the limited case number. In this study, we examined 48 cytokines in the plasma samples from 53 COVID-19 cases, among whom 34 were severe cases, and the others moderate. Results showed that 14 cytokines were significantly elevated upon admission in COVID-19 cases. Moreover, IP-10, MCP-3, and IL-1ra were significantly higher in severe cases, and highly associated with the PaO2/FaO2 and Murray score. Furthermore, the three cytokines were independent predictors for the progression of COVID-19, and the combination of IP-10, MCP-3 and IL-1ra showed the biggest area under the curve (AUC) of the receiver-operating characteristics (ROC) calculations. Serial detection of IP-10, MCP-3 and IL-1ra in 14 severe cases showed that the continuous high levels of these cytokines were associated with disease deterioration and fatal outcome. In conclusion, we report three cytokines that closely associated with disease severity and outcome of COVID-19. These findings add to our understanding of the immunopathologic mechanisms of SARS-CoV-2 infection, which suggested novel therapeutic targets and strategy.

positive: A complex COVID-19 case with rheumatoid arthritis treated with tocilizumab Recurrences of COVID-19 were observed in a patient with long-term usage of hydroxychloroquine, leflunomide, and glucocorticoids due to her 30-year history of rheumatoid arthritis (RA). Tocilizumab was applied and intended to target both COVID-19 and RA. However, disease of this patient aggravated after usage of tocilizumab. After the discussion of a multiple disciplinary team (MDT) including rheumatologists, antimicrobial treatments were applied to target the potential opportunistic infections (Pneumocystis jirovecii and Aspergillus fumigatus), which were authenticated several days later via high throughput sequencing. As an important cytokine in immune responses, IL-6 can be a double-edged sword: interference in the IL-6-IL-6 receptor signaling may save patients from cytokine release storm (CRS), but can also weaken the anti-infectious immunity, particularly in rheumatic patients, who may have received a long-term treatment with immunosuppressive/modulatory agents. Thus, we suggest careful considerations before and close monitoring in the administration of tocilizumab in rheumatic patients with COVID-19. Besides tocilizumab, several disease-modifying antirheumatic drugs (DMARDs) can also be applied in the treatment of COVID-19. Therefore, we also reviewed and discussed the application of these DMARDs in COVID-19 condition.

positive: Novel therapeutic approaches for treatment of COVID-19 To date, there is no licensed treatment or approved vaccine to combat the coronavirus disease of 2019 (COVID-19), and the number of new cases and mortality multiplies every day. Therefore, it is essential to develop an effective treatment strategy to control the virus spread and prevent the disease. Here, we summarized the therapeutic approaches that are used to treat this infection. Although it seems that antiviral drugs are effective in improving clinical manifestation, there is no definite treatment protocol. Lymphocytopenia, excessive inflammation, and cytokine storm followed by acute respiratory distress syndrome are still unsolved issues causing the severity of this disease. Therefore, immune response modulation and inflammation management can be considered as an essential step. There is no doubt that more studies are required to clarify immunopathogenesis and immune response; however, new therapeutic approaches including mesenchymal stromal cell and immune cell therapy showed inspiring results.

positive: Coronavirus Disease 2019 (COVID-19): Cytokine Storms, Hyper-Inflammatory Phenotypes, and Acute Respiratory Distress Syndrome Abstract Coronavirus Disease 2019 (COVID-19) was first identified in China at the end of 2019. Acute respiratory distress syndrome (ARDS) represents the most common and serious complication of COVID-19. Cytokine storms are a pathophysiological feature of COVID-19 and play an important role in distinguishing hyper-inflammatory subphenotypes of ARDS. Accordingly, in this review, we focus on hyper-inflammatory host responses in ARDS that play a critical role in the differentiated development of COVID-19. Furthermore, we discuss inflammation-related indicators that have the potential to identify hyper-inflammatory subphenotypes of COVID-19, especially for those with a high risk of ARDS. Finally, we explore the possibility of improving the quality of monitoring and treatment of COVID-19 patients and in reducing the incidence of critical illness and mortality via better distinguishing hyper- and hypo-inflammatory subphenotypes of COVID-19.

positive: Host-directed therapies for infectious diseases: current status, recent progress, and future prospects Despite extensive global efforts in the fight against killer infectious diseases, they still cause one in four deaths worldwide and are important causes of long-term functional disability arising from tissue damage. The continuing epidemics of tuberculosis, HIV, malaria, and influenza, and the emergence of novel zoonotic pathogens represent major clinical management challenges worldwide. Newer approaches to improving treatment outcomes are needed to reduce the high morbidity and mortality caused by infectious diseases. Recent insights into pathogen–host interactions, pathogenesis, inflammatory pathways, and the host's innate and acquired immune responses are leading to identification and development of a wide range of host-directed therapies with different mechanisms of action. Host-directed therapeutic strategies are now becoming viable adjuncts to standard antimicrobial treatment. Host-directed therapies include commonly used drugs for non-communicable diseases with good safety profiles, immunomodulatory agents, biologics (eg monoclonal antibodies), nutritional products, and cellular therapy using the patient's own immune or bone marrow mesenchymal stromal cells. We discuss clinically relevant examples of progress in identifying host-directed therapies as adjunct treatment options for bacterial, viral, and parasitic infectious diseases.

positive: Thrombotic complications of COVID-19 may reflect an upregulation of endothelial tissue factor expression that is contingent on activation of endosomal NADPH oxidase The high rate of thrombotic complications associated with COVID-19 seems likely to reflect viral infection of vascular endothelial cells, which express the ACE2 protein that enables SARS-CoV-2 to invade cells. Various proinflammatory stimuli can promote thrombosis by inducing luminal endothelial expression of tissue factor (TF), which interacts with circulating coagulation factor VII to trigger extrinsic coagulation. The signalling mechanism whereby these stimuli evoke TF expression entails activation of NADPH oxidase, upstream from activation of the NF-kappaB transcription factor that drives the induced transcription of the TF gene. When single-stranded RNA viruses are taken up into cellular endosomes, they stimulate endosomal formation and activation of NADPH oxidase complexes via RNA-responsive toll-like receptor 7. It is therefore proposed that SARS-CoV-2 infection of endothelial cells evokes the expression of TF which is contingent on endosomal NADPH oxidase activation. If this hypothesis is correct, hydroxychloroquine, spirulina (more specifically, its chromophore phycocyanobilin) and high-dose glycine may have practical potential for mitigating the elevated thrombotic risk associated with COVID-19.

positive: Can cell therapies halt cytokine storm in severe COVID-19 patients? A pilot study of COVID-19 patients treated with mesenchymal stem cells demonstrates safety. Mesenchymal stromal cell (MSC) therapies, which have been explored for decades as a treatment for inflammatory diseases, are now being called into action to combat the cytokine storm induced by COVID-19. The severity of COVID-19 may be due in part to the patient's response to the infection. In some patients, the virus induces an outpouring of inflammatory mediators that leads to swelling, inflammatory infiltration, and reduced gas exchange in the alveoli of the lungs. To combat this cytokine storm, over 20 clinical trials aiming to treat COVID-19 with MSCs have been registered with ClinicalTrials.gov. Leng et al. recently conducted a pilot study of MSC transplantation in 10 patients in China. All patients tested positive for SARS-CoV-2 by polymerase chain reaction and had fever, shortness of breath, cough, and oxygen saturation at rest <95%. Seven of the patients received intravenous infusions of allogeneic MSCs while three received saline as a placebo control. All seven MSC treated patients experienced resolution of symptoms while one of the placebo-treated patients went on to develop ARDS and another died. The response of the most severely ill patient treated with MSCs was monitored throughout recovery. Of note, C-reactive protein levels dropped 10-fold after MSC treatment, suggesting a drop in systemic inflammation. Analysis of cytokine levels before and after treatment revealed that MSC treatment, but not placebo, was associated with a halt in the increase of serum tumor necrosis factor–α and an increase in anti-inflammatory interleukin-10 concentrations in the serum. Although this study is not designed to make definitive claims regarding the efficacy of MSC therapy for COVID-19 or the mechanisms by which MSCs may function to prevent or treat cytokine storm, it does provide important safety data and hints of efficacy that have motivated further exploration of MSCs as a treatment for COVID-19. Of particular note is a randomized, multicenter, placebo-controlled, Phase 2/3 trial enrolling 240 patients being conducted through a public-private partnership between the U.S. National Institutes of Health–funded Cardiothoracic Surgical Trials Network and Mesoblast. As multiple clinical trials are launched around the world, we should not have to wait long to determine if MSCs are a viable and effective treatment option for severe COVID-19.

positive: Cardiovascular Impairment in COVID-19: Learning From Current Options for Cardiovascular Anti-Inflammatory Therapy In December 2019, Coronavirus Disease 2019 (COVID-19) caused by SARS-CoV-2, occurred in China and has currently led to a global pandemic. In addition to respiratory involvement, COVID-19 was also associated with significant multiple organ dysfunction syndrome (MODS). Cardiovascular impairment has been observed and is now drawing growing attention. Cardiovascular protective strategies are urgent and of great significance to the overall prognosis of COVID-19 patients. Direct viral infection, cytokine storm, and aggravation of existing cardiovascular diseases were recognized as possible mechanisms of cardiovascular impairment in COVID-19. Hyperactivated inflammation plays an important role in all three mechanisms and is considered to be fundamental in the development of cardiovascular impairment and MODS in COVID-19. Therefore, in addition to conventional cardiovascular treatment, anti-inflammatory therapy is a reasonable strategy for severe cases to further enhance cardiovascular protection and potentially mitigate MODS. We reviewed the inflammatory features and current promising treatments of COVID-19 as well as cardiovascular anti-inflammatory therapies that have been verified in previous clinical trials with positive outcomes. We believe that targeting the central pathway (IL-1β, TNF-α, IL-6), balancing the Th1 and Th2 response, and administering long-term anti-inflammatory therapy might be promising prospects to reduce cardiovascular impairment and even MODS during the acute and recovery phases of COVID-19. The cardiovascular anti-inflammatory therapies might be of great application value to the management of COVID-19 patients and we further propose an algorithm for the selection of anti-inflammatory therapy for COVID-19 patients with or at high risk of cardiovascular impairment. We recommend to take the experiences in cardiovascular anti-inflammatory therapy as references in the management of COVID-19 and conduct related clinical trials, while the clinical translation of novel treatments from preclinical studies or in vitro drug screening should proceed with caution due to unguaranteed efficacy and safety profiles.

positive: Is there a role for blood purification therapies targeting cytokine storm syndrome in critically severe COVID-19 patients? The coronavirus disease-19 (COVID-19) has spread over many countries and regions since the end of 2019, becoming the most severe public health event at present. Most of the critical cases developed multiple organ dysfunction, including acute kidney injury (AKI). Cytokine storm syndrome (CSS) may complicate the process of severe COVID-19 patients. This manuscript reviews the different aspects of blood purification in critically ill patients with AKI and increased inflammatory factors, and examines its potential role in severe COVID-19 treatment. Continuous renal replacement therapy (CRRT) has been practiced in many sepsis patients with AKI. Still, the timing and dosing need further robust evidence. In addition to the traditional CRRT, the high-throughput membrane with adsorption function and cytokine adsorption column are two representatives of recently emerging novel membrane technologies. Their potential in removing inflammatory factors and other toxins prospects for the treatment of severe COVID-19.

positive: Targeting T-cell senescence and cytokine storm with rapamycin to prevent severe progression in COVID-19

positive: Considerations on Biologicals for Patients with allergic disease in times of the COVID‐19 pandemic: an EAACI Statement The outbreak of the SARS‐CoV‐2‐induced Coronavirus Disease 2019 (COVID‐19) pandemic re‐shaped doctor‐patient interaction and challenged capacities of healthcare systems. It created many issues around the optimal and safest way to treat complex patients with severe allergic disease. A significant numberof the patients are on treatment with biologicals and clinicians face the challenge to provide optimal care during the pandemic. Uncertainty of the potential risks for these patients is related to the fact that the exact sequence of immunological events during SARS‐CoV‐2 is not known. Severe COVID‐19 patients may experience a “cytokine storm” and associated organ damage characterized by an exaggerated release of proinflammatory type 1 and type 3 cytokines. These inflammatory responses are potentially counteracted by anti‐inflammatory cytokines and type 2 responses. This expert based EAACI statement aims to provide guidance on the application of biologicals targeting type 2 inflammation in patients with allergic disease. Currently, there is very little evidence for an enhanced risk of patients with allergic diseases to develop severe COVID‐19 with studies focusing on severe allergic phenotypes lacking. At present, non‐infected patients on biologicals for the treatment of asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps or chronic spontaneous urticaria should continue their biologicals targeting type 2 inflammation via self‐application. In case of an active SARS‐CoV‐2 infection, biological treatment needs to be stopped until clinical recovery and SARS‐CoV‐2 negativity is established and treatment with biologicals should be re‐initiated. Maintenance of add‐on therapy and a constant assessment of disease control, apart from acute management is demanded.

positive: Lessons learned and concepts formed from study of the pathogenesis of the two negative-strand viruses lymphocytic choriomeningitis and influenza. Viruses have unique lifestyles. To describe the pathogenesis and significance of viral infection in terms of host responses, resultant injury, and therapy, we focused on two RNA viruses: lymphocytic choriomeningitis (LCMV) and influenza (Flu). Many of the currently established concepts and consequences about viruses and immunologic tolerance, virus-induced immunosuppression, virus-induced autoimmunity, immune complex disease, and virus-lymphocyte and virus-dendritic cell interactions evolved through studies of LCMV in its natural murine host. Similarly, the mechanisms, aftermath, and treatment of persistent RNA viruses emerged, in large part, from research on LCMV. Analysis of acute influenza virus infections uncovered the prominent direct role that cytokine storm plays in the pathogenesis, morbidity, and mortality from this disease. Cytokine storm of influenza virus infection is initiated via a pulmonary endothelial cell amplification loop involving IFN-producing cells and virus-infected pulmonary epithelial cells. Importantly, the cytokine storm is chemically treatable with specific agonist therapy directed to the sphingosphine 1 phosphate receptor 1, which is located on pulmonary endothelial cells, pointing to the endothelial cells as the gatekeepers of this hyperaggressive host immune response.

positive: COVID-19-associated cardiovascular morbidity in older adults: a position paper from the Italian Society of Cardiovascular Researches Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells following binding with the cell surface ACE2 receptors, thereby leading to coronavirus disease 2019 (COVID-19). SARS-CoV-2 causes viral pneumonia with additional extrapulmonary manifestations and major complications, including acute myocardial injury, arrhythmia, and shock mainly in elderly patients. Furthermore, patients with existing cardiovascular comorbidities, such as hypertension and coronary heart disease, have a worse clinical outcome following contraction of the viral illness. A striking feature of COVID-19 pandemics is the high incidence of fatalities in advanced aged patients: this might be due to the prevalence of frailty and cardiovascular disease increase with age due to endothelial dysfunction and loss of endogenous cardioprotective mechanisms. Although experimental evidence on this topic is still at its infancy, the aim of this position paper is to hypothesize and discuss more suggestive cellular and molecular mechanisms whereby SARS-CoV-2 may lead to detrimental consequences to the cardiovascular system. We will focus on aging, cytokine storm, NLRP3/inflammasome, hypoxemia, and air pollution, which is an emerging cardiovascular risk factor associated with rapid urbanization and globalization. We will finally discuss the impact of clinically available CV drugs on the clinical course of COVID-19 patients. Understanding the role played by SARS-CoV2 on the CV system is indeed mandatory to get further insights into COVID-19 pathogenesis and to design a therapeutic strategy of cardio-protection for frail patients.

positive: ß-Glucan extracts from the same edible shiitake mushroom Lentinus edodes produce differential in-vitro immunomodulatory and pulmonary cytoprotective effects - Implications for coronavirus disease (COVID-19) immunotherapies Coronavirus pneumonia is accompanied by rapid virus replication, where a large number of inflammatory cell infiltration and cytokine storm may lead to acute lung injury, acute respiratory distress syndrome (ARDS) and death. The uncontrolled release of pro-inflammatory cytokines, including interleukin (IL)-1ß and IL-6, is associated with ARDS. This constituted the first study to report on the variability in physicochemical properties of ß-glucans extracts from the same edible mushroom Lentinus edodes on the reduction of these pro-inflammatory cytokines and oxidative stress. Specifically, the impact on the immunomodulatory and cytoprotective properties of our novel in 'house' (IH-Lentinan, IHL) and a commercial (Carbosynth-Lentinan, CL) Lentinan extract were investigated using in vitro models of lung injury and macrophage phagocytosis. CL comprised higher amounts of α-glucans and correspondingly less ß-glucans. The two lentinan extracts demonstrated varying immunomodulatory activities. Both Lentinan extracts reduced cytokine-induced NF-κB activation in human alveolar epithelial A549 cells, with the IHL extract proving more effective at lower doses. In contrast, in activated THP-1 derived macrophages, the CL extract more effectively attenuated pro-inflammatory cytokine production (TNF-α, IL-8, IL-2, IL-6, IL-22) as well as TGF-ß and IL-10. The CL extract attenuated oxidative stress-induced early apoptosis, while the IHL extract attenuated late apoptosis. Our findings demonstrate significant physicochemical differences between Lentinan extracts, which produce differential in vitro immunomodulatory and pulmonary cytoprotective effects that may also have positive relevance to candidate COVID-19 therapeutics targeting cytokine storm.

positive: SARS‐CoV‐2 virus and liver expression of host receptors: Putative mechanisms of liver involvement in COVID‐19 Zhang et al. showed that COVID‐19 affected patients’ present liver biochemistry abnormalities, including elevation of aminotransferases, gamma‐glutamyl transferase, and alkaline phosphatase (1). Hence, several possible clinical scenarios in the setting of liver diseases have been postulated. First, patients with chronic liver disease may be more vulnerable to the severe clinical consequences of COVID‐19, including oxygen desaturation and hypoxemia due to severe pneumonia or the cytokine storm (1;2). Second, liver biochemistry abnormalities are the consequence of drug toxicity.

positive: Severe COVID-19 and aging: are monocytes the key? The ongoing pandemic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes a disproportionate number of severe cases and deaths in older adults. Severe SARS-CoV-2-associated disease (coronavirus disease 2019 (COVID-19)) was declared a pandemic by the World Health Organization in March 2020 and is characterized by cytokine storm, acute respiratory distress syndrome, and in some cases by systemic inflammation–related pathology. Currently, our knowledge of the determinants of severe COVID-19 is primarily observational. Here, I review emerging evidence to argue that monocytes, a circulating innate immune cell, are principal players in cytokine storm and associated pathologies in COVID-19. I also describe changes in monocyte function and phenotype that are characteristic of both aging and severe COVID-19, which suggests a potential mechanism underlying increased morbidity and mortality due to SARS-CoV-2 infection in older adults. The innate immune system is therefore a potentially important target for therapeutic treatment of COVID-19, but experimental studies are needed, and SARS-CoV-2 presents unique challenges for pre-clinical and mechanistic studies in vivo. The immediate establishment of colonies of SARS-CoV-2-susceptible animal models for aging studies, as well as strong collaborative efforts in the geroscience community, will be required in order to develop the therapies needed to combat severe COVID-19 in older adult populations.

positive: Silibinin and SARS-CoV-2: Dual Targeting of Host Cytokine Storm and Virus Replication Machinery for Clinical Management of COVID-19 Patients. COVID-19, the illness caused by infection with the novel coronavirus SARS-CoV-2, is a rapidly spreading global pandemic in urgent need of effective treatments. Here we present a comprehensive examination of the host- and virus-targeted functions of the flavonolignan silibinin, a potential drug candidate against COVID-19/SARS-CoV-2. As a direct inhibitor of STAT3-a master checkpoint regulator of inflammatory cytokine signaling and immune response-silibinin might be expected to phenotypically integrate the mechanisms of action of IL-6-targeted monoclonal antibodies and pan-JAK1/2 inhibitors to limit the cytokine storm and T-cell lymphopenia in the clinical setting of severe COVID-19. As a computationally predicted, remdesivir-like inhibitor of RNA-dependent RNA polymerase (RdRp)-the central component of the replication/transcription machinery of SARS-CoV-2-silibinin is expected to reduce viral load and impede delayed interferon responses. The dual ability of silibinin to target both the host cytokine storm and the virus replication machinery provides a strong rationale for the clinical testing of silibinin against the COVID-19 global public health emergency. A randomized, open-label, phase II multicentric clinical trial (SIL-COVID19) will evaluate the therapeutic efficacy of silibinin in the prevention of acute respiratory distress syndrome in moderate-to-severe COVID-19-positive onco-hematological patients at the Catalan Institute of Oncology in Catalonia, Spain.

positive: Pathogenesis of COVID-19 from the Perspective of the Damage-Response Framework The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents the medical community with a significant challenge. COVID-19 is an entirely new disease with disparate clinical manifestations that are difficult to reconcile with a single pathogenic principle. Here, we explain how the flexible paradigm of the “damage-response framework” (DRF) of microbial pathogenesis can organize the varied manifestations of COVID-19 into a synthesis that accounts for differences in susceptibility of vulnerable populations as well as for differing manifestations of COVID-19 disease. By focusing on mechanisms of host damage, particularly immune-mediated damage, the DRF provides a lens to understand COVID-19 pathogenesis and to consider how potential therapies could alter the outcome of this disease.

positive: Intravenous Anakinra for Macrophage Activation Syndrome May Hold Lessons for Treatment of Cytokine Storm in the Setting of Coronavirus Disease 2019 Macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH) are increasingly recognized as being on a continuum of cytokine storm syndromes, with different initiating pathways culminating in cytotoxic dysfunction and uncontrolled activation and proliferation of T lymphocytes and macrophages. The activated immune cells produce large amounts of proinflammatory cytokines, including interleukin 1β (IL)‐1β. Management depends on the recognized diagnosis. In the setting of a cytokine storm syndrome and infection, collaborative involvement of specialists, including infectious disease and rheumatology is ideal. Anakinra, a recombinant IL‐1 receptor antagonist, has been used subcutaneously and intravenously in pediatric patients and is considered a first‐line treatment for MAS and secondary HLH (sHLH) among many pediatric rheumatologists. Previous reports of anakinra used in adults for treatment of MAS or sHLH are limited to subcutaneous administration. In this issue, Moneagudo et al. present a series of adult patients with sHLH treated with intravenous anakinra, including patients in whom subcutaneous anakinra was insufficient. As the authors suggest, there is a potential therapeutic use for anakinra in sHLH or the cytokine storm syndrome triggered by COVID19. Trial design will be key, with the patient subpopulation, timing of intervention, and doses tested important.

positive: The Establishment and Validation of the Human U937 Cell Line as a Cellular Model to Screen Immunomodulatory Agents Regulating Cytokine Release Induced by Influenza Virus Infection Severe influenza infections are often associated with the excessive induction of pro-inflammatory cytokines, which is also referred to as “cytokine storms”. Several studies have shown that cytokine storms are directly associated with influenza-induced fatal acute lung injury and acute respiratory distress syndrome. Due to the narrow administration window, current antiviral therapies are often inadequate. The efforts to use immunomodulatory agents alone or in combination with antiviral agents in the treatment of influenza in animal models have resulted in the achievement of protective effects accompanied with reduced cytokine production. Currently, there are no immunomodulatory drugs for influenza available for clinical use. Animal models, despite being ideal to study the anti-inflammatory responses to influenza virus infection, are very costly and time-consuming. Therefore, there is an urgent need to establish fast and economical screening methods using cell-based models to screen and develop novel immunomodulatory agents. In this study, we screened seven human cell lines and found that the human monocytic cell U937 supports the replication of different subtypes of influenza viruses as well as the production of the important pro-inflammatory cytokines and was selected to develop the cell-based model. The U937 cell model was validated by testing a panel of known antiviral and immunomodulatory agents and screening a drug library consisting of 1280 compounds comprised mostly of FDA-approved drugs. We demonstrated that the U937 cell model is robust and suitable for the high-throughput screening of immunomodulators and antivirals against influenza infection. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12250-019-00145-w) contains supplementary material, which is available to authorized users.

positive: Propuesta de uso de anakinra en el distrés respiratorio agudo secundario a COVID-19./ Propuesta de uso de anakinra en el distrés respiratorio agudo secundario a COVID-19./ Proposal for the use of anakinra in acute respiratory distress secondary to COVID-19 The outcome of the SARS-CoV-2 (COVID-19) infection fundamentally affects the lung field, causing acute respiratory distress syndrome (ARDS). This process is an inflammatory picture, involving an NLRP3 inflamosome-triggered cytokine storm, the main player in alveolar destruction. IL-1 beta stands out among the cytokines that are triggered in this picture. Anakinra is a potent biological drug, capable of blocking this IL-1ß. We propose its use in controlling ARDS secondary to COVID-19 infection.

positive: Potential Treatments for COVID-19 Related Cytokine Storm - Beyond Corticosteroids

positive: Lymphopenia in COVID-19: Therapeutic opportunities Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is uncontrollably spread all over the world. The host immune responses strongly try to confront it with all the potential cells and cytokines. With chronically condition of SARS-CoV-2, natural killer cells and T cells become exhausted and decreasing their count leads to lymphopenia. Inability to eradicate the infected organ makes hyperinitiation of the immune system, which releases the excessive inflammatory cytokines to compensate the exhausted one as well as the low lymphocytes counts; it consequently leads to the cytokine storm syndrome. These mechanisms and the potential therapeutic targeting are discussed in this paper.

positive: Acute myocardial injury in patients hospitalized with COVID-19 infection: A review The Coronavirus Disease 2019 (COVID-19) is now a global pandemic with millions affected and millions more at risk for contracting the infection. The COVID-19 virus, SARS-CoV-2, affects multiple organ systems particularly the lungs and heart. Elevation of cardiac biomarkers, particularly high-sensitivity troponin and/or creatine kinase MB, is common in patients with COVID-19 infection. In our review of clinical studies, we found that in 26 studies including 11,685 patients, the weighted pooled prevalence of acute myocardial injury was 20% (ranged from 5% to 38% depending on the criteria used). The plausible mechanisms of myocardial injury include, 1) hyperinflammation and cytokine storm mediated through pathologic T-cells and monocytes leading to myocarditis, 2) respiratory failure and hypoxemia resulting in damage to cardiac myocytes, 3) down regulation of ACE2 expression and subsequent protective signaling pathways in cardiac myocytes, 4) hypercoagulability and development of coronary microvascular thrombosis, 5) diffuse endothelial injury and ‘endotheliitis’ in several organs including heart, and, 6) inflammation and/or stress causing coronary plaque rupture or supply-demand mismatch leading to myocardial ischemia/infarction. Cardiac biomarkers can be used to aid in diagnosis as well as risk stratification. In patients with elevated hs-troponin, clinical context is important and myocarditis as well as stress induced cardiomyopathy should be considered in the differential, along with type I and type II myocardial infarction. Irrespective of etiology, patients with acute myocardial injury should be prioritized for treatment. Clinical decisions including interventions should be individualized and carefully tailored after thorough review of risks/benefits. Given the complex interplay of SARS-CoV-2 with the cardiovascular system, further investigation into potential mechanisms is needed to guide effective therapies. Randomized trials are urgently needed to investigate treatment modalities to reduce the incidence and mortality associated with COVID-19 related acute myocardial injury.

positive: SARS‐CoV‐2, the Virus that Causes COVID‐19: Cytometry and the New Challenge for Global Health

positive: Use of glucocorticoids in patients with adrenal insufficiency and COVID-19 infection

positive: Is COVID-19 receiving ADE from other coronaviruses? Abstract One of the most perplexing questions regarding the current COVID-19 coronavirus epidemic is the discrepancy between the severity of cases observed in the Hubei province of China and those occurring elsewhere in the world. One possible answer is antibody dependent enhancement (ADE) of SARS-CoV-2 due to prior exposure to other coronaviruses. ADE modulates the immune response and can elicit sustained inflammation, lymphopenia, and/or cytokine storm, one or all of which have been documented in severe cases and deaths. ADE also requires prior exposure to similar antigenic epitopes, presumably circulating in local viruses, making it a possible explanation for the observed geographic limitation of severe cases and deaths.

positive: Targeting Cytokine Storm to Manage Patients with COVID-19: A Mini-Review Abstract Corona Virus Disease 2019 (COVID-19) pandemic is rapidly spreading all over the world. Excessive immune responses trigger life-threatening cytokine release syndrome (CRS) which can result in overproduction of pro-inflammatory cytokines including tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and IL-1β with different pro-inflammatory roles. Anecdotal evidence suggests that the modulation of systemic immune responses may have a potential role in the treatment of patients with COVID-19. Given the importance of the issue and the lack of therapeutic treatment or vaccine; anti-cytokine therapy such as IL-6, TNFα and IL-1 antagonists have been suggested for the alleviation of hyper-inflammation status in these patients. In this mini-review, we addressed the inflammatory pathways of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its relationship with the host cytokine storm. Furthermore, the proposed therapeutic options to reverse hyper-inflammation in infected patients were mentioned.

positive: Transcription Factor Nrf2 as a Potential Therapeutic Target for Prevention of Cytokine Storm in COVID-19 Patients Nrf2 is a key transcription factor responsible for antioxidant defense in many tissues and cells, including alveolar epithelium, endothelium, and macrophages. Furthermore, Nrf2 functions as a transcriptional repressor that inhibits expression of the inflammatory cytokines in macrophages. Critically ill patients with COVID-19 infection often present signs of high oxidative stress and systemic inflammation – the leading causes of mortality. This article suggests rationale for the use of Nrf2 inducers to prevent development of an excessive inflammatory response in COVID-19 patients.

positive: Rheumatologists' perspective on coronavirus disease 19 (COVID-19) and potential therapeutic targets The ongoing pandemic coronavirus disease 19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a matter of global concern. Environmental factors such as air pollution and smoking and comorbid conditions (hypertension, diabetes mellitus and underlying cardio-respiratory illness) likely increase the severity of COVID-19. Rheumatic manifestations such as arthralgias and arthritis may be prevalent in about a seventh of individuals. COVID-19 can result in acute interstitial pneumonia, myocarditis, leucopenia (with lymphopenia) and thrombocytopenia, also seen in rheumatic diseases like lupus and Sjogren's syndrome. Severe disease in a subset of patients may be driven by cytokine storm, possibly due to secondary hemophagocytic lymphohistiocytosis (HLH), akin to that in systemic onset juvenile idiopathic arthritis or adult-onset Still's disease. In the absence of high-quality evidence in this emerging disease, understanding of pathogenesis may help postulate potential therapies. Angiotensin converting enzyme 2 (ACE2) appears important for viral entry into pneumocytes; dysbalance in ACE2 as caused by ACE inhibitors or ibuprofen may predispose to severe disease. Preliminary evidence suggests potential benefit with chloroquine or hydroxychloroquine. Antiviral drugs like lopinavir/ritonavir, favipiravir and remdesivir are also being explored. Cytokine storm and secondary HLH might require heightened immunosuppressive regimens. Current international society recommendations suggest that patients with rheumatic diseases on immunosuppressive therapy should not stop glucocorticoids during COVID-19 infection, although minimum possible doses may be used. Disease-modifying drugs should be continued; cessation may be considered during infection episodes as per standard practices. Development of a vaccine may be the only effective long-term protection against this disease.Key Pointsâ¢ Patients with coronavirus disease 19 (COVID-19) may have features mimicking rheumatic diseases, such as arthralgias, acute interstitial pneumonia, myocarditis, leucopenia, lymphopenia, thrombocytopenia and cytokine storm with features akin to secondary hemophagocytic lymphohistiocytosis.â¢ Although preliminary results may be encouraging, high-quality clinical trials are needed to better understand the role of drugs commonly used in rheumatology like hydroxychloroquine and tocilizumab in COVID-19.â¢ Until further evidence emerges, it may be cautiously recommended to continue glucocorticoids and other disease-modifying antirheumatic drugs (DMARDs) in patients receiving these therapies, with discontinuation of DMARDs during infections as per standard practice.

positive: COVID-19 and the Heart. Infection with the novel coronavirus, SARS-CoV-2, produces a clinical syndrome known as COVID-19. When severe, COVID-19 is a systemic illness characterized by hyperinflammation, cytokine storm and elevations of cardiac injury biomarkers. Here we review what is known about the pathophysiology of COVID-19, its cardiovascular manifestations, and emerging therapeutic prospects. In this rapidly moving field, this review was comprehensive as of April 3, 2020.

positive: Profiling COVID-19 pneumonia progressing into the cytokine storm syndrome: results from a single Italian Centre study on tocilizumab versus standard of care. Background Approximately 5% of patients with coronavirus disease 2019 (COVID-19) develop a life-threatening pneumonia that often occurs in the setting of increased inflammation or "cytokine storm". Anti-cytokine treatments are being evaluated but optimal patient selection remains unclear. Methods Between February 29 to April 6, 2020, 111 consecutive hospitalized patients with COVID-19 pneumonia were evaluated in a single centre retrospective study. Patients were divided in two groups: 42 severe cases (TOCI) with adverse prognostic features including raised CRP and IL-6 levels, who underwent anti-cytokine treatments, mostly tocilizumab, and 69 standard of care patients (SOC). Findings In the TOCI group, all received anti-viral therapy and 40% also received glucocorticoids. In TOCI, 62% of cases were ventilated and there were 3 deaths (17.8+/-10.6 days, mean follow up) with 7/26 cases remaining on ventilators, without improvement, and 17/26 developed bacterial superinfection. One fatality occurred in the 15 TOCI cases treated on noninvasive ventilation and 1 serious bacterial superinfection. Of the 69 cases in SOC, there was no fatalities and no bacterial complications. The TOCI group had higher baseline CRP and IL-6 elevations (p<0.0001 for both) and higher neutrophils and lower lymphocyte levels (p= 0.04 and p=0.001, respectively) with the TOCI ventilated patients having higher markers than non-ventilated TOCI patients. Interpretation Higher inflammatory markers, more superimposed infections and worse outcomes characterized ventilated TOCI cases compared to ward based TOCI therapy. Despite the confounding factors, this study suggests that therapy time in anti-cytokine randomized clinical trials will be key.

positive: Insights into the Use of C-Reactive Protein as a Diagnostic Index of Disease Severity in COVID-19 Infections. Approximately 20% of patients infected with SARS-CoV-2 (COVID-19) develop potentially life-threatening pathologies involving hyperinflammation, cytokine storm, septic shock complications, coagulation dysfunction, and multiple organ failure. Blood levels of the prototypic acute phase reactant, C-reactive protein (CRP), which is hepatically synthesized and released in response to interleukin-6 stimulation, is markedly elevated in patients with COVID-19. Markedly high CRP levels correlate with poor prognosis for survival. Insights into CRP structure-function relationships have uncovered both pro- and anti-inflammatory isoforms that may be used to monitor the extent of tissue damage associated with COVID-19 pathologies and prognoses. Herein, rationale is given for interpretation of CRP blood levels as a simple, rapid, and cost-effective way to assess disease severity and help guide therapeutic options in COVID-19 patients.

positive: Utilizing tocilizumab for the treatment of cytokine release syndrome in COVID-19

positive: Improvement of SARS‐CoV2 symptoms following Guselkumab injection in a psoriatic patient We read with great interest the publication of Messina et al (1) reporting the first case of SARS‐CoV2 infection in a young patient of 32‐year‐old suffering from psoriasis and psoriatic arthritis treated by Guselkumab, a monoclonal antibody that targets specifically the p19 subunit of Interleukin (IL)‐23(2).The patient contracted the SARS‐CoV2 infection after a dinner with some friends but fortunately she developed very discrete symptoms including only mild fever and rhinorrhea. These findings support the potential role of IL‐23p19 inhibitors to counteract the « cytokine storm » triggered by the SARS‐CoV2 and which is potentially implicated in the severity of the symptoms (3).

positive: The Role of Vitamin D in Suppressing Cytokine Storm in COVID-19 Patients and Associated Mortality The authors have withdrawn this manuscript because they have noticed idiosyncrasies in the reporting of 25(OH)D data across different countries. Therefore, the authors do not wish this work to be cited until after this issue is addressed. If you have any questions, please contact the corresponding author.

positive: Citokinellenes terápia az új típusú koronavírus okozta megbetegedés (COVID-19) kezelésében - tocilizumab elsoként való alkalmazása egy hazai infektológiai osztályon./ Anti-cytokine therapy in novel coronavirus disease (COVID-19)  the first administration of tocilizumab in Hungary at a department of infectology During the past few months, a pandemic originating from China named new coronavirus disease (COVID-19) has shown how vulnerable the world is. To date, no medication supported by randomized clinical trials has been approved for the treatment of COVID-19. At the time of writing of this paper, severe acute respiratory syndrome caused by coronavirus-2 (SARS-CoV-2) has been responsible - according to modest estimations - for around 4 million of infections and 300 000 deaths. Unveiling details of patomechanism, in fatal cases the role of immune dysregulation, namely cytokine release syndrome (CRS) has been discovered. Based on the current knowledge, interleukin-6 (IL6) plays a pivotal role in COVID-19 associated CRS. Case reports and result of small case series suggest efficacy of an IL6 inhibitor monoclonal antibody (tocilizumab) in treating CRS. Authors describe a case and review recent knowledge on the treatment of COVID-19. To our knowledge, the first case of severe COVID-19-associated cytokine storm syndrome - treated succesfully with IL6 monoclocal antibody at a Hungarian department of infectology - is presented here. Orv Hetil. 2020; 161(26): 1070-1077.

positive: Cytokine storm and the prospects for immunotherapy with COVID-19 Knowledge about the pathobiology of SARS-COV-2 as it interacts with immune defenses is limited. SARS-COV-2 is spread by droplets that come into contact with mucous membranes. COVID-19 is characterized by 3 stages: asymptomatic-paucisymptomatic incubation, nonsevere symptomatic illness for 80% of those infected, and severe respiratory illness. A syndrome characterized by hypercytokinemic inflammation referred to as a "cytokine storm" can occur in patients with advanced disease. Effective antiviral agents that can prevent viral infection in exposed individuals are needed.

positive: Fetal heart rate changes on the cardiotocograph trace secondary to maternal COVID-19 infection OBJECTIVE: To determine the cardiotocograph (CTG) changes in women with symptomatic COVID-19 infection. STUDY DESIGN: 12 anonymised CTG traces from 2 hospitals in Spain were retrospectively analysed by 2 independent assessors. CTG parameters were studied based on fetal pathophysiological responses to inflammation and hypoxia that would be expected based on the pathogenesis of COVID-19 patients. Correlation was made with perinatal outcomes (Apgar score at 5 min and umbilical cord pH). RESULTS: All fetuses showed an increased baseline FHR > 10 percent compared to the initial recording, in addition to absence of accelerations. 10 out of 12 CTG traces (83.3 percent) demonstrated late or prolonged decelerations and 7 out of 12 fetuses (58.3 percent) showed absence of cycling. Not a single case of sinusoidal pattern was observed. ZigZag pattern was found in 4 CTG traces (33 percent). Excessive uterine activity was observed in all CTG traces where uterine activity was monitored (10 out of 12). Apgar scores at 5 min were normal (>7) and absence of metabolic acidosis was found in the umbilical cord arterial pH (pH > 7.0) in the cases that were available (11 and 9, respectively). CONCLUSION: Fetuses of COVID-19 patients showed a raised baseline FHR (>10 percent), loss of accelerations, late decelerations, ZigZag pattern and absence of cycling probably due to the effects of maternal pyrexia, maternal inflammatory response and the “cytokine storm”. However, the perinatal outcomes appear to be favourable. Therefore, healthcare providers should optimise the maternal environment first to rectify the reactive CTG changes instead of performing an urgent operative intervention.

positive: Can mesenchymal stem cell therapy be the interim management of COVID-19? COVID-19 pandemic has accounted for ~ 4.3 million confirmed cases and ~ 292,000 deaths (till 12th May, 2020) across the globe since its outbreak. Several anti-viral drugs such as RNA dependent RNA polymerase inhibitors (remdesivir, favipiravir, ribavirin), protease inhibitors (lopinavir, ritonavir) and drugs targeting endocytic pathway (hydroxychloroquine) are being evaluated for COVID-19 but standard therapeutics yet not available. Severe health deterioration in critically ill patients is characterized by pulmonary edema, severe respiratory distress, cytokine storm and septic shock. To combat cytokine storm, immune-therapy targeting IL-1, IL-2, IL-6 and TNFα are being evaluated and one of the promising immune-modulator is the mesenchymal stem cells (MSCs) that can surmount the severity of COVID-19 infections. Recent studies have shown that MSC-therapy significantly dampens the cytokine storm in critically ill COVID-19 patients. This communication endows with the insight of stem cell therapy and summarizes the recent studies on COVID-19 patients.

positive: Tocilizumab for cytokine storm syndrome in COVID-19 pneumonia: an increased risk for candidemia?

positive: Survival of COVID-19 patients requires precise immune regulation: The hypothetical immunoprotective role of nicotinic agonists recent studies have provided novel evidence regarding the effect of nicotine agonists on the prevention or modulation of cytokines storm and reduction of infection. In this study we tried to attempt to address these issues from a therapeutic perspective of nicotine agonists in this manner and we describe one of the most challenging theories of immunotherapy in coronavirus-19 (COVID-19). The analysis of the proposed mechanism goes beyond the physiological consequences of a way to design new strategies to provide anti-inflammatory drugs.

positive: COVID-19 Sepsis and Microcirculation Dysfunction The spreading of Coronavirus (SARS-CoV-2) pandemic, known as COVID-19, has caused a great number of fatalities all around the World. Up to date (2020 May 6) in Italy we had more than 28,000 deaths, while there were more than 205.000 infected. The majority of patients affected by COVID-19 complained only slight symptoms: fatigue, myalgia or cough, but more than 15% of Chinese patients progressed into severe complications, with acute respiratory distress syndrome (ARDS), needing intensive treatment. We tried to summarize data reported in the last months from several Countries, highlighting that COVID-19 was characterized by cytokine storm (CS) and endothelial dysfunction in severely ill patients, where the progression of the disease was fast and fatal. Endothelial dysfunction was the fundamental mechanism triggering a pro-coagulant state, finally evolving into intravascular disseminated coagulation, causing embolization of several organs and consequent multiorgan failure (MOF). The Italian Society of Clinical Hemorheology and Microcirculation was aimed to highlight the role of microcirculatory dysfunction in the pathogenetic mechanisms of COVID-19 during the spreading of the biggest challenges to the World Health.

positive: Coagulopathy, thromboembolic complications and the use of heparin in COVID-19 Pneumonia The SARS-CoV-2 (COVID-19) is causing a pandemic and potentially fatal disease, actually of global public health concern. Viral infections are known to be associated with coagulation impairment thus thrombosis, hemorrhage, or both, may occur. Understanding the pathophysiological mechanisms underlying the development of coagulation disorders during viral infection is essential for the development of therapeutic strategies. Coagulopathy in COVID-19 infection is emerging as a precipitant factor for severe respiratory complications and death. An increase in coagulation markers such as fibrinogen and D-Dimer has been found in severe COVID-19 cases. Heparin, clinically used as an anticoagulant, has also anti-inflammatory properties including binding of inflammatory cytokines, inhibition of neutrophil chemotaxis, protection of endothelial cells and a potential antiviral effect. We hypothesized that low molecular weight heparin (LMWH) may attenuate cytokine storm in COVID-19 patients therefore LMWH could be a valid adjunctive therapeutic drug for the treatment of COVID-19 pneumopathy. In this paper we review potential mechanisms involved in coagulation impairment following viral infection and the possible role of heparin in the treatment of COVID-19 patients.

positive: A current review of COVID-19 for the cardiovascular specialist Abstract Although Coronavirus Disease 2019 (COVID-19) predominantly disrupts the respiratory system, there is accumulating experience that the disease, particularly in its more severe manifestations, also affects the cardiovascular system. Cardiovascular risk factors and chronic cardiovascular conditions are prevalent among patients affected by COVID-19 and associated with adverse outcomes. However, whether pre-existing cardiovascular disease is an independent determinant of higher mortality risk with COVID-19 remains uncertain. Acute cardiac injury, manifest by increased blood levels of cardiac troponin, electrocardiographic abnormalities, or myocardial dysfunction, occurs in up to ~60% of hospitalized patients with severe COVID-19. Potential contributors to acute cardiac injury in the setting of COVID-19 include 1) acute changes in myocardial demand and supply due to tachycardia, hypotension, and hypoxemia resulting in type 2 myocardial infarction; 2) acute coronary syndrome due to acute atherothrombosis in a virally-induced thrombotic and inflammatory milieu; 3) microvascular dysfunction due to diffuse microthrombi or vascular injury; 4) stress-related cardiomyopathy (Takotsubo syndrome); 5) non-ischemic myocardial injury due to a hyperinflammatory cytokine storm; or 6) direct viral cardiomyocyte toxicity and myocarditis. Diffuse thrombosis is emerging as an important contributor to adverse outcomes in patients with COVID-19. Practitioners should be vigilant for cardiovascular complications of COVID-19. Monitoring may include serial cardiac troponin and natriuretic peptides, along with fibrinogen, d-dimer, and inflammatory biomarkers. Management decisions should rely on the clinical assessment for the probability of ongoing myocardial ischemia, as well as alternative non-ischemic causes of injury, integrating the level of suspicion for COVID-19.

positive: Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study BACKGROUND: Mortality of patients with coronavirus disease 2019 (COVID-19), acute respiratory distress syndrome (ARDS), and systemic inflammation is high. In areas of pandemic outbreak, the number of patients can exceed maximum capacity of intensive care units (ICUs), and, thus, these individuals often receive non-invasive ventilation outside of the ICU. Effective treatments for this population are needed urgently. Anakinra is a recombinant interleukin-1 receptor antagonist that might be beneficial in this patient population. METHODS: We conducted a retrospective cohort study at the San Raffaele Hospital in Milan, Italy. We included consecutive patients (aged ≥18 years) with COVID-19, moderate-to-severe ARDS, and hyperinflammation (defined as serum C-reactive protein ≥100 mg/L, ferritin ≥900 ng/mL, or both) who were managed with non-invasive ventilation outside of the ICU and who received standard treatment of 200 mg hydroxychloroquine twice a day orally and 400 mg lopinavir with 100 mg ritonavir twice a day orally. We compared survival, mechanical ventilation-free survival, changes in C-reactive protein, respiratory function, and clinical status in a cohort of patients who received additional treatment with anakinra (either 5 mg/kg twice a day intravenously [high dose] or 100 mg twice a day subcutaneously [low dose]) with a retrospective cohort of patients who did not receive anakinra (referred to as the standard treatment group). All outcomes were assessed at 21 days. This study is part of the COVID-19 Biobank study, which is registered with ClinicalTrials.gov, NCT04318366. FINDINGS: Between March 17 and March 27, 2020, 29 patients received high-dose intravenous anakinra, non-invasive ventilation, and standard treatment. Between March 10 and March 17, 2020, 16 patients received non-invasive ventilation and standard treatment only and comprised the comparison group for this study. A further seven patients received low-dose subcutaneous anakinra in addition to non-invasive ventilation and standard treatment; however, anakinra treatment was interrupted after 7 days because of a paucity of effects on serum C-reactive protein and clinical status. At 21 days, treatment with high-dose anakinra was associated with reductions in serum C-reactive protein and progressive improvements in respiratory function in 21 (72%) of 29 patients; five (17%) patients were on mechanical ventilation and three (10%) died. In the standard treatment group, eight (50%) of 16 patients showed respiratory improvement at 21 days; one (6%) patient was on mechanical ventilation and seven (44%) died. At 21 days, survival was 90% in the high-dose anakinra group and 56% in the standard treatment group (p=0·009). Mechanical ventilation-free survival was 72% in the anakinra group versus 50% in the standard treatment group (p=0·15). Bacteraemia occurred in four (14%) of 29 patients receiving high-dose anakinra and two (13%) of 16 patients receiving standard treatment. Discontinuation of anakinra was not followed by inflammatory relapses. INTERPRETATION: In this retrospective cohort study of patients with COVID-19 and ARDS managed with non-invasive ventilation outside of the ICU, treatment with high-dose anakinra was safe and associated with clinical improvement in 72% of patients. Confirmation of efficacy will require controlled trials. FUNDING: None.

positive: ''Tociluzumab challenge: A series of cytokine storm therapy experience in hospitalized Covid‐19 pneumonia patients'' OBJECTIVE: To recognize the period of exaggerated cytokine response in patients with Coronavirus disease 2019 (COVID‐19) pneumonia, and to describe the clinical outcomes of using tocilizumab as a treatment option. METHODS: The data of 12 adult COVID‐19 pneumonia patients who were followed in the inpatient clinics of Biruni University Medical Faculty Hospital (Istanbul, Turkey) were retrospectively analyzed. Diagnostic tests, laboratory examinations, clinical findings and computed tomography of the thorax imaging results were evaluated. RESULTS: A dramatic laboratory and clinical improvement was observed in 83% (10/12) of patients after tocilizumab. In 17% (2/12) of our patients, short‐term ventilator support was required in the intensive care unit. The longest hospital stay was 18 days. However, in the end, all of our patients were discharged home with health. While arterial oxygen saturations (87.58±3.12%) dropped in room air in the pre‐tocilizumab period, post‐tocilizumab they normalized in all patients (94.42±1%). None of them had fever after tocilizumab treatment and the levels of c‐reactive protein (13.08±12.89) were almost within normal limits. Eosinophil values were quite low at the time of diagnosis (10±17.06), but increased significantly post‐tocilizumab (155.33±192.69). CONCLUSION: There is currently no proven treatment for COVID‐19 induced by novel coronavirus SARS‐CoV‐2. Based on our experience with twelve adult COVID‐19 pneumonia patients, we can say that tocilizumab, an IL‐6 inhibitor, is more beneficial in preventing the damage caused by excessive cytokine response in the body if administered at the right time and provides clinical and radiological recovery. This article is protected by copyright. All rights reserved.

positive: Use of Tocilizumab for COVID-19-Induced Cytokine Release Syndrome: A Cautionary Case Report Novel coronavirus disease 2019 (COVID-19) emerged in late December 2019 in Wuhan, China. Since then, COVID-19 has become a pandemic affecting more than 4.1 million people worldwide. Patients with COVID-19 have a wide spectrum of manifestations, one being cytokine release syndrome (CRS) and its fatal correlate, secondary hemophagocytic lymphohistiocytosis (sHLH). Anti-cytokine therapy such as tocilizumab, an IL-6 receptor antagonist, is a potential treatment for COVID-19; however, data regarding the efficacy of this anti-IL-6 therapy are currently lacking. We report two cases of patients who received a diagnosis of COVID-19 complicated by CRS and were treated with tocilizumab. Both patients progressed to sHLH despite treatment with tocilizumab, and one developed viral myocarditis, challenging the safety and clinical usefulness of tocilizumab in the treatment of COVID-19-induced CRS. These cases highlight the need for clinical trials to determine optimal patient selection and timing for the use of tocilizumab during this disease process.

positive: Cardiovascular implications of the COVID-19 pandemic: a global perspective The Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), represents the pandemic of the century, with approximately 3.5 million cases and 250,000 deaths worldwide as of May 2020. Although respiratory symptoms usually dominate the clinical presentation, COVID-19 is now known to also have potentially serious cardiovascular consequences, including myocardial injury, myocarditis, acute coronary syndromes, pulmonary embolism, stroke, arrhythmias, heart failure, and cardiogenic shock. The cardiac manifestations of COVID-19 might be related to the adrenergic drive, systemic inflammatory milieu and cytokine-release syndrome caused by SARS-CoV-2, direct viral infection of myocardial and endothelial cells, hypoxia due to respiratory failure, electrolytic imbalances, fluid overload, and side effects of certain COVID-19 medications. COVID-19 has profoundly reshaped usual care of both ambulatory and acute cardiac patients, by leading to the cancellation of elective procedures and by reducing the efficiency of existing pathways of urgent care, respectively. Decreased utilization of healthcare services for acute conditions by non-COVID-19 patients has also been reported and attributed to concerns about acquiring in-hospital infection. Innovative approaches that leverage modern technologies to tackle the COVID-19 pandemic have been introduced, which include telemedicine, dissemination of educational material over social media, smartphone apps for case tracking, and artificial intelligence for pandemic modelling, among others. This article provides a comprehensive overview of the pathophysiology and cardiovascular implications of COVID-19, its impact on existing pathways of care, the role of modern technologies to tackle the pandemic, and a proposal of novel management algorithms for the most common acute cardiac conditions.

positive: COVID-19 as a Viral Functional ACE2 Deficiency Disorder with ACE2 Related Multi-organ Disease SARS-CoV-2, the agent of COVID-19, shares a lineage with SARS-CoV-1, and a common fatal pulmonary profile but with striking differences in presentation, clinical course, and response to treatment. In contrast to SARS-CoV-1 (SARS), COVID-19 has presented as an often bi-phasic, multi-organ pathology, with a proclivity for severe disease in the elderly and those with hypertension, diabetes and cardiovascular disease. Whilst death is usually related to respiratory collapse, autopsy reveals multi-organ pathology. Chronic pulmonary disease is underrepresented in the group with severe COVID-19. A commonality of aberrant renin angiotensin system (RAS) is suggested in the at-risk group. The identification of angiotensin-converting-enzyme 2 (ACE2) as the receptor allowing viral entry to cells precipitated our interest in the role of ACE2 in COVID-19 pathogenesis. We propose that COVID-19 is a viral multisystem disease, with dominant vascular pathology, mediated by global reduction in ACE2 function, pronounced in disease conditions with RAS bias toward angiotensin-converting-enzyme (ACE) over ACE2. It is further complicated by organ specific pathology related to loss of ACE2 expressing cells particularly affecting the endothelium, alveolus, glomerulus and cardiac microvasculature. The possible upregulation in ACE2 receptor expression may predispose individuals with aberrant RAS status to higher viral load on infection and relatively more cell loss. Relative ACE2 deficiency leads to enhanced and protracted tissue, and vessel exposure to angiotensin II, characterised by vasoconstriction, enhanced thrombosis, cell proliferation and recruitment, increased tissue permeability, and cytokine production (including IL-6) resulting in inflammation. Additionally, there is a profound loss of the “protective” angiotensin (1-7), a vasodilator with anti-inflammatory, anti-thrombotic, antiproliferative, antifibrotic, anti-arrhythmic, and antioxidant activity. Our model predicts global vascular insult related to direct endothelial cell damage, vasoconstriction and thrombosis with a disease specific cytokine profile related to angiotensin II rather than “cytokine storm”. Our proposed mechanism of lung injury provides an explanation for early hypoxia without reduction in lung compliance and suggests a need for revision of treatment protocols to address vasoconstriction, thromboprophylaxis, and to minimize additional small airways and alveolar trauma via ventilation choice. Our model predicts long term sequelae of scarring/fibrosis in vessels, lungs, renal and cardiac tissue with protracted illness in at-risk individuals. It is hoped that our model stimulates review of current diagnostic and therapeutic intervention protocols, particularly with respect to early anticoagulation, vasodilatation and revision of ventilatory support choices.

positive: Dysfunctional Coagulation in COVID-19: From Cell to Bedside Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which can induce multisystem disease. Human angiotensin-converting enzyme 2 (ACE2) widely expressing in arterial and venous endothelial cells and arterial smooth muscle cells has been identified as a functional receptor for SARS-CoV-2. Dysfunction of ACE2 leads to abnormal activation of the renin-angiotensin system and a systemic endotheliitis that may relate to abnormal coagulation and sepsis. Meanwhile, innate immune response and inflammation activation participate in dysfunctional coagulation. Previous research indicated that dysfunctional coagulation was one of the important risk factors accountable for a high risk of severe disease and death in patients with COVID-19. Understanding the possible mechanisms of dysfunctional coagulation and appropriate anticoagulation therapeutic strategies are important to prevent disease deterioration and reduce fatality rates during the ongoing COVID-19 pandemic.

positive: Therapeutic Temperature Modulation for a Critically Ill Patient with COVID-19 We report a rapidly deteriorating coronavirus disease 2019 (COVID-19) patient, a-58-year-old woman, with severe acute respiratory distress syndrome and shock with hyperpyrexia up to 41.8°C, probably due to the cytokine storm syndrome. Considering extracorporeal membrane oxygenation (ECMO) as the last resort, we applied therapeutic temperature modulation for management of hyperpyrexia. The patient demonstrated rapid improvement in oxygenation and shock after achieving normothermia, and fully recovered from COVID-19 three weeks later. Therapeutic temperature modulation may have successfully offloaded the failing cardiorespiratory system from metabolic cost and hyperinflammation induced by hyperpyrexia. The therapeutic temperature modulation can safely be applied in a specific group of patients with cytokine storm syndrome and hyperpyrexia, which may reduce the number of patients requiring ECMO in the global medical resource shortage.

positive: Inhibition of cytokine signaling by ruxolitinib and implications for COVID-19 treatment Approximately 15% of patients with coronavirus disease 2019 (COVID-19) experience severe disease, and 5% progress to critical stage that can result in rapid death. No vaccines or antiviral treatments have yet proven effective against COVID-19. Patients with severe COVID-19 experience elevated plasma levels of pro-inflammatory cytokines, which can result in cytokine storm, followed by massive immune cell infiltration into the lungs leading to alveolar damage, decreased lung function, and rapid progression to death. As many of the elevated cytokines signal through Janus kinase (JAK)1/JAK2, inhibition of these pathways with ruxolitinib has the potential to mitigate the COVID-19-associated cytokine storm and reduce mortality. This is supported by preclinical and clinical data from other diseases with hyperinflammatory states, where ruxolitinib has been shown to reduce cytokine levels and improve outcomes. The urgent need for treatments for patients with severe disease support expedited investigation of ruxolitinib for patients with COVID-19.

positive: Systemic autoimmune diseases, anti-rheumatic therapies, COVID-19 infection risk and patient outcomes As of June 10th 2020 about 7.2 million individuals have tested positive for, and more than 410,000 have died due to COVID-19. In this review we outline the pathophysiology that underpins the potential use of anti-rheumatic therapies for severe COVID-19 infection and summarize the current evidence regarding the risk and outcome of COVID-19 in patients with systemic autoimmune diseases. Thus far there is no convincing evidence that any disease-modifying anti-rheumatic drug (conventional synthetic, biologic or targeted synthetic) including hydroxychloroquine, may protect against severe COVID-19 infection; answers about their possible usefulness in the management of the cytokine storm associated with severe COVID-9 infection will only arise from ongoing randomized controlled trials. Evidence on COVID-19 risk and outcome in patients with systemic autoimmune diseases is extremely limited; thus, any conclusions would be unsafe and should be seen with great caution. At present, the risk and severity (hospitalization, intensive care unit admission and death) of COVID-19 infection in people with autoimmune diseases do not appear particularly dissimilar to the general population, with the possible exception of hospitalization in patients exposed to high glucocorticoid doses. At this stage it is impossible to draw any conclusions for differences in COVID-19 risk and outcome between different autoimmune diseases and between the various immunomodulatory therapies used for them. More research in the field is obviously required, including as a minimum careful and systematic epidemiology and appropriately controlled clinical trials.

positive: Targeting potential drivers of COVID-19: Neutrophil extracellular traps Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory disease that in â¼10-15% of patients progresses to acute respiratory distress syndrome (ARDS) triggered by a cytokine storm. In this Perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils-the ability to form neutrophil extracellular traps (NETs)-may contribute to organ damage and mortality in COVID-19. We show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to COVID-19. We discuss prior reports linking aberrant NET formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19.

positive: Cytokine Storm in COVID19: A Neural Hypothesis. Cytokine storm in COVID-19 is characterized by an excessive inflammatory response to SARS-CoV-2 that is caused by a dysregulated immune system of the host. We are proposing a new hypothesis that SARS-CoV-2 mediated inflammation of nucleus tractus solitarius (NTS) may be responsible for the cytokine storm in COVID 19. The inflamed NTS may result in a dysregulated cholinergic anti-inflammatory pathway and hypothalamic-pituitary-adrenal axis.

positive: Is the oncologic patient more susceptible to covid19 but perhaps less likely to undergo severe infection-related complications due to fewer cytokines storm as a consequent of the associated immunodeficiency?

positive: Pirfenidone: A novel hypothetical treatment for COVID-19 Cytokine storm, multiorgan failure, and particularly acute respiratory distress syndrome (ARDS) is the leading cause of mortality and morbidity in patients with COVID-19. A fulminant ARDS kills the majority of COVID-19 victims. Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone), is a novel anti-fibrotic agent with trivial adverse effects. Pirfenidone is approved for the treatment of Idiopathic Pulmonary Fibrosis (IPF) for patients with mild to moderate disease. Pirfenidone could inhibit apoptosis, downregulate ACE receptors expression, decrease inflammation by several mechanisms and ameliorate oxidative stress and hence protect pneumocytes and other cells from COVID-19 invasion and cytokine storm simultaneously. Based on the pirfenidone mechanism of action and the known pathophysiology of COVID-19, I believe that pirfenidone has the potential for the treatment of COVID-19 patients.

positive: Eficacia de los pulsos de corticoides en pacientes con síndrome de liberación de citocinas inducido por infección por SARS-CoV-2./ Eficacia de los pulsos de corticoides en pacientes con síndrome de liberación de citocinas inducido por infección por SARS-CoV-2./ Effectiveness of corticoid pulses in patients with cytokine storm syndrome induced by SARS-CoV-2 infection INTRODUCTION: Cytokine storm syndrome (CSS) is a serious complication of COVID-19 patients. Treatment is tocilizumab. The use of glucocorticoids (GC) is controversial. In other very similar CSS, such as macrophage activation syndrome (MAS) and hemophagocytic syndrome (HFS), the main treatment are corticosteroids. Our objective is to evaluate the efficacy of GC in the CSS by COVID-19. PATIENTS: We included 92 patients with CSS associated to COVID-19 who received GC, GC, and tocilizumab and only tocilizumab. We determine CSS markers. We evaluated mortality, intubation, and a combined variable. RESULTS: In all cases the percentages of events were lower in the group of patients with GC was administered. The hazard ratio of the final variables with GC versus the group in which only tocilizumab was administered was lower as CGs were considered, with statistical significance for survival. DISCUSSION: The early use of GC pulses could control SLC, with a lower requirement to use tocilizumab and a decrease in events such as intubation and death.

positive: Expanded Umbilical Cord Mesenchymal Stem Cells (UC-MSCs) as a Therapeutic Strategy in Managing Critically Ill COVID-19 Patients: The Case for Compassionate Use. COVID-19 has affected the United States leading to a national emergency with health care and economic impact, propelling the country into a recession with disrupted lifestyles not seen in recent history. COVID-19 is a serious illness leading to multiple deaths in various countries including the United States. Several million Americans satisfy the Center for Disease Control and Prevention (CDC) criteria for being high risk. Unfortunately, the available supply of medical beds and equipment for mechanical ventilation are much less than is projected to be needed. The World Health Organization (WHO) and multiple agencies led by the CDC in the United States have attempted to organize intensive outbreak investigation programs utilizing appropriate preventive measures, evaluation, and treatment. The clinical spectrum of COVID-19 varies from asymptomatic forms to conditions encompassing multiorgan and systemic manifestations in terms of septic shock, and multiple organ dysfunction (MOD) syndromes. The presently approved treatments are supportive but not curative for the disease. There are multiple treatments being studied. These include vaccines, medications Remdesivir and hydroxychloroquine and potentially combination therapy. Finally, expanded umbilical cord mesenchymal stem cells or (UC-MSCs) may have a role and are being studied. The cure of COVID-19 is essentially dependent on the patients' own immune system. When the immune system is over activated in an attempt to kill the virus, this can lead to the production of a large number of inflammatory factors, resulting in severe cytokine storm. The cytokine storm may induce organ damage followed by the edema, dysfunction of air exchange, acute respiratory distress syndrome (ARDS), acute cardiac injury, and secondary infection, which may lead to death. Thus, at this point, the avoidance of the cytokine storm may be the key for the treatment of HCOV-19 infected patients.In China, where there was limited availability of effective modalities to manage COVID-19 several patients were treated with expanded UC-MSCs. Additionally, the Italian College of Anesthesia, Analgesia, Resuscitation and Intensive Care have reported guidelines to treat coronavirus patients with stem cells in the hope of decreasing the number of patients going to the ICU, and, also relatively quickly getting them out of ICU. In this manuscript, we describe the urgent need for various solutions, pathogenesis of coronavirus and the clinical evidence for treatment of COVID-19 with stem cells. The limited but emerging evidence regarding UC MSC in managing COVID-19 suggests that it might be considered for compassionate use in critically ill patients to reduce morbidity and mortality in the United States. The administration and Coronavirus Task Force might wish to approach the potential of expanded UC-MSCs as an evolutionary therapeutic strategy in managing COVID-19 illness with a 3-pronged approach: If proven safe and effective on a specific and limited basis…1. Minimize regulatory burden by all agencies so that critically ill COVID-19 patients will have access regardless of their financial circumstance.2. Institute appropriate safeguards to avoid negative consequences from unscrupulous actors.3. With proper informed consent from patients or proxy when necessary, and subject to accumulation of data in that cohort, allow the procedure to be initiated in critically ill patients who are not responding to conventional therapies.KEY WORDS: Coronavirus, COVID-19, cytokine storm, multiorgan failure, expanded umbilical cord mesenchymal stem cells.

positive: Old and new antirheumatic drugs for the treatment of COVID-19

positive: Preventing COVID-19-induced pneumonia with anticytokine therapy

positive: Understanding the COVID-19 coagulopathy spectrum

positive: Can steroids reverse the severe COVID‐19 induced ‘cytokine storm’? Severe COVID‐19 is characterized by an excessive pro‐inflammatory cytokine storm, resulting in acute lung injury and development of ARDS. The role of corticosteroids is controversial in severe COVID‐19 pneumonia and associated hyper‐inflammatory syndrome. We reported a case series of six consecutive COVID‐19 patients with severe pneumonia, ARDS and laboratory indices of hyper‐inflammatory syndrome. All patients were treated early with a short course of corticosteroids, and clinical outcomes were compared before and after corticosteroids administration. All patients evaded intubation and intensive care admission, ARDS resolved within 11.8 days (median), viral clearance was achieved in 4 patients within 17.2 days (median), and all patients were discharged from the hospital in 16.8 days (median). Early administration of short course corticosteroids improves clinical outcome of patients with severe COVID‐19 pneumonia and evidence of immune hyper‐reactivity. This article is protected by copyright. All rights reserved.

positive: Concerns about intensive therapies for critically ill COVID-19: Summary of a panel discussion by global intensivists

positive: Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing COVID-19, caused by SARS-CoV-2, has recently affected over 1,200,000 people and killed more than 60,000. The key immune cell subsets change and their states during the course of COVID-19 remain unclear. We sought to comprehensively characterize the transcriptional changes in peripheral blood mononuclear cells during the recovery stage of COVID-19 by single-cell RNA sequencing technique. It was found that T cells decreased remarkably, whereas monocytes increased in patients in the early recovery stage (ERS) of COVID-19. There was an increased ratio of classical CD14(++) monocytes with high inflammatory gene expression as well as a greater abundance of CD14(++)IL1β(+) monocytes in the ERS. CD4(+) T cells and CD8(+) T cells decreased significantly and expressed high levels of inflammatory genes in the ERS. Among the B cells, the plasma cells increased remarkably, whereas the naïve B cells decreased. Several novel B cell-receptor (BCR) changes were identified, such as IGHV3-23 and IGHV3-7, and isotypes (IGHV3-15, IGHV3-30, and IGKV3-11) previously used for virus vaccine development were confirmed. The strongest pairing frequencies, IGHV3-23-IGHJ4, indicated a monoclonal state associated with SARS-CoV-2 specificity, which had not been reported yet. Furthermore, integrated analysis predicted that IL-1β and M-CSF may be novel candidate target genes for inflammatory storm and that TNFSF13, IL-18, IL-2, and IL-4 may be beneficial for the recovery of COVID-19 patients. Our study provides the first evidence of an inflammatory immune signature in the ERS, suggesting COVID-19 patients are still vulnerable after hospital discharge. Identification of novel BCR signaling may lead to the development of vaccines and antibodies for the treatment of COVID-19.

positive: Targeting the NLRP3 Inflammasome in Severe COVID-19 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the genus Betacoronavirus within the family Coronaviridae. It is an enveloped single-stranded positive-sense RNA virus. Since December of 2019, a global expansion of the infection has occurred with widespread dissemination of coronavirus disease 2019 (COVID-19). COVID-19 often manifests as only mild cold-like symptomatology, but severe disease with complications occurs in 15% of cases. Respiratory failure occurs in severe disease that can be accompanied by a systemic inflammatory reaction characterized by inflammatory cytokine release. In severe cases, fatality is caused by the rapid development of severe lung injury characteristic of acute respiratory distress syndrome (ARDS). Although ARDS is a complication of SARS-CoV-2 infection, it is not viral replication or infection that causes tissue injury; rather, it is the result of dysregulated hyperinflammation in response to viral infection. This pathology is characterized by intense, rapid stimulation of the innate immune response that triggers activation of the Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome pathway and release of its products including the proinflammatory cytokines IL-6 and IL-1β. Here we review the literature that describes the pathogenesis of severe COVID-19 and NLRP3 activation and describe an important role in targeting this pathway for the treatment of severe COVID-19.

positive: Can steroids reverse the severe COVID-19 induced "cytokine storm"? Severe coronavirus disease (COVID-19) is characterized by an excessive proinflammatory cytokine storm, resulting in acute lung injury and development of acute respiratory distress syndrome (ARDS). The role of corticosteroids is controversial in severe COVID-19 pneumonia and associated hyper-inflammatory syndrome. We reported a case series of six consecutive COVID-19 patients with severe pneumonia, ARDS and laboratory indices of hyper-inflammatory syndrome. All patients were treated early with a short course of corticosteroids, and clinical outcomes were compared before and after corticosteroids administration. All patients evaded intubation and intensive care admission, ARDS resolved within 11.8 days (median), viral clearance was achieved in four patients within 17.2 days (median), and all patients were discharged from the hospital in 16.8 days (median). Early administration of short course corticosteroids improves clinical outcome of patients with severe COVID-19 pneumonia and evidence of immune hyperreactivity.

positive: Biochemical indicators of coronavirus disease 2019 exacerbation and the clinical implications Coronavirus Disease 2019 (COVID-19) has sparked a global pandemic, affecting more than 4 million people worldwide. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause acute lung injury (ALI) and even acute respiratory distress syndrome (ARDS); with a fatality of 7.0 %. Accumulating evidence suggested that the progression of COVID-19 is associated with lymphopenia and excessive inflammation, and a subset of severe cases might exhibit cytokine storm triggered by secondary hemophagocytic lymphohistiocytosis (sHLH). Furthermore, secondary bacterial infection may contribute to the exacerbation of COVID-19. We recommend using both IL-10 and IL-6 as the indicators of cytokine storm, and monitoring the elevation of procalcitonin (PCT) as an alert for initiating antibacterial agents. Understanding the dynamic progression of SARS-CoV-2 infection is crucial to determine an effective treatment strategy to reduce the rising mortality of this global pandemic.

positive: Lymphopenia in COVID‐19: Therapeutic opportunities Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is uncontrollably spread all over the world. The host immune responses strongly try to confront it with all the potential cells and cytokines. With chronically condition of SARS‐CoV‐2, natural killer cells and T cells become exhausted and decreasing their count leads to lymphopenia. Inability to eradicate the infected organ makes hyperinitiation of the immune system, which releases the excessive inflammatory cytokines to compensate the exhausted one as well as the low lymphocytes counts; it consequently leads to the cytokine storm syndrome. These mechanisms and the potential therapeutic targeting are discussed in this paper.

positive: SARS Cov-2 infection in a renal-transplanted patient: A case report The clinical manifestation of COVID-19 can vary from an asymptomatic course to ARDS requiring invasive mechanical ventilation and extracorporeal membrane oxygenation. A kidney transplanted patient infected with SARS CoV-2 infection showed a mild disease despite immune suppression. It is possible that Immunosuppression can "be protective" as the cytokine storm is an important factor in the disease story. Despite the good outcome reported in the present case report, is remains of vital importance the solid organ transplant patients use precautions in order to avoid the infection.

positive: COVID-19 and Asthma: Reflection During the Pandemic. Coronavirus disease 2019 (COVID-19) is a global pandemic infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and abnormal, overactivated innate immunity and "cytokine storms" have been proposed as potential pathological mechanisms for rapid COVID-19 progression. Theoretically, asthmatic patients should have increased susceptibility and severity for SARS-CoV-2 infection due to a deficient antiviral immune response and the tendency for exacerbation elicited by common respiratory viruses. However, existing studies have not shown an expected prevalence of asthmatic individuals among COVID-19 patients. Certain aspects of type 2 immune response, including type 2 cytokines (IL-4, IL-13, etc.) and accumulation of eosinophils, might provide potential protective effects against COVID-19. Furthermore, conventional therapeutics for asthma, including inhaled corticosteroids, allergen immunotherapy (AIT), and anti-IgE monoclonal antibody, might also reduce the risks of asthmatics suffering infection of the virus through alleviating inflammation or enhancing antiviral defense. The interactions between COVID-19 and asthma deserve further attention and clarification.

positive: Targeting lymphocyte Kv1.3-channels to suppress cytokine storm in severe COVID-19: Can it be a novel therapeutic strategy? In the midst of a pandemic, finding effective treatments for coronavirus disease 2019 (COVID-19) is the urgent issue. In "chronic inflammatory diseases", the overexpression of delayed rectifier K+-channels (Kv1.3) in leukocytes is responsible for the overactivation of cellular immunity and the subsequent cytokine storm. In our previous basic studies, drugs including chloroquine and azithromycin strongly suppressed the channel activity and pro-inflammatory cytokine production from lymphocytes. These findings suggest a novel pharmacological mechanism by which chloroquine, with or without azithromycin, is effective for severe cases of COVID-19, in which the overactivation of cellular immunity and the subsequent cytokine storm are responsible for the pathogenesis.

positive: The COVID-19 Cytokine Storm; What We Know So Far COVID-19 is a rapidly spreading global threat that has been declared as a pandemic by the WHO. COVID-19 is transmitted via droplets or direct contact and infects the respiratory tract resulting in pneumonia in most of the cases and acute respiratory distress syndrome (ARDS) in about 15 % of the cases. Mortality in COVID-19 patients has been linked to the presence of the so-called "cytokine storm" induced by the virus. Excessive production of proinflammatory cytokines leads to ARDS aggravation and widespread tissue damage resulting in multi-organ failure and death. Targeting cytokines during the management of COVID-19 patients could improve survival rates and reduce mortality.

positive: Inhibition of cytokine signaling by ruxolitinib and implications for COVID-19 treatment Approximately 15% of patients with coronavirus disease 2019 (COVID-19) experience severe disease, and 5% progress to critical stage that can result in rapid death. No vaccines or antiviral treatments have yet proven effective against COVID-19. Patients with severe COVID-19 experience elevated plasma levels of pro-inflammatory cytokines, which can result in cytokine storm, followed by massive immune cell infiltration into the lungs leading to alveolar damage, decreased lung function, and rapid progression to death. As many of the elevated cytokines signal through Janus kinase (JAK)1/JAK2, inhibition of these pathways with ruxolitinib has the potential to mitigate the COVID-19–associated cytokine storm and reduce mortality. This is supported by preclinical and clinical data from other diseases with hyperinflammatory states, where ruxolitinib has been shown to reduce cytokine levels and improve outcomes. The urgent need for treatments for patients with severe disease support expedited investigation of ruxolitinib for patients with COVID-19.

positive: [Expert consensus on Corona Virus Disease 2019 with special blood purification technology] The outbreak of Corona Virus Disease 2019 (COVID-19) has spread to more than 70 countries worldwide and there was a higher mortality in those who developed serious illness.Cytokine storm syndrome is an important pathophysiological basis for COVID-19 patients developing into severe or critical conditions. It was indicated in the diagnosis and treatment scheme, by the National Health Commission of the People's Republic of China, that blood purifications such as plasma exchange, plasma adsorption, hemoperfusion, hemofiltration and plasmafiltration could be considered for use in the critical patients with cytokine storm syndrome. This expert consensus, proposed by the Chinese Society of Nephrology and the Nephrology Committee of Chinese Research Hospital Association, is to guide and standardize the clinical application of blood purifications in the treatment of severe or critical patients with COVID-19.

positive: Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients Infection caused by SARS-CoV-2 can result in severe respiratory complications and death. Patients with a compromised immune system are expected to be more susceptible to a severe disease course. In this report we suggest that patients with systemic lupus erythematous might be especially prone to severe COVID-19 independent of their immunosuppressed state from lupus treatment. Specifically, we provide evidence in lupus to suggest hypomethylation and overexpression of ACE2, which is located on the X chromosome and encodes a functional receptor for the SARS-CoV-2 spike glycoprotein. Oxidative stress induced by viral infections exacerbates the DNA methylation defect in lupus, possibly resulting in further ACE2 hypomethylation and enhanced viremia. In addition, demethylation of interferon-regulated genes, NFκB, and key cytokine genes in lupus patients might exacerbate the immune response to SARS-CoV-2 and increase the likelihood of cytokine storm. These arguments suggest that inherent epigenetic dysregulation in lupus might facilitate viral entry, viremia, and an excessive immune response to SARS-CoV-2. Further, maintaining disease remission in lupus patients is critical to prevent a vicious cycle of demethylation and increased oxidative stress, which will exacerbate susceptibility to SARS-CoV-2 infection during the current pandemic. Epigenetic control of the ACE2 gene might be a target for prevention and therapy in COVID-19.

positive: Type I astrocytes and microglia induce a cytokine response in an encephalitic murine coronavirus infection The pathogenesis of viral infections involves an immune response by cytokines, causing a deleterious effect on organ function, in addition to tissue destruction due to viral replication. Clinical symptoms and laboratory findings of the human coronavirus disease COVID-19, caused by the novel coronavirus SARS CoV-2, indicate cytokine involvement. Our laboratory showed that an experimental murine coronavirus (MHV-A59) can be transmitted into the brain by intranasal or intracerebral exposure and that neurovirulence is mediated by cytokine secretion. In this study we investigated which cells in the brain produce cytokines, thus functioning as the brain's innate immune system. Using tissue cultures of microglia, and clonal populations of astrocytes, we found that microglia and type I astrocytes (but not types II and III), produced pro-inflammatory cytokines in response to MHV-A59 infection. A molecularly closely related, non-encephalitic strain of the virus (MHV-2) caused in vitro infection, but without cytokine induction. Furthermore, immunofluorescence and immunohistochemistry revealed that type I astrocytes and microglia have perivascular foot processes necessary for the formation of the perivascular glymphatic system, the anatomical site of the brain's innate immune system. Cytokine secretion by type I astrocytes and microglia, as part of the brain's glymphatic and innate immune system, contributes to the pathogenesis of an encephalitic coronavirus infection, and indicates the rationale for anti-cytokine therapies for COVID-19.

positive: The Cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system In 2019-2020 a new coronavirus named SARS-CoV-2 was identified as the causative agent of a several acute respiratory infection named COVID-19, which is causing a worldwide pandemic. There are still many unresolved questions regarding the pathogenesis of this disease and especially the reasons underlying the extremely different clinical course, ranging from asymptomatic forms to severe manifestations, including the Acute Respiratory Distress Syndrome (ARDS). SARS-CoV-2 showed phylogenetic similarities to both SARS-CoV and MERS-CoV viruses, and some of the clinical features are shared between COVID-19 and previously identified beta-coronavirus infections. Available evidence indicate that the so called “cytokine storm” an uncontrolled over-production of soluble markers of inflammation which, in turn, sustain an aberrant systemic inflammatory response, is a major responsible for the occurrence of ARDS. Chemokines are low molecular weight proteins with powerful chemoattractant activity which play a role in the immune cell recruitment during inflammation. This review will be aimed at providing an overview of the current knowledge on the involvement of the chemokine/chemokine-receptor system in the cytokine storm related to SARS-CoV-2 infection. Basic and clinical evidences obtained from previous SARS and MERS epidemics and available data from COVID-19 will be taken into account.

positive: Hemorrhagic encephalopathy associated with COVID-19 The mechanisms for neurological complications of COVID-19, the disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), are not yet well understood. We present a critically ill man with a COVID-19-associated hemorrhagic encephalopathy. SARS-CoV-2 RNA was not detected in cerebrospinal fluid (CSF) or blood. CSF analyses suggested dysregulation of pro-inflammatory cytokine pathways, particularly tumor necrosis factor-α and interleukin-6, consistent with a cytokine release syndrome. The patient gradually recovered with supportive care and neurological rehabilitation. Awareness of this clinical entity may facilitate the identification of patients with a potentially remediable cause of encephalopathy in COVID-19.

positive: Characteristics of inflammatory factors and lymphocyte subsets in patients with severe COVID‐19 To investigate the inflammatory factors and lymphocyte subsets which play an important role in the course of severe coronavirus disease 2019 (COVID‐19). A total of 27 patients with severe COVID‐19 who were admitted to Tongji Hospital in Wuhan from 1 to 21 February 2020 were recruited to the study. The characteristics of interleukin‐1β (IL‐1β), IL‐2 receptor (IL‐2R), IL‐6, IL‐8, IL‐10, tumor necrosis factor‐α (TNF)‐α, C‐reactive protein (CRP), serum ferritin and procalcitonin (PCT), and lymphocyte subsets of these patients were retrospectively compared before and after treatment. Before treatment, there was no significant difference in most inflammatory factors (IL‐1β, IL‐2R, IL‐6, IL‐8, IL‐10, CRP, and serum ferritin) between male and female patients. Levels of IL‐2R, IL‐6, TNF‐α, and CRP decreased significantly after treatment, followed by IL‐8, IL‐10, and PCT. Serum ferritin was increased in all patients before treatment but did not decrease significantly after treatment. IL‐1β was normal in most patients before treatment. Lymphopenia was common among these patients with severe COVID‐19. Analysis of lymphocyte subsets showed that CD4+ and particularly CD8+ T lymphocytes increased significantly after treatment. However, B lymphocytes and natural killer cells showed no significant changes after treatment. A pro‐inflammatory response and decreased level of T lymphocytes were associated with severe COVID‐19.

positive: TWIRLS, an automated topic-wise inference method based on massive literature, suggests a possible mechanism via ACE2 for the pathological changes in the human host after coronavirus infection Faced with the current large-scale public health emergency, collecting, sorting, and analyzing biomedical information related to the "coronavirus" should be done as quickly as possible to gain a global perspective, which is a basic requirement for strengthening epidemic control capacity. However, for human researchers studying the viruses and the hosts, the vast amount of information available cannot be processed effectively and in a timely manner, particularly when the scientific understanding may be limited, which can further lower the information processing efficiency. We present TWIRLS, a method that can automatically acquire, organize, and classify information. Additionally, independent functional data sources can be added to build an inference system using a machine-based approach, which can provide relevant knowledge to help human researchers quickly establish subject cognition and to make more effective decisions. TWIRLS can automatically analyze more than three million words in more than 14,000 literature articles in only 4 hours. Combining with generalized gene interaction databases creates a data interface that can help researchers to further analyze the information. Using the TWIRLS system, we found that an important regulatory factor angiotensin-converting enzyme 2 (ACE2) may be involved in the host pathological changes on binding to the coronavirus after infection. After triggering functional changes in ACE2/AT2R, an imbalance in the steady-state cytokine regulatory axis involving the Renin-Angiotensin System and IP-10 leads to a cytokine storm.

positive: Clinical and biological data on the use of hydroxychloroquine against SARS‐CoV‐2 could support the role of the NLRP3 inflammasome in the pathogenesis of respiratory disease The use of hydroxychloroquine (HCL) has been very common in countries with a rapid spread of coronavirus disease 2019 (COVID-19), although controversial and the subject of heated scientific discussions with implications for the whole society. This article is protected by copyright. All rights reserved.

positive: Immune Status of COVID-19 Patients with Reference to SARS and MERS During this global pandemic of COVID-19 infection, it became well known that morbidity and mortality is especially high at the extreme of life especially in certain racial or ethnic groups like Americans and Africans This is presumed due to low immunity associated with other comorbid conditions like diabetes, hypertension, cardiovascular disease, obesity and metabolic syndrome But the information available on the immune status of COVID-19 patients is limited Attempts must be made to enhance our understanding of the immune status of COVID-19 patients by revisiting our knowledge on the immune mechanisms of already known coronaviruses such as SARS-CoV and MERS-CoV Early elevation of the serum levels of pro-inflammatory cytokines observed in SARS and MERS infection suggests a possible same type of cytokine storm-mediated lung damage in COVID-19 patients too Dysregulation of interferon-1 response and downstream cascade in initial innate immune response at virus entry point has been related to lethal pneumonia in COVID-19 patients Adaptive response of increased CD8+ levels in COVID-19 patients seems to be useful in mild cases where it causes deteriorating effects in progressed severe disease patients resulting in destruction of type 2 pneumocytes hence inability to regenerate the alveolar epithelium A phenomenon called cytokine storm activates violent immunological reactions in the lung tissue resulting in ARDS followed by multiple organ system damages in COVID-19 patients Several immune evading mechanisms are thought to be employed by severe respiratory syndrome virus-2 (SARS-CoV-2) that might have resulted in its extremely increased contagiousness probably related with its frequent RNA mutations Failure to develop adequate virus limiting immune reactions by some cured patients warrant monitoring of all recovered patients This rapid mini review is aimed to enhance our knowledge of the immune status of COVID-19 infected patients with reference to SARS-CoV and MERS-CoV

positive: Role of oxidized LDL-induced "trained macrophages" in the pathogenesis of COVID-19 and benefits of pioglitazone: A hypothesis BACKGROUND AND AIMS: Older adults and people who have cardiovascular disorders (their common pathogenetic mechanism is progressive atherosclerosis) are at higher risk for severe illness from COVID-19 (coronavirus disease 2019). Their common pathogenetic mechanism is progressive atherosclerosis in which oxLDL (oxidized LDL) plays major role. Receptor-mediated uptake of oxLDL by the monocyte-derived macrophages activates the long-term epigenetic reprogramming of innate immunity, which is termed "trained immunity." The aim of this work is to investigate the mechanisms and treatment possibilities that can control the activities of these specific macrophages. METHODS: Search in Medline and PubMed relevant articles on the trained immunity and cytokine storm of COVID-19. RESULTS AND CONCLUSIONS: When oxLDL-trained macrophages encounter SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in the lung, it causes unregulated cytokine secretion, leading to the alveolar damage. Therefore, blocking macrophage training by pioglitazone, a thiazolidinedione, could control the hyperactivation that the virus would trigger.

positive: Early Use of Tocilizumab in Respiratory Failure Associated with Acute COVID -19 Pneumonia in Recipients with Solid Organ Transplantation As of May 14, 2020, the World Health Organization has reported approximately 4.3 million cases of the novel Coronavirus Disease (COVID-19) with approximately 294,046 deaths worldwide.(1) Solid organ transplant recipients who are on chronic immunosuppressants fall within a special population of COVID-19 patients since they are more susceptible to complications secondary to COVID-19. Currently, we do not have data on treating COVID-19 patients with solid organ transplants with tocilizumab, an interleukin-6 (IL-6) inhibitor. We report a case of COVID-19 in a patient with a kidney and liver transplant and discuss the early use of tocilizumab to prevent the cytokine storm and attempt to reduce the likelihood of progression to Acute Respiratory Distress Syndrome (ARDS). In addition, we present other COVID-19 related transplant cases reported in the literature outlining the presenting clinical signs and outcomes.

positive: Emerging Trends in COVID-19 Treatment: Learning from Inflammatory Conditions Associated with Cellular Therapies Coronavirus disease 2019 (SARS-CoV2) is an active global health threat for which treatments are desperately being sought. Even though most people infected experience mild to moderate respiratory symptoms and recover with supportive care, certain vulnerable hosts develop severe clinical deterioration. While several drugs are currently being investigated in clinical trials, there are currently no approved treatments or vaccines for COVID-19 and hence there is an unmet need to explore additional therapeutic options. At least three inflammatory disorders or syndromes associated with immune dysfunction have been described in the context of cellular therapy. Specifically, Cytokine Release Syndrome (CRS), Immune Reconstitution Inflammatory Syndrome (IRIS), and Secondary Hemophagocytic Lymphohistiocytosis (sHLH) all have clinical and laboratory characteristics in common with COVID19 and associated therapies that could be worth testing in the context of clinical trials. Here we discuss these diseases, their management, and potential applications of these treatment in the context of COVID-19. We also discuss current cellular therapies that are being evaluated for the treatment of COVID-19 and/or its associated symptoms.

positive: Inappropriate Antibiotic Consumption as a Possible Cause of Inflammatory Storm and Septic Shock in Patients Diagnosed with Coronavirus-19 Disease (COVID-19) The novel coronavirus (SARS-CoV-2) infection which has been known as Coronavirus diseases 2019 (COVID-19) has become an endemic emergent situation by the World Health Organization. So far, no successful specific treatment has been found for this disease. As has been reported, most of non-survivor patients with COVID-19 (70%) had septic shock which was significantly higher than survived ones. Although the exact pathophysiology of septic shock in these patients is still unclear, it seems to be possible that part of it would be due to the administration of empiric antibiotics with inflammatory properties especially in the absence of bacterial infection. Herein, we have reviewed possible molecular pathways of septic shock in the patients who have received antibiotics with inflammatory properties which mainly is release of interleukin 1β (IL-1β), IL-6, and tumor necrosis factor α (TNF- α) through different routes. Altogether, we highly recommend clinicians to look after those antibiotics with anti-inflammatory activity for both empiric antibiotic therapy and reducing the inflammation to prevent septic shock in patients with diagnosed COVID-19.

positive: COVID-19 and lung cancer: risks, mechanisms and treatment interactions Cases of the 2019 novel coronavirus also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to rise worldwide. To date, there is no effective treatment. Clinical management is largely symptomatic, with organ support in intensive care for critically ill patients. The first phase I trial to test the efficacy of a vaccine has recently begun, but in the meantime there is an urgent need to decrease the morbidity and mortality of severe cases. It is known that patients with cancer are more susceptible to infection than individuals without cancer because of their systemic immunosuppressive state caused by the malignancy and anticancer treatments. Therefore, these patients might be at increased risk of pulmonary complications from COVID-19. The SARS-CoV-2 could in some case induce excessive and aberrant non-effective host immune responses that are associated with potentially fatal severe lung injury and patients can develop acute respiratory distress syndrome (ARDS). Cytokine release syndrome and viral ARDS result from uncontrolled severe acute inflammation. Acute lung injury results from inflammatory monocyte and macrophage activation in the pulmonary luminal epithelium which lead to a release of proinflammatory cytokines including interleukin (IL)-6, IL-1 and tumor necrosis factor-α. These cytokines play a crucial role in immune-related pneumonitis, and could represent a promising target when the infiltration is T cell predominant or there are indirect signs of high IL-6-related inflammation, such as elevated C-reactive protein. A monoclonal anti-IL-6 receptor antibody, tocilizumab has been administered in a number of cases in China and Italy. Positive clinical and radiological outcomes have been reported. These early findings have led to an ongoing randomized controlled clinical trial in China and Italy. While data from those trials are eagerly awaited, patients’ management will continue to rely for the vast majority on local guidelines. Among many other aspects, this crisis has proven that different specialists must join forces to deliver the best possible care to patients.

positive: Cytokine release syndrome and the prospects for immunotherapy with COVID-19. Part 2: The role of interleukin 1 Interleukin 1 (IL-1) is a potential target of therapy in COVID-19 during the severe respiratory-inflammatory phase ("cytokine release syndrome"), when pulmonary macrophages are hyperactivated, releasing IL-1 and other cytokines. Preliminary evidence indicates that anakinra and canakinumab, drugs that block the action of IL-1 and have a good safety profile, improve the outcomes of patients with COVID-19 cytokine release syndrome. Results from large, randomized clinical trials are pending.

positive: Statins as early therapy to mitigate COVID-19 (SARS-CoV-2)-associated ARDS and cytokine storm syndrome – time is of the essence

positive: Therapeutic potential of mesenchymal stem cells and their exosomes in severe novel coronavirus disease 2019 (COVID-19) cases The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19) and the ensuing worldwide pandemic. The spread of the virus has had global effects such as activity restriction, economic stagnation, and collapse of healthcare infrastructure. Severe SARS-CoV-2 infection induces a cytokine storm, leading to acute respiratory distress syndrome (ARDS) and multiple organ failure, which are very serious health conditions and must be mitigated or resolved as soon as possible. Mesenchymal stem cells (MSCs) and their exosomes can affect immune cells by inducing anti-inflammatory macrophages, regulatory T and B cells, and regulatory dendritic cells, and can inactivate T cells. Hence, they are potential candidate agents for treatment of severe cases of COVID-19. In this review, we report the background of severe cases of COVID-19, basic aspects and mechanisms of action of MSCs and their exosomes, and discuss basic and clinical studies based on MSCs and exosomes for influenza-induced ARDS. Finally, we report the potential of MSC and exosome therapy in severe cases of COVID-19 in recently initiated or planned clinical trials of MSCs (33 trials) and exosomes (1 trial) registered in 13 countries on ClinicalTrials.gov.

positive: First Clinical Use of Lenzilumab to Neutralize GM-CSF in Patients with Severe and Critical COVID-19 Pneumonia Background: In COVID-19, high levels of granulocyte macrophage-colony stimulating factor (GM-CSF) and inflammatory myeloid cells correlate with disease severity, cytokine storm, and respiratory failure. With this rationale, we used lenzilumab, an anti-human GM-CSF monoclonal antibody, to treat patients with severe COVID-19 pneumonia. Methods: Hospitalized patients with COVID-19 pneumonia and risk factors for poor outcomes were treated with lenzilumab 600 mg intravenously for three doses through an emergency single-use IND application. Patient characteristics, clinical and laboratory outcomes, and adverse events were recorded. All patients receiving lenzilumab through May 1, 2020 were included in this report. Results: Twelve patients were treated with lenzilumab. Clinical improvement was observed in 11 out of 12 (92%), with a median time to discharge of 5 days. There was a significant improvement in oxygenation: The proportion of patients with SpO2/FiO2 < 315 at the end of observation was 8% vs. compared to 67% at baseline (p=0.00015). A significant improvement in mean CRP and IL-6 values on day 3 following lenzilumab administration was also observed (137.3 mg/L vs 51.2 mg/L, p = 0.040; 26.8 pg/mL vs 16.1 pg/mL, p = 0.035; respectively). Cytokine analysis showed a reduction in inflammatory myeloid cells two days after lenzilumab treatment. There were no treatment-emergent adverse events attributable to lenzilumab, and no mortality in this cohort of patients with severe COVID-19 pneumonia. Conclusions: In high-risk COVID-19 patients with severe pneumonia, GM-CSF neutralization with lenzilumab was safe and associated with improved clinical outcomes, oxygen requirement, and cytokine storm.

positive: Immune response to SARS‐CoV‐2 and mechanisms of immunopathological changes in COVID‐19 As a zoonotic disease that has already spread globally to several million human beings and possibly to domestic and wild animals, eradication of coronavirus disease 2019 (COVID‐19) appears practically impossible. There is a pressing need to improve our understanding of the immunology of this disease to contain the pandemic by developing vaccines and medicines for the prevention and treatment of patients. In this review, we aim to improve our understanding on the immune response and immunopathological changes in patients linked to detoriating clinical conditions such as, cytokine storm, acute respiratory distress syndrome, autopsy findings and changes in acute phase reactants and serum biochemistry in COVID‐19. Similar to many other viral infections, asymptomatic disease is present in a significant but currently unknown fraction of the affected individuals.In the majority of the patients, a one‐week, self‐limiting viral respiratory disease typically occurs, which ends with the development of neutralizing anti‐viral T cell and antibody immunity. The IgM, IgA and IgG type virus‐specific antibodies levels are important measurements to predict population immunity against this disease and whether cross‐reactivity with other coronaviruses is taking place.High viral‐load during the first infection and repeated exposure to virus especially in healthcare workers can be an important factor for severity of disease. It should be noted that many aspects of severe patients are unique to COVID‐19 and are rarely observed in other respiratory viral infections, such as severe lymphopenia and eosinopenia, extensive pneumonia and lung tissue damage, a cytokine storm leading to acute respiratory distress syndrome and multiorgan failure. Lymphopenia causes a defect in antiviral and immune regulatory immunity. At the same time, a cytokine storm starts with extensive activation of cytokine‐secreting cells with innate and adaptive immune mechanisms both of with contribute to a poor prognosis. Elevated levels of acute phase reactants and lymphopenia are early predictors of high disease severity. Prevention of development to severe disease, cytokine storm, acute respiratory distress syndrome and novel approachs to prevent their development will be main routes for future research areas. As we learn to live amidst the virus, understanding the immunology of the disease can assist in containing the pandemic and in developing vaccines and medicines to prevent and treat individual patients.

positive: Comment on “Central Nervous System Involvement by Severe Acute Respiratory Syndrome Coronavirus ‐2 (SARS‐CoV‐2)” A very interesting report, for the first time, provided direct evidence that the ongoing pandemic etiological agent, SARS‐CoV‐2, may be able to directly infect central nervous system (CNS) through an endothelial route. If proven true, this may explain frequent neurological symptoms associated with severe COVID‐19 diseases. A corresponding therapeutic intervention will be urgently needed to prevent such dangerous infections of CNS and associated high mortality rate. This article is protected by copyright. All rights reserved.

positive: Cannabinoid Receptor Type 2: A Possible Target in SARS-CoV-2 (CoV-19) Infection? In late December 2019, a novel coronavirus (SARS-CoV-2 or CoV-19) appeared in Wuhan, China, causing a global pandemic. SARS-CoV-2 causes mild to severe respiratory tract inflammation, often developing into lung fibrosis with thrombosis in pulmonary small vessels and causing even death. COronaVIrus Disease (COVID-19) patients manifest exacerbated inflammatory and immune responses, cytokine storm, prevalence of pro-inflammatory M1 macrophages and increased levels of resident and circulating immune cells. Men show higher susceptibility to SARS-CoV-2 infection than women, likely due to estrogens production. The protective role of estrogens, as well as an immune-suppressive activity that limits the excessive inflammation, can be mediated by cannabinoid receptor type 2 (CB2). The role of this receptor in modulating inflammation and immune response is well documented in fact in several settings. The stimulation of CB2 receptors is known to limit the release of pro-inflammatory cytokines, shift the macrophage phenotype towards the anti-inflammatory M2 type and enhance the immune-modulating properties of mesenchymal stromal cells. For these reasons, we hypothesize that CB2 receptor can be a therapeutic target in COVID-19 pandemic emergency.

positive: Immunomodulatory therapy for the management of severe COVID-19. Beyond the anti-viral therapy: A comprehensive review Severe Acute Respiratory Syndrome related to Coronavirus-2 (SARS-CoV-2), coronavirus disease-2019 (COVID-19) may cause severe illness in 20% of patients. This may be in part due to an uncontrolled immune-response to SARS-CoV-2 infection triggering a systemic hyperinflammatory response, the so-called "cytokine storm". The reduction of this inflammatory immune-response could be considered as a potential therapeutic target against severe COVID-19. The relationship between inflammation and clot activation must also be considered. Furthermore, we must keep in mind that currently, no specific antiviral treatment is available for SARS-CoV-2. While moderate-severe forms need in-hospital surveillance plus antivirals and/or hydroxychloroquine; in severe and life-threating subsets a high intensity anti-inflammatory and immunomodulatory therapy could be a therapeutic option. However, right data on the effectiveness of different immunomodulating drugs are scarce. Herein, we discuss the pathogenesis and the possible role played by drugs such as: antimalarials, anti-IL6, anti-IL-1, calcineurin and JAK inhibitors, corticosteroids, immunoglobulins, heparins, angiotensin-converting enzyme agonists and statins in severe COVID-19.

positive: Autoinflammatory and autoimmune conditions at the crossroad of COVID-19 Coronavirus disease 2019 (COVID-19) has been categorized as evolving in overlapping phases. First, there is a viral phase that may well be asymptomatic or mild in the majority, perhaps 80% of patients. The pathophysiological mechanisms resulting in minimal disease in this initial phase are not well known. In the remaining 20% of cases, the disease may become severe and/or critical. In most patients of this latter group, there is a phase characterized by the hyperresponsiveness of the immune system. A third phase corresponds to a state of hypercoagulability. Finally, in the fourth stage organ injury and failure occur. Appearance of autoinflammatory/autoimmune phenomena in patients with COVID-19 calls attention for the development of new strategies for the management of life-threatening conditions in critically ill patients. Antiphospholipid syndrome, autoimmune cytopenia, Guillain-Barré syndrome and Kawasaki disease have each been reported in patients with COVID-19. Here we present a scoping review of the relevant immunological findings in COVID-19 as well as the current reports about autoimmune/autoinflammatory conditions associated with the disease. These observations have crucial therapeutic implications since immunomodulatory drugs are at present the most likely best candidates for COVID-19 therapy. Clinicians should be aware of these conditions in patients with COVID-19, and these observations should be considered in the current development of vaccines.

positive: Cytokine Storm Induced by SARS-CoV-2 A novel coronavirus disease 2019 (COVID-19) triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently spreading globally, causing severe pneumonia and acute lung injury in many patients. Even worse, severe respiratory may develop into acute respiratory distress syndrome and multiple organ dysfunction syndrome in COVID-19. The cytokine storm caused by immune over-activation due to virus infection may be an important cause of death in the late period of progress, but the pathogenesis of cytokine storm is still unclear. This article reviews the mechanisms of SARS-CoV-2-induced cytokine storm in detail based on the current discovered researches, and put forward some valuable medication ideas for the targeted cytokines drug researches and treatment. The goal of this work will be helpful for reducing excessive immune response.

positive: The pathogenesis and treatment of the `Cytokine Storm' in COVID-19 Summary Cytokine storm is an excessive immune response to external stimuli. The pathogenesis of the cytokine storm is complex. The disease progresses rapidly, and the mortality is high. Certain evidence shows that, during the coronavirus disease 2019 (COVID-19) epidemic, the severe deterioration of some patients has been closely related to the cytokine storm in their bodies. This article reviews the occurrence mechanism and treatment strategies of the COVID-19 virus-induced inflammatory storm in attempt to provide valuable medication guidance for clinical treatment.

positive: Hemophagocytic lymphohistiocytosis: a review inspired by the COVID-19 pandemic Hemophagocytic syndrome (HPS) or hemophagocytic lymphohistiocytosis (HLH) is an acute and rapidly progressive systemic inflammatory disorder characterized by cytopenia, excessive cytokine production, and hyperferritinemia. Common clinical manifestations of HLH are acute unremitting fever, lymphadenopathy, hepatosplenomegaly, and multiorgan failure. Due to a massive cytokine release, this clinical condition is considered as a cytokine storm syndrome. HPS has primary and acquired (secondary, reactive) forms. Its primary form is mostly seen in childhood and caused by various mutations with genetic inheritance and, therefore, is called familial HLH. Secondary HLH may be caused in the presence of an underlying disorder, that is, secondary to a malignant, infectious, or autoimmune/autoinflammatory stimulus. This paper aims to review the pathogenesis and the clinical picture of HLH, and its severe complication, the cytokine storm, with a special emphasis on the developed classification criteria sets for rheumatologists, since COVID-19 infection has clinical symptoms resembling those of the common rheumatologic conditions and possibly triggers HLH. MED-LINE/Pubmed was searched from inception to April 2020, and the following terms were used for data searching: “hemophagocytic syndrome” OR “macrophage activation syndrome” OR “hemophagocytic lymphohistiocytosis”, OR “cytokine storm”. Finally, AND “COVID-19” was included in this algorithm. The selection is restricted to the past 5 years and limited numbers of earlier key references were manually selected. Only full-text manuscripts, published in an English language peer-reviewed journal were included. Manuscript selection procedure and numbers are given in Fig. 2. Briefly, the database search with the following terms of “Hemophagocytic syndrome” OR “Macrophage activation syndrome” OR “Hemophagocytic lymphohistiocytosis” OR “Cytokine storm” yielded 6744 results from inception to April 2020. The selection is restricted to the past 5 years and only limited numbers of earlier key references were selected, and this algorithm resulted in 3080 manuscripts. The addition of (AND “COVID-19”) resulted in 115 publications of which 47 studies, together with four sections of an online book were used in the final review. No statistical method was used. HLH is triggered by genetic conditions, infections, malignancies, autoimmune-autoinflammatory diseases, and some drugs. In COVID-19 patients, secondary HLH and cytokine storm may be responsible for unexplained progressive fever, cytopenia, ARDS, neurological and renal impairment. Differentiation between the primary and secondary forms of HLH is utterly important, since primary form of HLH requires complicated treatments such as hematopoietic stem cell transplantation. Further studies addressing the performance of HScore and other recommendations in the classification of these patients is necessary.

positive: PROPOSED USE OF THALIDOMIDE FOR THE CYTOKINE STORM OF COVID-19

positive: Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology Human coronaviruses (hCoVs) can be divided into low pathogenic and highly pathogenic coronaviruses. The low pathogenic CoVs infect the upper respiratory tract and cause mild, cold-like respiratory illness. In contrast, highly pathogenic hCoVs such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) predominantly infect lower airways and cause fatal pneumonia. Severe pneumonia caused by pathogenic hCoVs is often associated with rapid virus replication, massive inflammatory cell infiltration and elevated pro-inflammatory cytokine/chemokine responses resulting in acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Recent studies in experimentally infected animal strongly suggest a crucial role for virus-induced immunopathological events in causing fatal pneumonia after hCoV infections. Here we review the current understanding of how a dysregulated immune response may cause lung immunopathology leading to deleterious clinical manifestations after pathogenic hCoV infections.

positive: Potential Benefits of Tryptophan Metabolism to the Efficacy of Tocilizumab in COVID-19 Tocilizumab has been proposed as a means of opposing hyperinflammatory responses in intensive care patients with COVID-19. Here, we briefly discuss the potentially multiple, synergistic mechanisms whereby tocilizumab might exert therapeutic activity, mostly focusing on the production of tryptophan-derived catabolites that would result from blockade of IL-6 signaling, as contextualized to the cytokine storm occurring in COVID-19 patients.

positive: Cytokine profile in plasma of severe COVID-19 does not differ from ARDS and sepsis Rationale: Elevated levels of inflammatory cytokines have been associated with poor outcomes among COVID-19 patients. It is unknown, however, how these levels compare to those observed in critically ill patients with ARDS or sepsis due to other causes. Objectives: To directly compare plasma levels of inflammatory cytokines, with a focus on 6 cytokines associated with cytokine storm (IL-1b, IL-1RA, IL-6, IL-8, IL-18, and TNF), between hospitalized COVID-19 patients and banked plasma samples from ARDS and sepsis patients from prior to the COVID-19 pandemic. Findings: 15 hospitalized COVID-19 patients, 9 of whom were critically ill, were compared to 28 critically ill patients with ARDS or sepsis. There were no statistically significant differences in baseline levels of IL-1b, IL-1RA, IL-6, IL-8, IL-18, and TNF between patients with severe COVID-19 and critically ill controls with ARDS or sepsis. Conclusions: Levels of inflammatory cytokines IL-1b, IL-1RA, IL-6, IL-8, IL-18, and TNF were not higher in critically ill COVID-19 patients than in critically ill patients admitted with ARDS or sepsis due to other causes in this small cohort. Broad use of immunosuppressive therapies in ARDS has failed in numerous Phase 3 studies; use of these therapies in unselected patients with COVID-19 is likely unwarranted.

positive: Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients Background: Although the SARS-CoV-2 viral load detection of respiratory specimen has been widely used for novel coronavirus disease (COVID-19) diagnosis, it is undeniable that serum SARS-CoV-2 nucleic acid (RNAaemia) could be detected in a fraction of the COVID-19 patients. However, it is not clear that if the incidence of RNAaemia could be correlated with the occurrence of cytokine storm or with the specific class of patients. Methods: This study enrolled 48 patients with COVID-19 admitted to the General Hospital of Central Theater Command, PLA, a designated hospital in Wuhan, China. The patients were divided into three groups according to the Diagnosis and Treatment of New Coronavirus Pneumonia (version 6) published by the National Health Commission of China. The clinical and laboratory data were collected. The serum viral load detection and serum IL-6 levels were determined. Except for routine statistical analysis, Generalized Linear Models (GLMs) analysis was used to establish a patient status prediction model based on real-time RT-PCR Ct value. Findings: The Result showed that cases with RNAaemia were exclusively confirmed in critically ill patients group and appeared to reflect the illness severity. Further more, the inflammatory cytokine IL-6 levels were significantly elevated in critically ill patients, which is almost 10-folds higher than those in other patients. More importantly, the extremely high IL-6 level was closely correlated with the incidence of RNAaemia (R=0.902) and the vital signs of COVID-19 patients (R= -0.682). Interpretation: Serum SARS-CoV-2 viral load (RNAaemia) is strongly associated with cytokine storm and can be used to predict the poor prognosis of COVID-19 patients. Moreover, our results strongly suggest that cytokine IL-6 should be considered as a therapeutic target in critically ill patients with excessive inflammatory response.

positive: Neurological Manifestations of COVID-19 (SARS-CoV-2): A Review Background: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with many neurological symptoms but there is a little evidence-based published material on the neurological manifestations of COVID-19. The purpose of this article is to review the spectrum of the various neurological manifestations and underlying associated pathophysiology in COVID-19 patients. Method: We conducted a review of the various case reports and retrospective clinical studies published on the neurological manifestations, associated literature, and related pathophysiology of COVID-19 using PUBMED and subsequent proceedings. A total of 118 articles were thoroughly reviewed in order to highlight the plausible spectrum of neurological manifestations of COVID 19. Every article was either based on descriptive analysis, clinical scenarios, correspondence, and editorials emphasizing the neurological manifestations either directly or indirectly. We then tried to highlight the significant plausible manifestations and complications that could be related to the pandemic. With little known about the dynamics and the presentation spectrum of the virus apart from the respiratory symptoms, this area needs further consideration. Conclusion: The neurological manifestations associated with COVID-19 such as Encephalitis, Meningitis, acute cerebrovascular disease, and Guillain Barré Syndrome (GBS) are of great concern. But in the presence of life-threatening abnormal vitals in severely ill COVID-19 patients, these are not usually underscored. There is a need to diagnose these manifestations at the earliest to limit long term sequelae. Much research is needed to explore the role of SARS-CoV-2 in causing these neurological manifestations by isolating it either from cerebrospinal fluid or brain tissues of the deceased on autopsy. We also recommend exploring the risk factors that lead to the development of these neurological manifestations.

positive: Rapid Radiological Worsening and Cytokine Storm Syndrome in COVID-19 Pneumonia BACKGROUND: In June 2020, a large randomised controlled clinical trial in the UK found that dexamethasone was effective in reducing the number of deaths in patients with severe coronavirus disease 2019 (COVID-19). CASE DESCRIPTION: We describe a patient with rapid worsening of COVID-19 pneumonia and its dramatic improvement under corticosteroids. DISCUSSION: Corticosteroids could be useful in patients with an inflammatory profile, considering that acute respiratory distress syndrome may be the consequence of cytokine storm syndrome. LEARNING POINTS: One of the main pathophysiological hypotheses for severe COVID-19 pneumonia is inappropriate immunological hyperactivation. Corticosteroid therapy may be useful in these patients.

positive: Commentary: Phosphodiesterase 4 inhibitors as potential adjunct treatment targeting the cytokine storm in COVID-19 The most severe presentation of COVID-19 is characterized by a hyperinflammatory state attributed to the massive pro-inflammatory cytokine release, called "cytokine storm". Several specific anti-inflammatory/immunosuppressive agents are being evaluated by ongoing clinical trials; however, there is currently insufficient evidence for their efficacy and safety in COVID-19 treatment. Given the role of phosphodiesterase 4 (PDE) 4 and cyclic adenosine monophosphate in the inflammatory response, we hypothesize that selective PDE4 inhibition may attenuate the cytokine storm in COVID-19, through the upstream inhibition of pro-inflammatory molecules, particularly TNF-α, and the regulation of the pro-inflammatory/anti-inflammatory balance. Conversely, other anti-cytokine agents lead to the downstream inhibition of specific targets, such as IL-1, IL-6 or TNF-α, and may not be efficient in blocking the cytokine storm, once it has been triggered. Due to their mechanism of action targeting an early stage of the inflammatory response and ameliorating lung inflammation, we believe that selective PDE4 inhibitors may represent a promising treatment option for the early phase of COVID-19 pneumonia before the cytokine storm and severe multiorgan dysfunction take place. Furthermore, PDE4 inhibitors present several advantages including an excellent safety profile; the oral route of administration; the convenient dosing; and beneficial metabolic properties. Interestingly, obesity and diabetes mellitus type 2 have been reported to be risk factors for the severity of COVID-19. Therefore, randomized clinical trials of PDE4 inhibitors are necessary to explore their potential therapeutic effect as an adjunct to supportive measures and other therapeutic regiments.

positive: The cytokine storm of COVID-19: a spotlight on prevention and protection. INTRODUCTION The cytokine release syndrome (CRS) of COVID-19 is associated with the development of critical illness requiring multi-organ support. Further research is required to halt progression of multi-organ injury induced by hyper-inflammation. AREAS COVERED PubMed/MEDLINETM databases were accessed between May 9th-June 9th, 2020, to review the latest perspectives on the treatment and pathogenesis of CRS. EXPERT OPINION Over-activity of chemotaxis triggers a macrophage activation syndrome (MAS) resulting in the release of pro-inflammatory cytokines. IL-6 and TNF- α are at the forefront of hyper-inflammation. The inflammatory cascade induces endothelial activation and capillary leak, leading to circulatory collapse and shock. As endothelial dysfunction persists, there is activation of the clotting cascade and microvascular obstruction. Continued endothelial activation results in multi-organ failure, regardless of pulmonary tissue damage. We propose that targeting the endothelium may interrupt this cycle. Immuno-modulating therapies have been suggested, however, further data is necessary to confirm that they do not jeopardize adaptive immunity. Inhibition of IL-6 and the Janus Kinase, signal transducer and activator of transcription proteins pathway (JAK/STAT), are favorable targets. Remote ischemic conditioning (RIC) reduces the inflammation of sepsis in animal models and should be considered as a low risk intervention, in combination with cardiovascular protection.

positive: Neurological manifestations and complications of COVID-19: A Literature Review Abstract The Coronavirus disease due to SARS-CoV-2 emerged in Wuhan city, China in December 2109 and rapidly spread to more than 200 countries as a global health pandemic. There are more than 2.3 million confirmed cases and around 165,000 fatalities. The primary manifestation is respiratory and cardiac but neurological features are also being reported in the literature as case reports and case series. The most common reported symptoms to include headache and dizziness followed by encephalopathy and delirium. Among the complications noted are Cerebrovascular accident, Guillian barre syndrome, acute transverse myelitis, and acute encephalitis. The most common peripheral manifestation was hyposmia. It is further noted that sometimes the neurological manifestations can precede the typical features like fever and cough and later on typical manifestations develop in these patients. Hence a high index of suspicion is required for timely diagnosis and isolation of cases to prevent the spread in neurology wards. We present a narrative review of the neurological manifestations and complications of COVID-19. Our aim is to update the neurologists and physicians working with suspected cases of COVID-19 about the possible neurological presentations and the probable neurological complications resulting from this novel virus infection.

positive: COVID‐19: a collision of complement, coagulation and inflammatory pathways COVID‐19 is frequently accompanied by a hypercoagulable inflammatory state with microangiopathic pulmonary changes that can precede the diffuse alveolar damage characteristic of typical ARDS seen in other severe pathogenic infections. Parallels with systemic inflammatory disorders such as atypical haemolytic uraemic syndrome (aHUS) have implicated the complement pathway in the pathogenesis of COVID‐19, and particularly the anaphylatoxins C3a and C5a released from cleavage of C3 and C5 respectively. C5a is a potent cell signalling protein that activates a cytokine storm – a hyper‐inflammatory phenomenon – within hours of infection and the innate immune response. However, excess C5a can result in a pro‐inflammatory environment orchestrated through a plethora of mechanisms, that propagates lung injury, lymphocyte exhaustion and an immune paresis. Furthermore, disruption of the homeostatic interactions between complement and extrinsic and intrinsic coagulation pathways contributes to a net pro‐coagulant state in the microvasculature of critical organs. Fatal COVID‐19 has been associated with a systemic inflammatory response accompanied by a pro‐coagulant state and organ damage, particularly microvascular thrombi in the lungs and kidneys. Pathologic studies report strong evidence of complement activation. C5 blockade reduces inflammatory cytokines and their manifestations in animal studies, and has shown benefits in patients with aHUS, prompting investigation of this approach in the treatment of COVID‐19. This review describes the role of the complement pathway and particularly C5a and its aberrations in highly pathogenic virus infections, and therefore its potential as a therapeutic target in COVID‐19.

positive: Eicosanoids: the Overlooked Storm in COVID-19? Severe coronavirus-19 (COVID-19) symptoms, including systemic inflammatory response and multi-system organ failure, are now affecting thousands of infected patients and causing widespread mortality. Coronavirus infection causes tissue damage, which triggers the endoplasmic reticulum (ER) stress response and subsequent eicosanoid and cytokine storms. While pro-inflammatory eicosanoids including prostaglandins, thromboxanes, and leukotrienes are critical mediators of physiological processes such as inflammation, fever, allergy, and pain, their role in COVID-19 are poorly characterized. Arachidonic acid derived epoxyeicosatrienoic acids (EETs) could alleviate the systemic hyper-inflammatory response in COVID-19 infection by modulating ER stress and stimulating the resolution of inflammation. Soluble epoxide hydrolase (sEH) inhibitors, which increase endogenous EET levels, exhibit potent anti-inflammatory activity and inhibit various pathologic processes in preclinical disease models including pulmonary fibrosis, thrombosis, and acute respiratory distress syndrome. Therefore, targeting eicosanoids and sEH could be a novel therapeutic approach in combating COVID-19. In this review, we discuss the predominant role of eicosanoids in regulating the inflammatory cascade and propose the potential application of sEH inhibitors in alleviating COVID-19 symptoms. We also discuss the host-protective action of omega-3 fatty acid-derived epoxyeicosanoids and specialized pro-resolving mediators (SPMs) in regulating anti-inflammation and anti-viral response. Future studies determining the eicosanoid profile in COVID-19 patient or preclinical model are pivotal in providing the novel insight of coronavirus-host interaction and inflammation modulation.

positive: The Society for Immunotherapy of Cancer perspective on regulation of interleukin-6 signaling in COVID-19-related systemic inflammatory response The pandemic caused by the novel coronavirus SARS-CoV-2 has placed an unprecedented burden on healthcare systems around the world. In patients who experience severe disease, acute respiratory distress is often accompanied by a pathological immune reaction, sometimes referred to as ‘cytokine storm’. One hallmark feature of the profound inflammatory state seen in patients with COVID-19 who succumb to pneumonia and hypoxia is marked elevation of serum cytokines, especially interferon gamma, tumor necrosis factor alpha, interleukin 17 (IL-17), interleukin 8 (IL-8) and interleukin 6 (IL-6). Initial experience from the outbreaks in Italy, China and the USA has anecdotally demonstrated improved outcomes for critically ill patients with COVID-19 with the administration of cytokine-modulatory therapies, especially anti-IL-6 agents. Although ongoing trials are investigating anti-IL-6 therapies, access to these therapies is a concern, especially as the numbers of cases worldwide continue to climb. An immunology-informed approach may help identify alternative agents to modulate the pathological inflammation seen in patients with COVID-19. Drawing on extensive experience administering these and other immune-modulating therapies, the Society for Immunotherapy of Cancer offers this perspective on potential alternatives to anti-IL-6 that may also warrant consideration for management of the systemic inflammatory response and pulmonary compromise that can be seen in patients with severe COVID-19.

positive: Current pharmacological treatments for COVID‐19: What's next? Since December 2019 SARS‐Cov‐2 was found responsible for the disease COVID‐19, which has spread worldwide. No specific therapies/vaccines are yet available for the treatment of COVID‐19. Drug repositioning may offer a strategy and a number of drugs have been repurposed, including lopinavir/ritonavir, remdesivir, favipiravir and tocilizumab. This paper describes the main pharmacological properties of such drugs administered to patients with COVID‐19, focusing on their antiviral, immune‐modulatory and/or anti‐inflammatory actions. Where available, data from clinical trials involving patients with COVID‐19 are reported. Preliminary clinical trials seem to support their benefit. However, such drugs in COVID‐19 patients have peculiar safety profiles. Thus, adequate clinical trials are necessary for these compounds. Nevertheless, while waiting for effective preventive measures i.e. vaccines, many clinical trials on drugs belonging to different therapeutic classes are currently underway. Their results will help us in defining the best way to treat COVID‐19 and reducing its symptoms and complications.

positive: Expert recommendations on blood purification treatment protocol for patients with severe COVID-19 Recommendation and consensus Abstract Coronavirus disease (COVID-19) was first diagnosed in Wuhan in December 2019. The World Health Organization defined the subsequent outbreak of COVID-19 worldwide as a public health emergency of international concern. Epidemiological data indicate that at least 20% of COVID-19 patients have severe disease. In addition to impairment of the respiratory system, acute kidney injury (AKI) is a major complication. Immune damage mediated by cytokine storms and concomitant AKI is a key factor for poor prognosis. Based on previous experience of blood purification for patients with severe acute respiratory syndrome and Middle East respiratory syndrome combined with clinical front-line practice, we developed a blood purification protocol for patients with severe COVID-19. This protocol is divided into four major steps. The first step is to assess whether patients with severe COVID-19 require blood purification. The second step is to prescribe a blood purification treatment for patients with COVID-19. The third step is to monitor and adjust parameters of blood purification. The fourth step is to evaluate the timing of discontinuation of blood purification. It is expected that blood purification will play a key role in effectively reducing the mortality of patients with severe COVID-19 through the standardized implementation of the present protocol.

positive: Potential effect of blood purification therapy in reducing cytokine storm as a late complication of critically ill COVID-19

positive: Metformin and SARS-CoV-2: mechanistic lessons on air pollution to weather the cytokine/thrombotic storm in COVID-19 Pathological signaling in the lung induced by particulate matter (PM) air pollution partially overlaps with that provoked by COVID-19, the pandemic disease caused by infection with the novel coronavirus SARS-CoV-2. Metformin is capable of suppressing one of the molecular triggers of the proinflammatory and prothrombotic processes of urban PM air pollution, namely the mitochondrial ROS/Ca2+ release-activated Ca2+ channels (CRAC)/IL-6 cascade. Given the linkage between mitochondrial functionality, ion channels, and inflamm-aging, the ability of metformin to target mitochondrial electron transport and prevent ROS/CRAC-mediated IL-6 release might illuminate new therapeutic avenues to quell the raging of the cytokine and thrombotic-like storms that are the leading causes of COVID-19 morbidity and mortality in older people. The incorporation of infection rates, severity and lethality of SARS-CoV-2 infections as new outcomes of metformin usage in elderly populations at risk of developing severe COVID-19, together with the assessment of bronchial/serological titers of inflammatory cytokines and D-dimers, could provide a novel mechanistic basis for the consideration of metformin as a therapeutic strategy against the inflammatory and thrombotic states underlying the gerolavic traits of SARS-CoV-2 infection.

positive: Tocilizumab administration in patients with SARS-CoV-2 infection: Subcutaneous injection vs intravenous infusion

positive: Pulmonary radiological change of COVID-19 patients with 99mTc-MDP treatment Background: As increasing cases of COVID-19 around world, urgent need for effective COVID-19-specific therapeutic drugs is necessary; therefore, we conducted a pilot randomized-controlled study to evaluate the efficacy of 99mTc-MDP for COVID-19 therapeutic treatment. Methods: A total of 21 mild patients with COVID-19 were enrolled in this pilot RCT from February 2020 through March 2020, and then were assigned, in a 1:1 ratio, into control (11 patients) and 99mTc-MDP group (10 patients). Patients in the control group received routine treatment and patients assigned to the 99mTc-MDP group received a combination of routine treatment and an administration of 99mTc-MDP injection of 5ml/day. Both of the patients in the control and 99mTc-MDP groups were treated for 7 days with the primary end point of CT-based radiological pulmonary changes during 7-day follow-up. Findings: From baseline to the day 7, 8 (80%) of 10 mild patients in the 99mTc-MDP group had a significant radiological improvement in lung and a decline in inflammatory infiltration, whereas only 1 (9.1%) of 11 patients in the control group had a radiological improvement in lung. None of the patients in the 99mTc-MDP group had disease progression from mild to severe, as well as an inflammatory cytokine storm, and 2 mild patients (18.2%) in the control group developed severe. During days 7 through 14, the number of patients with radiological improvement in the 99mTc-MDP group remained consistent, and only 1 additional case (22%) in the control group were reported. Conclusion: In this randomized pilot study, 99mTc-MDP had an effective inhibitory effect on the inflammatory disease progression for the therapy of COVID-19, and it can accelerate the absorption of pulmonary inflammation in a short period of time during the process of treatment.

positive: The Doctor's Dilemma: lessons from GB Shaw in a modern pandemic COVID-19. In the current COVID 19 pandemic, the only treatments are supportive as no definitive pharmacological intervention is available. The heterogeneity of the immune response in different patient groups is clear with less severe illness in children. Understanding these disparities is particularly important as severely affected patients with COVID19 cannot always be predicted before they experience a cytokine storm and multiorgan dysfunction. Over 100 years ago, the concept of individualised immunotherapy was introduced by Sir Almroth Wright and immortalised in GB Shaw's play The Doctor's Dilemma. Shaw's play The Doctor's Dilemma explores the issues of private medical practice, equality of health care delivery, rationing of scarce resources (intensive care) and high-risk therapies. The play also describes the dilemma of rationing of resources and selecting the correct patient for new experimental therapies. Immunological theories of the time are now reflected in current understanding of inflammatory responses in sepsis and immunomodulation during the COVID19 pandemic.

positive: Extracorporeal blood purification treatment options for COVID-19: The role of immunoadsorption The activation of the innate and adaptive immune systems by SARS-CoV-2 causes the release of several inflammatory cytokines, including IL-6. The inflammatory hypercytokinemia causes immunopathological changes in the lungs including vascular leakage, and alveolar edema. As a result of these changes in the lungs, hypoxia and acute respiratory distress syndrome occur in patients with COVID-19. Even though there are clinical trials on the development of therapeutics and vaccines, there are currently no licensed vaccines or therapeutics for COVID-19. Pharmacological approaches have shown poor results in sepsis-like syndromes caused by the hypercytokinemia. Suppressing the cytokine storm is an important way to prevent the organ damage in patients with COVID-19. Extracorporeal blood purification could be proposed as an adjunctive therapy for sepsis, aiming to control the associated dysregulation of the immune system, which is known to protect organ functions. Several extracorporeal blood purification therapies are now available, and most of them target endotoxins and/or the cytokines and aim improving the immune response. For this purpose, plasmapheresis and immunoadsorption may be an important adjunctive treatment option to manage the complications caused by cytokine storm in critically ill patients with COVID-19.

positive: The Application Of Plasmapheresis For Covid‐19 Patients Coronaviruses are known human and animal pathogens, but a novel type of coronavirus, designated as severe acute respiratory syndrome coronavirus 2(SARS‐CoV‐2) is defined by World Health Organisation(WHO).This novel type has created a pandemia throughout the world most notably causing death owing to pneumonia.Nowadays the entire world is searching the curative treatment but outcomes are discouraging for intensive care critical patients. In this article we'd like to highlight that plasmapheresis,although it’ s an unproven strategy, could be a useful approach by the mechanism of alleviating the cytokine storm and decreasing the viral load. This article is protected by copyright. All rights reserved.

positive: Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome Summary The term cytokine storm syndromes describes conditions characterised by a life-threatening, fulminant hypercytokinaemia with high mortality. Cytokine storm syndromes can be genetic or a secondary complication of autoimmune or autoinflammatory disorders, infections, and haematological malignancies. These syndromes represent a key area of interface between rheumatology and general medicine. Rheumatologists often lead in management, in view of their experience using intensive immunosuppressive regimens and managing cytokine storm syndromes in the context of rheumatic disorders or infection (known as secondary haemophagocytic lymphohistiocytosis or macrophage activation syndrome [sHLH/MAS]). Interleukin (IL)-1 is pivotal in hyperinflammation. Anakinra, a recombinant humanised IL-1 receptor antagonist, is licenced at a dose of 100 mg once daily by subcutaneous injection for rheumatoid arthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, and cryopyrin-associated periodic syndromes. In cytokine storm syndromes, the subcutaneous route is often problematic, as absorption can be unreliable in patients with critical illness, and multiple injections are needed to achieve the high doses required. As a result, intravenous anakinra is used in clinical practice for sHLH/MAS, despite this being an off-licence indication and route of administration. Among 46 patients admitted to our three international, tertiary centres for sHLH/MAS and treated with anakinra over 12 months, the intravenous route of delivery was used in 18 (39%) patients. In this Viewpoint, we describe current challenges in the management of cytokine storm syndromes and review the pharmacokinetic and safety profile of intravenous anakinra. There is accumulating evidence to support the rationale for, and safety of, intravenous anakinra as a first-line treatment in patients with sHLH/MAS. Intravenous anakinra has important clinical relevance when high doses of drug are required or if patients have subcutaneous oedema, severe thrombocytopenia, or neurological involvement. Cross-speciality management and collaboration, with the generation of international, multi-centre registries and biobanks, are needed to better understand the aetiopathogenesis and improve the poor prognosis of cytokine storm syndromes.

positive: Advances in respiratory virus therapeutics – A meeting report from the 6th isirv Antiviral Group conference Abstract The International Society for Influenza and other Respiratory Virus Diseases held its 6th Antiviral Group (isirv-AVG) conference in Rockville, Maryland, November 13–15, 2018. The three-day program was focused on therapeutics towards seasonal and pandemic influenza, respiratory syncytial virus, coronaviruses including MERS-CoV and SARS-CoV, human rhinovirus, and other respiratory viruses. Updates were presented on several influenza antivirals including baloxavir, CC-42344, VIS410, immunoglobulin, immune plasma, MHAA4549A, pimodivir (JNJ-63623872), umifenovir, and HA minibinders; RSV antivirals including presatovir (GS-5806), ziresovir (AK0529), lumicitabine (ALS-008176), JNJ-53718678, JNJ-64417184, and EDP-938; broad spectrum antivirals such as favipiravir, VH244, remdesivir, and EIDD-1931/EIDD-2801; and host directed strategies including nitazoxanide, eritoran, and diltiazem. Other topics included considerations of novel endpoints such as ordinal scales and patient reported outcomes (PRO), and study design issues, and other regulatory considerations for antiviral drug development. The aim of this report is to provide a summary of the presentations given at this meeting.

positive: Convalescent plasma in Covid-19: Possible mechanisms of action Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible of the coronavirus disease 2019 (COVID-19) pandemic. Therapeutic options including antimalarials, antivirals, antibiotics and vaccines are under study. Meanwhile the current pandemic has called attention over old therapeutic tools to treat infectious diseases. Convalescent plasma (CP) constitutes the first option in the current situation, since it has been successfully used in other coronaviruses outbreaks. Herein, we discuss the possible mechanisms of action of CP and their repercussion in COVID-19 pathogenesis, including direct neutralization of the virus, control of an overactive immune system (i.e., cytokine storm, Th1/Th17 ratio, complement activation) and immunomodulation of a hypercoagulable state. All these benefits of PC are expected to be better achieved if used in non-critically hospitalized patients, in the hope of reducing morbidity and mortality.

positive: Hydroxychloroquine treatment in COVID‐19: a descriptive observational analysis of 30 cases from a single center in Wuhan, China Hydroxychloroquine (HCQ) garnered scientific attention in early February following publication of reports showing in vitro activity of chloroquine (CQ) against COVID‐19. While studies are mixed on this topic, the therapeutic effect of HCQ or CQ still need more valid clinical evidence. In this descriptive observational study, we aimed to discuss the treatment response of HCQ in COVID‐19 infected patients and 30 cases were included. The demographic, treatment, laboratory parameters of C‐reactive protein (CRP) and interleukin‐6 (IL‐6) before and after HCQ therapy and clinical outcome in the 30 COVID‐19 patients were assessed. In order to evaluate the effect of mediation time point, we also divided these cases into two groups, patients began administrated with HCQ within 7 days hospital (defined as early delivery group) and 7 days after hospital (defined as later delivery group). We found that, the elevated IL‐6, a risk factor in severe patients were reduced to normal level after HCQ treatment. More importantly, patients treated with HCQ at the time of early hospital recovered faster than those who treated later or taken as second line choose for their obvious shorter hospitalization time. In summary, early use of HCQ was better than later use and the effect of IL‐6 and CRP level can not be ruled out. This article is protected by copyright. All rights reserved.

positive: Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2 To date, no vaccines or effective drugs have been approved to prevent or treat COVID-19 and the current standard care relies on supportive treatments. Therefore, based on the fast and global spread of the virus, urgent investigations are warranted in order to develop preventive and therapeutic drugs. In this regard, treatments addressing the immunopathology of SARS-CoV-2 infection have become a major focus. Notably, while a rapid and well-coordinated immune response represents the first line of defense against viral infection, excessive inflammatory innate response and impaired adaptive host immune defense may lead to tissue damage both at the site of virus entry and at systemic level. Several studies highlight relevant changes occurring both in innate and adaptive immune system in COVID-19 patients. In particular, the massive cytokine and chemokine release, the so-called “cytokine storm”, clearly reflects a widespread uncontrolled dysregulation of the host immune defense. Although the prospective of counteracting cytokine storm is compelling, a major limitation relies on the limited understanding of the immune signaling pathways triggered by SARS-CoV-2 infection. The identification of signaling pathways altered during viral infections may help to unravel the most relevant molecular cascades implicated in biological processes mediating viral infections and to unveil key molecular players that may be targeted. Thus, given the key role of the immune system in COVID-19, a deeper understanding of the mechanism behind the immune dysregulation might give us clues for the clinical management of the severe cases and for preventing the transition from mild to severe stages.

positive: Indomethacin and resveratrol as potential treatment adjuncts for SARS-CoV-2/COVID-19 The ongoing pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2, also known as COVID-19) has led to unprecedented challenges for the global healthcare system. This novel coronavirus disease phenotype ranges from asymptomatic carriage to fulminant cytokine storm with respiratory failure, polyorgan dysfunction and death. Severe disease is characterised by exuberant inflammation resulting from high circulating cytokines such as interleukin-6 and tumour necrosis factor. These inflammatory mediators are responsible for the detrimental effects on the immune, hematologic, respiratory, renal, gastrointestinal and other body systems. In addition to inhibition of viral replication, blunting this inflammatory response before overt cytokine storm is important to improve outcomes. Although there are upcoming promising agents such as remdesivir and convalescent plasma, inexpensive, safe and widely available adjunct treatments to ameliorate disease burden would be welcome. Two potential anti-inflammatory agents include indomethacin, which has been shown in experimental models to decrease canine coronavirus levels in dogs and exhibit antiviral activity against several other viruses and the polyphenol, resveratrol, a potent antioxidant that has shown antiviral activity against several viruses.

positive: COVID-19 for the Cardiologist: A Current Review of the Virology, Clinical Epidemiology, Cardiac and Other Clinical Manifestations and Potential Therapeutic Strategies Summary The coronavirus disease-2019 (COVID-19), a contagious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV2), has reached pandemic status. As it spreads across the world, it has overwhelmed healthcare systems, strangled the global economy and led to a devastating loss of life. Widespread efforts from regulators, clinicians and scientists are driving a rapid expansion of knowledge of the SARS-CoV2 virus and the COVID-19 disease. We review the most current data with a focus on our basic understanding of the mechanism(s) of disease and translation to the clinical syndrome and potential therapeutics. We discuss the basic virology, epidemiology, clinical manifestation, multi-organ consequences, and outcomes. With a focus on cardiovascular complications, we propose several mechanisms of injury. The virology and potential mechanism of injury form the basis for a discussion of potential disease-modifying therapies.

positive: Low dose radiation therapy for COVID-19 pneumonia: a double-edged sword

positive: Cytokine storms are primarily responsible for the rapid death of ducklings infected with duck hepatitis A virus type 1 Duck hepatitis A virus type 1 (DHAV-1) is one of the most harmful pathogens in the duck industry. The infection of adult ducks with DHAV-1 was previously shown to result in transient cytokine storms in their kidneys. To understand how DHAV-1 infection impacts the host liver, we conducted animal experiments with the virulent CH DHAV-1 strain and the attenuated CH60 commercial vaccine strain. Visual observation and standard hematoxylin and eosin staining were performed to detect pathological damage in the liver, and viral copy numbers and cytokine expression in the liver were evaluated by quantitative PCR. The CH strain (10(8.4) copies/mg) had higher viral titers than the CH60 strain (10(4.9) copies/mg) in the liver and caused ecchymotic hemorrhaging on the liver surface. Additionally, livers from ducklings inoculated with the CH strain were significantly infiltrated by numerous red blood cells, accompanied by severe cytokine storms, but similar signs were not observed in the livers of ducklings inoculated with the CH60 strain. In conclusion, the severe cytokine storm caused by the CH strain apparently induces hemorrhagic lesions in the liver, which might be a key factor in the rapid death of ducklings.

positive: The Potential Beneficial Effect of EPA and DHA Supplementation Managing Cytokine Storm in Coronavirus Disease

positive: Tocilizumab, Adipokines and Severe Complications of COVID-19 Acute ischemic stroke (AIS) is a life-threatening complication of coronavirus disease 2019 (COVID-19) infection Increasing reports suggest an association between COVID-19 and AIS, although the underlying mechanism remains uncertain We performed a systematic review to characterize the clinical characteristics, neuroimaging findings, and outcomes of AIS in COVID-19 patients A literature search was performed in PubMed and Embase using a suitable keyword search strategy from 1st December 2019 to 29th May 2020 All studies reporting AIS occurrence in COVID-19 patients were included A total of 39 studies comprising 135 patients were studied The pooled incidence of AIS in COVID-19 patients from observational studies was 1 2% (54/4466) with a mean age of 63 4 ± 13 1 years The mean duration of AIS from COVID-19 symptoms onset was 10 ± 8 days, and the mean NIHSS score was 19 ± 8 Laboratory investigations revealed an elevated mean d-dimer (9 2 ± 14 8 mg/L) and fibrinogen (5 8 ± 2 0 g/L) Antiphospholipid antibodies were detected in a significant number of cases The majority of AIS neuroimaging patterns observed was large vessel thrombosis, embolism or stenosis (62 1%, 64/103), followed by multiple vascular territory (26 2%, 27/103) A high mortality rate was reported (38 0%, 49/129) We report the pooled incidence of AIS in COVID-19 patients to be 1 2%, with a high mortality rate Elevated d-dimer, fibrinogen and the presence of antiphospholipid antibodies appear to be prominent in COVID-19 patients with concomitant AIS, but further mechanistic studies are required to elucidate their role in pathogenesis

positive: Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation

positive: The cytokine storm and COVID-19 Coronavirus disease 2019 (COVID-19), which began in Wuhan, China in December 2019 has caused a large global pandemic and poses a serious threat to public health. More than four million cases of COVID-19, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have been confirmed as of May 11, 2020. SARS-CoV-2 is a highly pathogenic and transmissible coronavirus that primarily spreads through respiratory droplets and close contact. A growing body of clinical data suggests that a cytokine storm is associated with COVID-19 severity and is also a crucial cause of death from COVID-19. In the absence of antivirals and vaccines for COVID-19, there is an urgent need to understand the cytokine storm in COVID-19. Here, we have reviewed the current understanding of the features of SARS-CoV-2 and the pathological features, pathophysiological mechanisms, and treatments of the cytokine storm induced by COVID-19. Additionally, we suggest that the identification and treatment of the cytokine storm are important components for rescuing patients with severe COVID-19. This article is protected by copyright. All rights reserved.

positive: Cytokine Storm Plays a Direct Role in the Morbidity and Mortality from Influenza Virus Infection and is Chemically Treatable with a Single Sphingosine-1-Phosphate Agonist Molecule Cytokine storm defines a dysregulation of and an excessively exaggerated immune response most often accompanying selected viral infections and several autoimmune diseases. Newly emerging and re-emerging infections of the respiratory tract, especially influenza, SARS, and hantavirus post considerable medical problems. Their morbidities and mortalities are often a direct result of cytokine storm. This chapter visits primarily influenza virus infection and resultant cytokine storm. It provides the compelling evidence that illuminates cytokine storm in influenza pathogenesis and the clear findings that cytokine storm is chemically tractable by therapy directed toward sphingosine-1-phosphate receptor (S1PR) modulation, specifically S1P1R agonist therapy. The mechanism(s) of how S1P1R signaling works and the pathways involved are subjects of this review.

positive: Devilishly radical NETwork in COVID-19: Oxidative stress, neutrophil extracellular traps (NETs), and T cell suppression Pandemic coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and poses an unprecedented challenge to healthcare systems due to the lack of a vaccine and specific treatment options. Accordingly, there is an urgent need to understand precisely the pathogenic mechanisms underlying this multifaceted disease. There is increasing evidence that the immune system reacts insufficiently to SARS-CoV-2 and thus contributes to organ damage and to lethality. In this review, we suggest that the overwhelming production of reactive oxygen species (ROS) resulting in oxidative stress is a major cause of local or systemic tissue damage that leads to severe COVID-19. It increases the formation of neutrophil extracellular traps (NETs) and suppresses the adaptive arm of the immune system, i.e. T cells that are necessary to kill virus-infected cells. This creates a vicious cycle that prevents a specific immune response against SARS-CoV-2. The key role of oxidative stress in the pathogenesis of severe COVID-19 implies that therapeutic counterbalancing of ROS by antioxidants such as vitamin C or NAC and/or by antagonizing ROS production by cells of the MPS and neutrophil granulocytes and/or by blocking of TNF-α can prevent COVID-19 from becoming severe. Controlled clinical trials and preclinical models of COVID-19 are needed to evaluate this hypothesis.

positive: Immunoregulation with mTOR inhibitors to prevent COVID-19 severity: A novel intervention strategy beyond vaccines and specific antiviral medicines Coronavirus disease 2019 (COVID-19) has become a major global public health concern. The mortality rate for critically ill patients is up to 60%, and, thus, reducing the disease severity and case mortality is a top priority. Currently, cytokine storms are considered as the major cause of critical illness and death due to COVID-19. After a systematical review of the literature, we propose that cross-reactive antibodies associated with antibody-dependent enhancement (ADE) may actually be the cause of cytokine storms. It would be more difficult to develop vaccines for highly pathogenic human coronaviruses (CoVs) if ADE characteristics are taken into consideration. Therefore, it is urgent to find an effective way to prevent the occurrence of severe illness as severe acute respiratory syndrome CoV-2 specific drugs or vaccines are still in development. If the activation of memory B cells can be selectively inhibited in high-risk patients at an early stage of COVID-19 to reduce the production of cross-reactive antibodies against the virus, we speculate that ADE can be circumvented and severe symptoms can be prevented. The mammalian target of rapamycin (mTOR) inhibitors satisfy such needs and it is recommended to conduct clinical trials for mTOR inhibitors in preventing the severity of COVID-19.

positive: VEGF-D: a novel biomarker for detection of COVID-19 progression

positive: Unraveling the mystery of Covid‐19 Cytokine storm: From skin to organ systems. COVID‐19 is a global pandemic that emerged from Wuhan, China. Besides pneumonia and acute respiratory distress syndrome, the disease leads to multisystem involvement in the form of myocarditis, arrhythmias, cardiac arrest, gastrointestinal symptoms, hypoxemic brain injury, acute liver and renal function impairment. There are also reports of cutaneous lesions in form of urticarial and maculopapular rashes, chilblain like fingers and toes (covid feet), livedoid vasculopathy and chicken‐pox like or varicelliform vesicles. Clinically, many of these skin lesions are likely secondary to occlusion of small to medium blood vessels due to microthrombi formation or due to viral laden antigen‐antibody immune complexes; and same explanation may hold true for possible hypoxemic injury simultaneously occurring in other vital organs like lungs, heart, brain and kidneys. The histopathology, immunoflorescence and RT‐PCR analysis of skin biopsies can provide useful insights for ascertaining the pathogenesis of this complex viral syndrome. Apparently, it is interplay of disarmed cellular immunity and over‐activated humoral immunity that culminates in end‐organ changes. The morbidity and mortality can be significantly reduced by upgrading the cellular immunity and downgrading the humoral response; along with prevention of hypoxemic and reperfusion injuries by using antivirals, immunomodulators, antioxidants, anti‐platelets and anticoagulants in judicious and phased manner. This article is protected by copyright. All rights reserved.

positive: Cytokine Storms: Understanding COVID-19 The elevated circulating levels of cytokines associated with a variety of infectious and immune-mediated conditions are frequently termed a cytokine storm. Here, we explain the protective functions of cytokines in “ideal” responses; the multi-factorial origins that can drive these responses to become pathological; and how this ultimately leads to vascular damage, immunopathology, and worsening clinical outcomes.

positive: Noradrenergic and serotonergic drugs may have opposing effects on COVID-19 cytokine storm and associated psychological effects

positive: Remdesivir and Tocilizumab: Mix or Match To date, no therapy has demonstrated definite efficacy for patients with COVID‐19. Antiviral, as well as, anti‐inflammatory approaches, as these represented by remdesivir (RDV) and tocilizumab (TCZ) use, have been recently put forward. However, data upon optimal choice of one over the other, or potential need for regimen combination, remains an open question. We hereby report two well‐matched cases of SARS‐CoV‐2 (+) patients, developing respiratory failure, both receiving TCZ following severe inflammatory response, with or without RDV. We argue that, RDV administration is pivotal early in the course of the disease, since TCZ use alone cannot ensure inflammation control. This article is protected by copyright. All rights reserved.

positive: Amelioration of COVID‐19 related cytokine storm syndrome: Parallels to chimeric antigen receptor‐T cell cytokine release syndrome Coronavirus disease‐2019 (COVID‐19) severity appears to parallel the host immune response, with a subset of patients developing COVID‐19 cytokine storm syndrome (CSS).(1) Serum inflammatory cytokines are elevated in COVID‐19,(2–5) and interleukin (IL)‐6 appears to play a central role in COVID‐19 related CSS.(6–8) Based on the success of IL‐6 receptor blockade for chimeric antigen receptor T‐cell therapy associated cytokine release syndrome (CAR T‐cell CRS), similar strategies using tocilizumab are being investigated in COVID‐19.

positive: Mechanisms involved in the development of thrombocytopenia in patients with COVID-19 Corona Virus Disease 2019 (COVID-19) is caused by the novel coronavirus SARS-CoV-2. Emerging genetic and clinical evidence suggests similarities between COVID-19 patients and those with severe acute respiratory syndrome and Middle East respiratory syndrome. Hematological changes such as lymphopenia and thrombocytopenia are not rare in COVID-19 patients, and a smaller population of these patients had leukopenia. Thrombocytopenia was detected in 5–41.7% of the patients with COVID-19. Analyzing the dynamic decrease in platelet counts may be useful in the prognosis of patients with COVID-19. However, the mechanisms underlying the development of thrombocytopenia remain to be elucidated. This review summarizes the hematological changes in patients infected with SARS-CoV-2 and possible underlying mechanisms of thrombocytopenia development.

positive: Cytokine Release Syndrome (CRS) and Nicotine in COVID-19 Patients: Trying to Calm the Storm SARS-CoV-2 is a new coronavirus that has caused a worldwide pandemic. It causes severe acute respiratory syndrome (COVID-19), which is fatal in many cases, and is characterized by a cytokine release syndrome (CRS). Great efforts are currently being made to block the signal transduction pathway of pro-inflammatory cytokines in order to control this “cytokine storm” and rescue severely affected patients. Consequently, possible treatments for cytokine-mediated hyperinflammation, preferably within approved safe therapies, are urgently being researched to reduce rising mortality. One approach to inhibit proinflammatory cytokine release is to activate the cholinergic anti-inflammatory pathway through nicotinic acetylcholine receptors (α7nAchR). Nicotine, an exogenous α7nAchR agonist, is clinically used in ulcerative colitis to counteract inflammation. We have found epidemiological evidence, based on recent clinical SARS-CoV-2 studies in China, that suggest that smokers are statistically less likely to be hospitalized. In conclusion, our hypothesis proposes that nicotine could constitute a novel potential CRS therapy in severe SARS-CoV-2 patients.

positive: SARS-CoV-2 infection and overactivation of Nlrp3 inflammasome as a trigger of cytokine "storm" and risk factor for damage of hematopoietic stem cells The scientific community faces an unexpected and urgent challenge related to the SARS-CoV-2 pandemic and is investigating the role of receptors involved in entry of this virus into cells as well as pathomechanisms leading to a cytokine "storm," which in many cases ends in severe acute respiratory syndrome, fulminant myocarditis and kidney injury. An important question is if it may also damage hematopoietic stem progenitor cells?

positive: The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status An acute respiratory disease, caused by a novel coronavirus (SARS-CoV-2, previously known as 2019-nCoV), the coronavirus disease 2019 (COVID-19) has spread throughout China and received worldwide attention. On 30 January 2020, World Health Organization (WHO) officially declared the COVID-19 epidemic as a public health emergency of international concern. The emergence of SARS-CoV-2, since the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, marked the third introduction of a highly pathogenic and large-scale epidemic coronavirus into the human population in the twenty-first century. As of 1 March 2020, a total of 87,137 confirmed cases globally, 79,968 confirmed in China and 7169 outside of China, with 2977 deaths (3.4%) had been reported by WHO. Meanwhile, several independent research groups have identified that SARS-CoV-2 belongs to ß-coronavirus, with highly identical genome to bat coronavirus, pointing to bat as the natural host. The novel coronavirus uses the same receptor, angiotensin-converting enzyme 2 (ACE2) as that for SARS-CoV, and mainly spreads through the respiratory tract. Importantly, increasingly evidence showed sustained human-to-human transmission, along with many exported cases across the globe. The clinical symptoms of COVID-19 patients include fever, cough, fatigue and a small population of patients appeared gastrointestinal infection symptoms. The elderly and people with underlying diseases are susceptible to infection and prone to serious outcomes, which may be associated with acute respiratory distress syndrome (ARDS) and cytokine storm. Currently, there are few specific antiviral strategies, but several potent candidates of antivirals and repurposed drugs are under urgent investigation. In this review, we summarized the latest research progress of the epidemiology, pathogenesis, and clinical characteristics of COVID-19, and discussed the current treatment and scientific advancements to combat the epidemic novel coronavirus.

positive: Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome SARS-CoV-2 has been identified as the causative agent of a global outbreak of respiratory tract disease (COVID-19). In some patients the infection results in moderate to severe acute respiratory distress syndrome (ARDS), requiring invasive mechanical ventilation. High serum levels of IL-6, IL-10 and an immune hyperresponsiveness referred to as a ‘cytokine storm’ have been associated with poor clinical outcome. Despite the large numbers of COVID-19 cases and deaths, information on the phenotype and kinetics of SARS-CoV-2-specific T cells is limited. Here, we studied 10 COVID-19 patients who required admission to an intensive care unit and detected SARS-CoV-2-specific CD4(+) and CD8(+) T cells in 10 out of 10 and 8 out of 10 patients, respectively. We also detected low levels of SARS-CoV-2-reactive T cells in 2 out of 10 healthy controls not previously exposed to SARS-CoV-2, which is indicative of cross-reactivity due to past infection with ‘common cold’ coronaviruses. The strongest T-cell responses were directed to the spike (S) surface glycoprotein, and SARS-CoV-2-specific T cells predominantly produced effector and Th1 cytokines, although Th2 and Th17 cytokines were also detected. Furthermore, we studied T-cell kinetics and showed that SARS-CoV-2-specific T cells are present relatively early and increase over time. Collectively, these data shed light on the potential variations in T-cell responses as a function of disease severity, an issue that is key to understanding the potential role of immunopathology in the disease, and also inform vaccine design and evaluation.

positive: Expression profile of immune response genes in patients with Severe Acute Respiratory Syndrome BACKGROUND: Severe acute respiratory syndrome (SARS) emerged in later February 2003, as a new epidemic form of life-threatening infection caused by a novel coronavirus. However, the immune-pathogenesis of SARS is poorly understood. To understand the host response to this pathogen, we investigated the gene expression profiles of peripheral blood mononuclear cells (PBMCs) derived from SARS patients, and compared with healthy controls. RESULTS: The number of differentially expressed genes was found to be 186 under stringent filtering criteria of microarray data analysis. Several genes were highly up-regulated in patients with SARS, such as, the genes coding for Lactoferrin, S100A9 and Lipocalin 2. The real-time PCR method verified the results of the gene array analysis and showed that those genes that were up-regulated as determined by microarray analysis were also found to be comparatively up-regulated by real-time PCR analysis. CONCLUSIONS: This differential gene expression profiling of PBMCs from patients with SARS strongly suggests that the response of SARS affected patients seems to be mainly an innate inflammatory response, rather than a specific immune response against a viral infection, as we observed a complete lack of cytokine genes usually triggered during a viral infection. Our study shows for the first time how the immune system responds to the SARS infection, and opens new possibilities for designing new diagnostics and treatments for this new life-threatening disease.

positive: INHIBITORY EFFECT OF EMODIN ON RAW 264.7 ACTIVATED WITH DOUBLE STRANDED RNA ANALOGUE POLY I:C BACKGROUND: Emodin (3-methyl-1, 6, 8-trihydroxyanthraquinone) is a compound which can be found in Polygoni Multiflori Radix (PMR). PMR is the root of Polygonum multiflorum. PMR is used to treat dizziness, spermatorrhea, sores, and scrofula as well as chronic malaria traditionally in China and Korea. The anti-tumor property of emodin was already reported. However, anti-viral activity of emodin on macrophages are not fully reported. MATERIALS AND METHODS: Effects of emodin on RAW 264.7 mouse macrophages induced by polyinosinic-polycytidylic acid (poly I:C), a synthetic analog of double-stranded RNA, were evaluated. RESULTS: Emodin restored the cell viability in poly I: C-induced RAW 264.7 at concentrations of up to 50 μM. Emodin significantly inhibited the production of nitric oxide, IL-1α, IL-Ιβ, IL-6, GM-CSF, G-CSF, M-CSF, MCP-1, MIP-1a, MIP-Ιβ, MIP-2, RANTES, and IP-10 as well as calcium release and mRNA expression of signal transducer and activated transcription 1 (STAT1) in poly I:C-induced RAW 264.7 (P < 0.05). CONCLUSION: This study shows the inhibitory effect of emodin on poly I: C-induced RAW 264.7 via calcium-STAT pathway.

positive: Cytokine storm and colchicine potential role in fighting SARS-CoV-2 pneumonia For some patients with SARS-CoV-2, the worst clinical damage is not caused by the virus itself, but by an overactive inflammatory state In fact, in some people the immune system goes into overdrive and launches a large-scale assault on the tissue known as cytokine storm This excessive inflammatory/immune reaction can damage tissue and eventually kill people Evidence shows that blocking such cytokine storms can be effective and trials are under way to test drugs that act by reducing cytokine response, such as tocilizumab and sarilumab which bind interleukin 6 (IL-6), or anakinra which is the interleukin 1 receptor antagonist (IL-1) However, other drugs that block the cytokine cascade can also be considered In this article we describe the scientific and molecular motivation for the use of drugs that act by modulating the hyperactive inflammatory system in severe patients suffering from SARS-CoV-2, considering in particular an old drug that has been in use for many years for other therapeutic indications such as colchicine, and that could be favorable to its use, with low cost and good tolerability

positive: Bradycardia in Patients With COVID-19: A Calm Before the Storm? Cardiac manifestations of coronavirus disease 19 (COVID-19), including arrhythmia, have been described in the literature. However, to our knowledge, association of COVID-19 with bradycardia has not been reported. This case study describes sinus bradycardia as a potential manifestation of COVID-19. This is a retrospective case series of four patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, admitted to St. Luke’s University Health Network ICU between 24 March 2020 and 5 April 2020. Medical records of these patients were reviewed using the EPIC electronic health record system. Demographic, clinical, laboratory, and treatment data were reviewed against periods of bradycardia in each patient. The patient group comprised two males and two females. Two patients had pre-existing cardiovascular (CV) comorbidities but no history of arrythmias. Heart rates ranged between 66 and 88 beats/min on admission. The lowest rates during bradycardia were between 42 and 49 beats/min. The onset of sinus bradycardia in patients 1, 2, and 3 were day nine, 15, and five of illness, respectively. Patient 4 had three episodes of bradycardia, starting on day 10 of illness. Patients’ bradycardia episodes lasted one to 14 days. During bradycardia, maximum body temperatures ranged between 99.9 and 100.2 degree Fahrenheit. Patients 2, 3, and 4 required vasopressors to maintain mean arterial pressure > 65 mmHg during episodes. All four patients were on propofol at some point during bradycardia with patients 1, 2, and 3 also receiving dexmedetomidine. There was no consistent correlation of these medications with bradycardia. Electrocardiogram (ECG) findings included sinus bradycardia. Prolonged QTc interval observed in patient 2 on admission improved during bradycardia. Transient sinus bradycardia is a possible manifestation of COVID-19 and is important for close CV surveillance. Etiology can be multifactorial, but severe hypoxia, inflammatory damage of cardiac pacemaker cells, and exaggerated response to medications are possible triggers. High levels of pro-inflammatory cytokines may act directly on the sinoatrial (SA) node contributing to the development of bradycardia. This may be a warning sign of the onset of a serious cytokine storm. An increased awareness of possible exaggerated bradycardia response is important to consider with the use of empiric medications which have arrhythmogenic effects.

positive: Treatment algorithm for COVID-19: a multidisciplinary point of view The novel coronavirus (Sars-CoV-2) pandemic has spread rapidly, from December to the end of March, to 185 countries, and there have been over 3,000,000 cases identified and over 200,000 deaths. For a proportion of hospitalized patients, death can occur within a few days, mainly for adult respiratory distress syndrome or multi-organ dysfunction syndrome. In these patients, clinical signs and symptoms, as well as laboratory abnormalities, suggest a cytokine storm syndrome in response to the viral infection. No current targeted treatment is yet available for COVID-19, an unknown disease up to 2 months ago, which challenges doctors and researchers to find new drugs or reallocate other treatments for these patients. Since the beginning of the COVID-19 outbreak, a growing body of information on diagnostic and therapeutic strategies has emerged, mainly based on preliminary experience on retrospective studies or small case series. Antivirals, antimalarials, corticosteroids, biotechnological and small molecules, convalescent plasma and anticoagulants are among the drugs proposed for the treatment or in tested for COVID-19. Given the complexity of this new condition, a multidisciplinary management seems to be the best approach. Sharing and integrating knowledge between specialists, to evaluate the correct timing and setting of every treatment, could greatly benefit our patients. We reviewed the literature, combining it with our experiences and our specialist knowledge, to propose a management algorithm, correlating the clinical features with laboratory and imaging findings to establish the right timing for each treatment.

positive: Colchicine may not be effective in COVID-19 infection; it may even be harmful?

positive: Animal model of respiratory syncytial virus: CD8+ T cells cause a cytokine storm that is chemically tractable by sphingosine-1-phosphate 1 receptor agonist therapy. UNLABELLED The cytokine storm is an intensified, dysregulated, tissue-injurious inflammatory response driven by cytokine and immune cell components. The cytokine storm during influenza virus infection, whereby the amplified innate immune response is primarily responsible for pulmonary damage, has been well characterized. Now we describe a novel event where virus-specific T cells induce a cytokine storm. The paramyxovirus pneumonia virus of mice (PVM) is a model of human respiratory syncytial virus (hRSV). Unexpectedly, when C57BL/6 mice were infected with PVM, the innate inflammatory response was undetectable until day 5 postinfection, at which time CD8(+) T cells infiltrated into the lung, initiating a cytokine storm by their production of gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α). Administration of an immunomodulatory sphingosine-1-phosphate (S1P) receptor 1 (S1P1R) agonist significantly inhibited PVM-elicited cytokine storm by blunting the PVM-specific CD8(+) T cell response, resulting in diminished pulmonary disease and enhanced survival. IMPORTANCE A dysregulated overly exuberant immune response, termed a "cytokine storm," accompanies virus-induced acute respiratory diseases (VARV), is primarily responsible for the accompanying high morbidity and mortality, and can be controlled therapeutically in influenza virus infection of mice and ferrets by administration of sphingosine-1-phosphate 1 receptor (S1P1R) agonists. Here, two novel findings are recorded. First, in contrast to influenza infection, where the cytokine storm is initiated early by the innate immune system, for pneumonia virus of mice (PVM), a model of RSV, the cytokine storm is initiated late in infection by the adaptive immune response: specifically, by virus-specific CD8 T cells via their release of IFN-γ and TNF-α. Blockading these cytokines with neutralizing antibodies blunts the cytokine storm and protects the host. Second, PVM infection is controlled by administration of an S1P1R agonist.

positive: Pentoxifylline: An Immunomodulatory Drug for the Treatment of COVID-19 Rapidly spreading outbreak of the novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is causing serious health concerns worldwide It started as an epidemic in Wuhan, Hubei province, central China, and has now become a pandemic, spreading over most of the continents of the planet The major clinical symptoms of the infection are dry cough, fever, pneumonia, respiratory failure, hypoxia, and in certain cases, even death Alveolar damage and respiratory system failure are observed in severe cases Initial mild infection leads to activation of the immune system in the lungs and accumulation of various inflammatory cells and molecules At a later phase during the infection, a "cytokine storm" causes an Acute Respiratory Distress Syndrome (ARDS), leading to an increase in the production of pro-inflammatory cytokines, migration of a large number of immune cells to the site of infection, and ultimately pulmonary damage The rapid and uncontrolled outbreak requires putative therapeutic drugs for treatment of patients suffering from COVID-19 Amongst the currently used antiviral drugs, such as hydroxychloroquine, lopinavir, remdesivir etc we would like to present an update on another effective drug, pentoxifylline Pentoxifylline has anti-inflammatory, immunomodulatory, anti-viral, and bronchodilatory properties Pentoxifylline is known to reduce cytokine production, immune cell migration, and suppress certain signal transduction pathways (e g NF-kappa beta and STAT3) Thus, it minimizes inflammatory damage in the lung tissues

positive: Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients Pathogenic human coronavirus infections, such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV), cause high morbidity and mortality1, 2 Recently, a severe pneumonia-associated respiratory syndrome caused by a new coronavirus (SARS-CoV-2) was reported at December 2019 in the city Wuhan, Hubei province, China3, 4, 5, which was also named as pneumonia-associated respiratory syndrome (PARS)6 and can cause coronavirus disease 2019 (COVID-19) to seriously endanger human health Up to 24th of February 2020, at least 77779 cases have been reported with 2666 fatal cases according to the report from China CDC However, the immune mechanism that potential orchestrated acute mortality from COVID-19 patients is still unknown Here we show that after the SARS-CoV-2 infection, CD4+ T lymphocytes are rapidly activated to become pathogenic T helper (Th) 1 cells and generate GM-CSF etc The cytokines environment induces inflammatory CD14+CD16+ monocytes with high expression of IL-6 and accelerate the inflammation Given that large amount of inflammatory cells infiltrations have been observed in lungs from severe COVID-19 patients7, 8, these aberrant pathogenic Th1 cells and inflammatory monocytes may enter the pulmonary circulation in huge numbers and play an immune damaging role to causing lung functional disability and quick mortality Our results demonstrate that excessive non-effective host immune responses by pathogenic T cells and inflammatory monocytes may associate with severe lung pathology Thus, we suggest that monoclonal antibodies targeting GM-CSF or interleukin 6 may be effective in blocking inflammatory storms and, therefore, be a promising treatment of severe COVID-19 patients

positive: Anti-cytokine therapy in novel coronavirus disease (COVID-19) – the first administration of tocilizumab in Hungary at a department of infectology During the past few months, a pandemic originating from China named new coronavirus disease (COVID-19) has shown how vulnerable the world is. To date, no medication supported by randomized clinical trials has been approved for the treatment of COVID-19. At the time of writing of this paper, severe acute respiratory syndrome caused by coronavirus-2 (SARS-CoV-2) has been responsible - according to modest estimations - for around 4 million of infections and 300 000 deaths. Unveiling details of patomechanism, in fatal cases the role of immune dysregulation, namely cytokine release syndrome (CRS) has been discovered. Based on the current knowledge, interleukin-6 (IL6) plays a pivotal role in COVID-19 associated CRS. Case reports and result of small case series suggest efficacy of an IL6 inhibitor monoclonal antibody (tocilizumab) in treating CRS. Authors describe a case and review recent knowledge on the treatment of COVID-19. To our knowledge, the first case of severe COVID-19-associated cytokine storm syndrome - treated succesfully with IL6 monoclocal antibody at a Hungarian department of infectology - is presented here. Orv Hetil. 2020; 161(26): 1070-1077.

positive: Low doses of radiation therapy increase the immunosuppressive profile of lung macrophages via IL-10 production and IFNγ/IL-6 suppression: a therapeutic strategy to counteract lung inflammation? Patients with severe COVID-19 have a marked inflammatory state characterized by a cytokine storm syndrome. Severe pneumonia and acute respiratory distress syndrome (ARDS) have been described in 14% of the reported cases. Several therapeutic approaches are under investigation but safety and potential efficacy remain to be determined. Chest irradiation at equivalent doses below 1 Gy has been used successfully in the past to treat pneumonia. However, after the onset of effective antimicrobial agents, the use of low doses in the treatment of patients has been discontinued and the involved mechanism remained unknown. The objective of this study was to determine the mechanism by which low doses of radiation therapy (RT) protect the lung from inflammation. Nerve- and airway-associated macrophages (NAMs) and the pro-versus anti-inflammatory cytokine balance (IL6-IFNγ/IL-10) were recently shown to regulate lung inflammation. Here, we used Toll-like receptor 3 (TLR3) ligand polyinosinic:polycytidylic acid [Poly(I:C)] and lipopolysaccharide (LPS) in human lung macrophages and murine model of lung inflammation for functional assays. Our results show that irradiation of Poly(I:C)-stimulated human lung macrophages in vitro using low doses of RT (0.5-1 Gy) increased IL-10 secretion and decreased IFNγ production in the culture supernatant. The percentage of human lung macrophages producing IL-6 was also decreased in vitro with low doses of RT. Furthermore, using experimental models (LPS- and Poly(I :C)-induced lung inflammation), we showed that chest irradiation using low doses of RT significantly increased the percentage of NAMs producing IL-10, leading to lung protection from inflammation. Altogether, our data highlight one of the mechanisms by which low doses of RT regulate lung inflammation and positively favor anti-inflammatory cytokine secretion by lung macrophages. These data strongly suggest that low doses of RT could be used in order to mitigate lung inflammatory processes in situations such as COVID-19-induced ARDS.

positive: Treatment Considerations for COVID-19: A Critical Review of the Evidence (or Lack Thereof) Abstract The novel severe acute respiratory syndrome coronavirus 2 is causing a worldwide pandemic that may lead to a highly morbid and potentially fatal coronavirus disease-19 (COVID-19). There is currently no drug that has been proven as an effective therapy for COVID-19. Several candidate drugs are being considered and evaluated for treatment. This includes clinically-available drugs, such as chloroquine, hydroxychloroquine, and lopinavir/ritonavir, which are being repurposed for the treatment of COVID-19. Novel experimental therapies, such as remdesivir and favipiravir, are also actively being investigated for antiviral efficacy. Clinically-available and investigational immunomodulators, such as the IL-6 inhibitors tocilizumab and sarilumab and the anti-GMCSF lenzilumab, are being tested for their anticipated effect in counteracting the pro-inflammatory cytokine environment that characterizes severe and critical COVID-19. This review article examines the evidence behind the potential use of these leading drug candidates for the treatment of COVID-19. The authors conclude, based on this review, that there is still no high-quality evidence to support any of these proposed drug therapies. The authors, therefore, encourage the enrollment of eligible patients to multiple ongoing clinical trials that assess the efficacy and safety of these candidate therapies. Until the results of controlled trials are available, none of the suggested therapeutics is clinically proven as an effective therapy for COVID-19.

positive: A consideration of publication-derived immune-related associations in Coronavirus and related lung damaging diseases The severe acute respiratory syndrome virus SARS-CoV-2, a close relative of the SARS-CoV virus, is the cause of recent COVID-19 pandemic affecting, to date, over a 2 million individuals across the globe and demonstrating relatively high rates of infection and mortality. A third virus, the H5N1, responsible for avian influenza, has caused infection with some clinical similarities to those in COVID-19 infections. Cytokines, small proteins that modulate immune responses, have been directly implicated in some of the severe responses seen in COVID-19 patients, e.g. cytokine storms. Understanding the immune processes related to COVID-19, and other similar infections, could help identify diagnostic markers and therapeutic targets. Here we examine data of cytokine, immune cell types, and disease associations captured from biomedical literature associated with coronavirus, SARS, and H5N1 influenza, with the objective of identifying potentially useful relationships and areas for future research. Cytokine and cell-type associations captured from MeSH terms linked to thousands of PubMed abstracts, has identified differing patterns of associations between the three corpuses of abstracts (coronavirus, SARS, or H5N1 influenza). Clustering of cytokine-disease co-occurrences in the context of coronavirus has identified compelling clusters of co-morbidities and symptoms, some of which already known to be linked to COVID-19. Finally, network analysis identified sub-networks of cytokines and immune cell types associated with different manifestations, co-morbidities and symptoms of coronavirus, SARS, and H5N1. Systematic review of research in medicine is essential to facilitate evidence-based choices about health interventions. In a fast moving pandemic the approach taken here will identify trends and enable rapid comparison to the literature of related diseases.

positive: COVID‐19: A review of therapeutics under investigation The COVID‐19 outbreak has disrupted global health care networks and caused thousands of deaths and an international economic downturn. Multiple drugs are being used on patients with COVID‐19 based on theoretical and in vitro therapeutic targets. Several of these therapies have been studied, but many have limited evidence behind their use, and clinical trials to evaluate their efficacy are either ongoing or have not yet begun. This review summarizes the existing evidence for medications currently under investigation for treatment of COVID‐19, including remdesivir, chloroquine/hydroxychlorquine, convalescent plasma, lopinavir/ritonavir, IL‐6 inhibitors, corticosteroids, and angiotensin‐converting enzyme inhibitors.

positive: Contrasting evidence for corticosteroid treatment for coronavirus-induced cytokine storm.

positive: Increased cardiovascular mortality in African Americans with COVID-19

positive: Use of systemic immunomodulatory therapies during the coronavirus disease 2019 (COVID-19) pandemic

positive: A Review of Acute Myocardial Injury in Coronavirus Disease 2019 In December 2019, an outbreak of pneumonia caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), occurred in Wuhan, Hubei province, China, and it has spread rapidly across the world, causing the coronavirus disease 2019 (COVID-19) pandemic. Although SARS-CoV-2 infection predominantly results in pulmonary issues, accumulating evidence suggests the increased frequency of a variety of cardiovascular complications in patients with COVID-19. Acute cardiac injury, defined as elevated cardiac troponin levels, is the most reported cardiac abnormality in COVID-19 and strongly associated with mortality. In this article, we summarize the currently available data on the association of SARS-CoV-2 and COVID-19 with acute myocardial injury.

positive: Understanding the cytokine storm during COVID-19: Contribution of preexisting chronic inflammation.

positive: COVID-19 and what pediatric rheumatologists should know: a review from a highly affected country On March 11th, 2020 the World Health Organization declared COVID-19 a global pandemic. The infection, transmitted by 2019 novel coronavirus (2019-nCov), was first discovered in December 2019, in Wuhan, Hubei Province, and then rapidly spread worldwide. Italy was early and severely involved, with a critical spread of the infection and a very high number of victims. Person-to-person spread mainly occurs via respiratory droplets and contact. The median incubation period is 5 days. The spectrum of respiratory symptoms may range from mild to severe, strictly depending on the age of the patient and the underlying comorbidities.In children COVID-19 related disease is less frequent and less aggressive. In Italy 1% of positive cases are under 18 years of age, and no deaths have been recorded before 29 years of age. For patients affected by rheumatic disease, despite the concerns related to the imbalance of their immune response and the effect of immunosuppressive treatments, there are still few data to understand the real consequences of this infection. Major scientific societies have issued recommendations to help rheumatologists in caring their patients. Interestingly, some of the drugs mostly used by rheumatologists appear to be promising in critical COVID-19 infected patients, where the hyperinflammation and cytokine storm seem to drive to the multiorgan failure.Pediatric rheumatologists are expected to play a supporting role in this new front of COVID-19 pandemic, both as general pediatricians treating infected children, and as rheumatologists taking care of their rheumatic patients, as well as offering their experience in the possible alternative use of immunomodulatory drugs.

positive: Clinical features, diagnostics, and outcomes of patients presenting with acute respiratory illness: a comparison of patients with and without COVID-19 BACKGROUND: Emerging data on the clinical presentation, diagnostics, and outcomes of patients with COVID-19 have largely been presented as case series. Few studies have compared these clinical features and outcomes of COVID-19 to other acute respiratory illnesses. METHODS: We examined all patients presenting to an emergency department in San Francisco, California between February 3 and March 31, 2020 with an acute respiratory illness who were tested for SARS-CoV-2. We determined COVID-19 status by PCR and metagenomic next generation sequencing (mNGS). We compared demographics, comorbidities, symptoms, vital signs, and laboratory results including viral diagnostics using PCR and mNGS. Among those hospitalized, we determined differences in treatment (antibiotics, antivirals, respiratory support) and outcomes (ICU admission, ICU interventions, acute respiratory distress syndrome, cardiac injury). FINDINGS: In a cohort of 316 patients, 33 (10%) tested positive for SARS-CoV-2; 31 patients, all without COVID-19, tested positive for another respiratory virus (16%). Among patients with additional viral testing, no co-infections with SARS-CoV-2 were identified by PCR or mNGS. Patients with COVID-19 reported longer symptoms duration (median 7 vs. 3 days), and were more likely to report fever (82% vs. 44%), fatigue (85% vs. 50%), and myalgias (61% vs 27%); p<0.001 for all comparisons. Lymphopenia (55% vs 34%, p=0.018) and bilateral opacities on initial chest radiograph (55% vs. 24%, p=0.001) were more common in patients with COVID-19. Patients with COVID-19 were more often hospitalized (79% vs. 56%, p=0.014). Of 186 hospitalized patients, patients with COVID-19 had longer hospitalizations (median 10.7d vs. 4.7d, p<0.001) and were more likely to develop ARDS (23% vs. 3%, p<0.001). Most comorbidities, home medications, signs and symptoms, vital signs, laboratory results, treatment, and outcomes did not differ by COVID-19 status. INTERPRETATION: While we found differences in clinical features of COVID-19 compared to other acute respiratory illnesses, there was significant overlap in presentation and comorbidities. Patients with COVID-19 were more likely to be admitted to the hospital, have longer hospitalizations and develop ARDS, and were unlikely to have co-existent viral infections. These findings enhance understanding of the clinical characteristics of COVID-19 in comparison to other acute respiratory illnesses.

positive: Purposing Saikosaponins for the treatment of COVID-19

positive: Possible Old Drugs for Repositioning in COVID-19 Treatment: Combating Cytokine Storms from Haloperidol to Anti-interleukin Agents

positive: Treatment of Severe COVID-19 with Tocilizumab Mitigates Cytokine Storm and Averts Mechanical Ventilation During Acute Respiratory Distress: A Case Report and Literature Review COVID-19, caused by the novel severe acute respiratory coronavirus 2 (SARS-CoV-2), emerged in Wuhan, China, in 2019 and has resulted in the current pandemic The disease continues to pose a major therapeutic challenge Patient mortality is ultimately caused by acute respiratory distress syndrome (ARDS) Cytokine release syndrome (or "cytokine storm") is likely to be a contributing factor to ARDS in many patients Because interleukin 6 (IL-6) is known to play a key role in inflammation, IL-6 receptor inhibitors such as tocilizumab may potentially treat COVID-19 by attenuating cytokine release We present the case of a 48-year-old male with severe COVID-19, on the verge of meeting intubation requirements, who needed progressive oxygen support for respiratory distress The patient was treated with a non-weight-based dosage of tocilizumab to prevent the onset of a cytokine storm We chose to administer an IL-6 inhibitor because of the gradually increasing levels of acute phase reactants identified on serial blood draws, as well as his declining respiratory status The treatment was well-tolerated in conjunction with standard drug therapies for COVID-19 (hydroxychloroquine, azithromycin, and zinc) The patient subsequently experienced marked improvements in his respiratory symptoms and overall clinical status over the following days We believe that tocilizumab played a substantial role in his ability to avert clinical decline, particularly the need for mechanical ventilation Ultimately, the patient was downgraded from the ICU and discharged within days We highlight the potential of IL-6 inhibitors to prevent the progression of respiratory disease to a point requiring ventilator support This case underscores the potential importance of early serial measurements of IL-6 and cytokine storm-associated acute phase reactants, such as ferritin, D-dimer, and C-reactive protein, in guiding clinical decision-making in the management of patients with suspected COVID-19 Conclusion: The early, proactive identification of serum acute phase reactants should be implemented in the treatment of COVID-19 in order to screen for a primary contributor to mortality-the cytokine storm This screening, when followed by aggressive early treatment for cytokine storm, may have optimal therapeutic benefits and obviate the need for mechanical ventilation, thereby decreasing mortality Additionally, we review current evidence regarding cytokine release syndrome in COVID-19 and the use of IL-6 receptor inhibition as a therapeutic strategy, and examine other reported cases in the literature describing IL-6 antagonist treatment for patients with COVID-19

positive: Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases Purpose: Infection with COVID-19 potentially can result in severe outcomes and death from "cytokine storm syndrome", resulting in novel coronavirus pneumonia (NCP) with severe dyspnea, acute respiratory distress syndrome (ARDS), fulminant myocarditis and multiorgan dysfunction with or without disseminated intravascular coagulation. No published treatment to date has been shown to adequately control the inflammation and respiratory symptoms associated with COVID-19, apart from oxygen therapy and assisted ventilation. We evaluated the effects of using high dose oral and/or IV glutathione in the treatment of 2 patients with dyspnea secondary to COVID-19 pneumonia. Methods: Two patients living in New York City (NYC) with a history of Lyme and tick-borne co-infections experienced a cough and dyspnea and demonstrated radiological findings consistent with novel coronavirus pneumonia (NCP). A trial of 2â¯g of PO or IV glutathione was used in both patients and improved their dyspnea within 1â¯h of use. Repeated use of both 2000 mg of PO and IV glutathione was effective in further relieving respiratory symptoms. Conclusion: Oral and IV glutathione, glutathione precursors (N-acetyl-cysteine) and alpha lipoic acid may represent a novel treatment approach for blocking NFKappaB and addressing "cytokine storm syndrome" and respiratory distress in patients with COVID-19 pneumonia.

positive: Laboratory characteristics of patients infected with the novel SARS-CoV-2 virus A subgroup of COVID-19 patients develop very severe disease with requirement for ICU treatment, ventilation, and ECMO therapy. Laboratory tests indicate that the immune and clotting system show marked alterations with hyper-activation, hyper-inflammation, cytokine storm development. Furthermore, organ-specific biomarkers demonstrate the involvement of cardiac muscle, kidney, and liver dysfunction in many patients. In this article the use of laboratory biomarkers is discussed with regard to their use for diagnosis, disease progression, and risk assessment.

positive: Anotaciones breves sobre el síndrome de liberación de citocinas y el bloqueo terapéutico de la interleucina-6 en SARS-CoV-2/COVID-19./ Brief annotations on cytokine release syndrome and interleukin-6 therapeutic blockage in SARS-CoV-2/COVID-19

positive: Hypothesis for the management and treatment of the COVID-19-induced acute respiratory distress syndrome and lung injury using mesenchymal stem cell-derived exosomes Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the coronaviridae that causes respiratory disorders. After infection, large amounts of inflammatory cytokines are secreted, known as the cytokine storm. These cytokines can cause pulmonary damage induced by inflammation resulting in acute respiratory distress syndrome (ARDS), and even death. One of the therapeutic approaches for treatment of ARDS is a mesenchymal stem cell (MSC). MSCs suppress inflammation and reduce lung injury through their immunomodulatory properties. MSCs also have the potential to prevent apoptosis of the lung cells and regenerate them. But our suggestion is using MSCs-derived exosomes. Because these exosomes apply the same immunomodulatory and tissue repair effects of MSCs and they don't have problems associated to cell maintenance and injections. For investigation the hypothesis, MSCs should be isolated from tissues and characterized. Then, the exosomes should be isolated from the supernatants and characterized. These exosomes should be injected into a transgenic animal for COVID-19. In the final section, lung function assessment, histological examination, micro-CT, differential leukocyte, viral load analysis, cytokine assay, and CRP level analysis can be investigated. COVID-19 treatment is currently focused on supportive therapies and no vaccine has been developed for it. So, numerous researches are needed to find potential therapies. Since the pathogenesis of this disease was identified in previous studies and can cause lung injury with ARDS, investigation of the therapeutic approaches that can suppress inflammation, cytokine storm and ARDS can be helpful in finding a novel therapeutic approach for this disease.

positive: COVID-19: The Inflammation Link and the Role of Nutrition in Potential Mitigation The novel coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has engulfed the world, affecting more than 180 countries. As a result, there has been considerable economic distress globally and a significant loss of life. Sadly, the vulnerable and immunocompromised in our societies seem to be more susceptible to severe COVID-19 complications. Global public health bodies and governments have ignited strategies and issued advisories on various handwashing and hygiene guidelines, social distancing strategies, and, in the most extreme cases, some countries have adopted “stay in place” or lockdown protocols to prevent COVID-19 spread. Notably, there are several significant risk factors for severe COVID-19 infection. These include the presence of poor nutritional status and pre-existing noncommunicable diseases (NCDs) such as diabetes mellitus, chronic lung diseases, cardiovascular diseases (CVD), obesity, and various other diseases that render the patient immunocompromised. These diseases are characterized by systemic inflammation, which may be a common feature of these NCDs, affecting patient outcomes against COVID-19. In this review, we discuss some of the anti-inflammatory therapies that are currently under investigation intended to dampen the cytokine storm of severe COVID-19 infections. Furthermore, nutritional status and the role of diet and lifestyle is considered, as it is known to affect patient outcomes in other severe infections and may play a role in COVID-19 infection. This review speculates the importance of nutrition as a mitigation strategy to support immune function amid the COVID-19 pandemic, identifying food groups and key nutrients of importance that may affect the outcomes of respiratory infections.

positive: [Study on treatment of "cytokine storm" by anti-2019-nCoV prescriptions based on arachidonic acid metabolic pathway] Since the outbreak of 2019-nCoV, the epidemic has developed rapidly and the situation is grim. LANCET figured out that the 2019-nCoV is closely related to "cytokine storm". "Cytokine storm" is an excessive immune response of the body to external stimuli such as viruses and bacteria. As the virus attacking the body, it stimulates the secretion of a large number of inflammatory factors: interleukin(IL), interferon(IFN), C-X-C motif chemokine(CXCL) and so on, which lead to cytokine cascade reaction. With the exudation of inflammatory factors, cytokines increase abnormally in tissues and organs, interfering with the immune system, causing excessive immune response of the body, resulting in diffuse damage of lung cells, pulmonary fibrosis, and multiple organ damage, even death. Arachidonic acid(AA) metabolic pathway is principally used to synthesize inflammatory cytokines, such as monocyte chemotactic protein 1(MCP-1), tumor necrosis factor(TNF), IL, IFN, etc., which is closely related to the occurrence, development and regression of inflammation. Therefore, the inhibition of AA metabolism pathway is benefit for inhibiting the release of inflammatory factors in the body and alleviating the "cytokine storm". Based on the pharmacophore models of the targets on AA metabolic pathway, the traditional Chinese medicine database 2009(TCMD 2009) was screened. The potential herbs were ranked by the number of hit molecules, which were scored by pharmacophore fit value. In the end, we obtained the potential active prescriptions on "cytokine storm" according to the potential herbs in the "National novel coronavirus pneumonia diagnosis and treatment plan(trial version sixth)". The results showed that the hit components with the inhibitory effect on AA were magnolignan â , lonicerin and physcion-8-O-ß-D-glucopy-ranoside, which mostly extracted from Magnoliae Officinalis Cortex, Zingiberis Rhizoma Recens, Lonicerae Japonicae Flos, Rhei Radix et Rhizoma, Salviae Miltiorrhizae Radix et Rhizoma, Scutellariae Radix, Gardeniae Fructus, Ginseng Radix et Rhizoma, Arctii Fructus, Dryopteridis Crassirhizomatis Rhizoma, Paeoniaeradix Rubra, Dioscoreae Rhizoma. Finally the anti-2019-nCoV prescriptions were analyzed to obtain the potential active prescriptions on AA metabolic pathway, Huoxiang Zhengqi Capsules, Jinhua Qinggan Granules, Lianhua Qingwen Capsules, Qingfei Paidu Decoction, Xuebijing Injection, Reduning Injection and Tanreqing Injection were found that may prevent 2019-nCoV via regulate cytokines. This study intends to provide reference for clinical use of traditional Chinese medicine to resist new coronavirus.

positive: The Question of Whether to Remain on Therapy for Chronic Rheumatic Diseases in the Setting of the Covid-19 Pandemic. We appreciate our Italian colleagues' interest in our editorial denoting the rheumatologist's role in helping to diagnose and treat cytokine storm syndrome (CSS) in the setting of the Covid-19 panemic (1). It is encouraging that none of the 123 pediatric rheumatology patients (primarily juvenile idiopathic arthritis) on background biological disease modifying anti-rheumatic drug (bDMARD) therapies in Milan, Italy surveyed over a 7-week period from February 25 through April 14, 2020 (during which time Covid-19 was hyper-endemic there) had either confirmed or suspected Covid-19 (2).

positive: Amelioration of COVID-19 related cytokine storm syndrome: Parallels to chimeric antigen receptor-T cell cytokine release syndrome Coronavirus disease-2019 (COVID-19) severity appears to parallel the host immune response, with a subset of patients developing COVID-19 cytokine storm syndrome (CSS).(1) Serum inflammatory cytokines are elevated in COVID-19,(2-5) and interleukin (IL)-6 appears to play a central role in COVID-19 related CSS.(6-8) Based on the success of IL-6 receptor blockade for chimeric antigen receptor T-cell therapy associated cytokine release syndrome (CAR T-cell CRS), similar strategies using tocilizumab are being investigated in COVID-19.

positive: Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial Abstract Background Accumulating evidence proposed JAK inhibitors as therapeutic targets warranting rapid investigation. Objective This study evaluated the efficacy and safety of ruxolitinib, a Janus-associated kinase (JAK1/2) inhibitor, for COVID-19. Methods We conducted a prospective, multicenter, single-blind, randomized controlled phase II trial involving patients with severe COVID-19. Results Forty-three patients were randomly assigned (1:1) to receive ruxolitinib plus SoC treatment (22 patients) or placebo based on SoC treatment (21 patients). After exclusion of 2 patients (1 ineligible, 1 consent withdrawn) from the ruxolitinib group, 20 patients in intervention group and 21 patients in control group were included in the study. Treatment with ruxolitinib plus SoC was not associated with significantly accelerated clinical improvement in severe patients with COVID-19, although ruxolitinib recipients had a numerically faster clinical improvement. Eighteen (90%) patients from the ruxolitinib group showed CT improvement at D14 compared with 13 (61.9%) patients from the control group (P = 0.0495). Three patients in the control group died of respiratory failure, with 14.3% overall mortality at D28; no patients died in the ruxolitinib group. Ruxolitinib was well tolerated with low toxicities and no new safety signals. Levels of 7 cytokines were significantly decreased in the ruxolitinib group in comparison to the control group. Conclusions Although no statistical difference was observed, ruxolitinib recipients had a numerically faster clinical improvement. Significant chest CT improvement, a faster recovery from lymphopenia and favorable side-effect profile in ruxolitinib group were encouraging and informative to future trials to test efficacy of ruxolitinib in a larger population. This trial is registered at www.chictr.org.cn as ChiCTR-OPN-2000029580.

positive: IL-13 Predicts the Need for Mechanical Ventilation in COVID-19 Patients Here we report on an inpatient cohort of COVID-19 positive patients where plasma cytokines were tested for association with future need for mechanical ventilation. Hierarchical clustering, Kaplan-Meier curves, and odds ratios demonstrated that two cytokines, IL-13 (OR: 1.57) and IL-7 (OR: 1.04) and the growth factor bFGF (OR: 1.04), were predictive for intubation.

positive: Preventing cytokine storm syndrome in COVID-19 using α-1 adrenergic receptor antagonists

positive: Coronavirus Disease 2019 (COVID–19): A Short Review on Hematological Manifestations Infection with severe acute respiratory syndrome coronavirus 2 (SARS–CoV–2) is a rapidly spreading and devastating global pandemic. Many researchers are attempting to clarify the mechanisms of infection and to develop a drug or vaccine against the virus, but there are still no proven effective treatments. The present article reviews the common presenting hematological manifestations of coronavirus disease 2019 (COVID–19). Elucidating the changes in hematological parameters in SARS–CoV–2 infected patients could help to understand the pathophysiology of the disease and may provide early clues to diagnosis. Several studies have shown that hematological parameters are markers of disease severity and suggest that they mediate disease progression.

positive: Regulation of interferon production as a potential strategy for COVID-19 treatment Regulating the upstream of the cytokines production could be a promising strategy to the treatment of COVID-19. We suggest to pay more attention to the dysregulated IFN-I production in COVID-19 and to considerate cGAS, ALK and STING as potential therapeutic targets preventing cytokine storm. Approved drugs like suramin and ALK inhibitors are worthy of clinical trials.

positive: Internal genes of a highly pathogenic H5N1 influenza virus determine high viral replication in myeloid cells and severe outcome of infection in mice The highly pathogenic avian influenza (HPAI) H5N1 influenza virus has been a public health concern for more than a decade because of its frequent zoonoses and the high case fatality rate associated with human infections. Severe disease following H5N1 influenza infection is often associated with dysregulated host innate immune response also known as cytokine storm but the virological and cellular basis of these responses has not been clearly described. We rescued a series of 6:2 reassortant viruses that combined a PR8 HA/NA pairing with the internal gene segments from human adapted H1N1, H3N2, or avian H5N1 viruses and found that mice infected with the virus with H5N1 internal genes suffered severe weight loss associated with increased lung cytokines but not high viral load. This phenotype did not map to the NS gene segment, and NS1 protein of H5N1 virus functioned as a type I IFN antagonist as efficient as NS1 of H1N1 or H3N2 viruses. Instead we discovered that the internal genes of H5N1 virus supported a much higher level of replication of viral RNAs in myeloid cells in vitro, but not in epithelial cells and that this was associated with high induction of type I IFN in myeloid cells. We also found that in vivo during H5N1 recombinant virus infection cells of haematopoetic origin were infected and produced type I IFN and proinflammatory cytokines. Taken together our data infer that human and avian influenza viruses are differently controlled by host factors in alternative cell types; internal gene segments of avian H5N1 virus uniquely drove high viral replication in myeloid cells, which triggered an excessive cytokine production, resulting in severe immunopathology.

positive: Immune response in Dobrava-Belgrade virus infections Dobrava-Belgrade virus (DOBV) is a hantavirus that causes a disease in humans known as hemorrhagic fever with renal syndrome. Hallmarks of hantaviral infections are increased vascular permeability due to dysregulation of the endothelial cell barrier and acute thrombocytopenia. In order to gain insight into the immune response in DOBV infections, the serum levels of 27 cytokines in 24 hospitalized Greek HFRS patients were evaluated. Compared to the control group, significantly higher IL-1ra, IL-6, IL-8, IL-9, IL-10, GM-CSF, IP-10, MIP-1b, TNF-α and VEGF levels were found in severe cases, while in non-severe cases, IL-13 and TNF-α levels were significantly higher (p < 0.05). In all groups, IP-10 was increased and RANTES was decreased. Significant and time- (after onset of illness) dependent differences among fatal, severe and non-severe cases were seen. VEGF was positively associated with disease severity. A strong immune response was seen during the first week of illness, especially in severe cases, while the response in non-severe cases was weaker and delayed. The Th1 response was strong in non-severe cases and weak in the fatal case, while a mixed Th1/Th2 immune response was seen in the survivors of severe disease.

positive: Potential Immunotherapeutic Targets For Hypoxia Due to COVI-FLU The world is currently embroiled in a pandemic of coronavirus disease 2019 (COVID-19), a respiratory illness caused by the novel betacoronavirus SARS-CoV-2. The severity of COVID-19 disease ranges from asymptomatic to fatal acute respiratory distress syndrome (ARDS). In few patients, the disease undergoes phenotypic differentiation between 7-14 days of acute illness, either resulting in full recovery or symptom escalation. However, the mechanism of such variation is not clear, but the facts suggest that patient's immune status, co-morbidities, and the systemic effects of the viral infection (potentially depending on the SARS-CoV-2 strain involved) play a key role. Subsequently, patients with the most severe symptoms tend to have poor outcomes, manifest severe hypoxia, and possess elevated levels of pro-inflammatory cytokines (including IL-1ß, IL-6, IFN-Î³, and TNF-α) along with elevated levels of the anti-inflammatory cytokine IL-10, marked lymphopenia, and elevated neutrophil-to-lymphocyte ratios. Based on the available evidence, we propose a mechanism wherein SARS-CoV-2 infection induces direct organ damage while also fueling an IL-6-mediated cytokine release syndrome (CRS) and hypoxia, resulting in escalating systemic inflammation, multi-organ damage, and end-organ failure. Elevated IL-6 and hypoxia together predisposes patients to pulmonary hypertension, and the presence of asymptomatic hypoxia in COVID-19 further compounds this problem. Due to the similar downstream mediators, we discuss the potential synergistic effects and systemic ramifications of SARS-CoV-2 and influenza virus during co-infection, a phenomenon we have termed "COVI-Flu." Additionally, the differences between CRS and cytokine storm are highlighted. Finally, novel management approaches, clinical trials, and therapeutic strategies toward both SARS-CoV-2 and COVI-Flu infection are discussed, highlighting host response optimization and systemic inflammation reduction.

positive: Association of hypertension, diabetes, stroke, cancer, kidney disease, and high-cholesterol with COVID-19 disease severity and fatality: a systematic review Objective: To undertake a review and critical appraisal of published/preprint reports that offer methods of determining the effects of hypertension, diabetes, stroke, cancer, kidney issues, and high-cholesterol on COVID-19 disease severity. Data sources: Google Scholar, PubMed, COVID-19 Open Research Dataset: a resource of over 128,000 scholarly articles, including over 59,000 articles with full text related to COVID-19, SARS-CoV-2, and coronaviruses. Methods: A search was conducted by two authors independently on the freely available COVID-19 Open Research Dataset (CORD-19). We developed an automated search engine to screen a total of 59,000 articles in a few seconds. The search engine was built using a retrieval function that ranks a set of documents based on the query terms appearing in each document regardless of their proximity within the document. Filtering of the articles was then undertaken using keywords and questions, e.g. "Effects of diabetes on COVID/normal coronavirus/SARS-CoV-2/nCoV/COVID-19 disease severity, mortality?". The search terms were repeated for all the comorbidities considered in this paper. Additional articles were retrieved by searching via Google Scholar and PubMed. Findings: A total of 54 articles were considered for a full review. It was observed that diabetes, hypertension, and cholesterol levels possess an apparent relation to COVID-19 severity. Other comorbidities, such as cancer, kidney disease, and stroke, must be further evaluated to determine a strong relationship to the virus. Reports associating cancer, kidney disease, and stroke with COVID-19 should be carefully interpreted, not only because of the size of the samples, but also because patients could be old, have a history of smoking, or have any other clinical condition suggesting that these factors might be associated with the poor COVID-19 outcomes rather than the comorbidity itself. Such reports could lead many oncologists and physicians to change their treatment strategies without solid evidence and recommendations. Further research regarding this relationship and its clinical management is warranted. Additionally, treatment options must be examined further to provide optimal treatment and ensure better outcomes for patients suffering from these comorbidities. It should be noted that, whether definitive measurements exist or not, the care of patients as well as the research involved should be largely prioritized to tackle this deadly pandemic.

positive: De Los Pulsos De Corticoides En Pacientes Con Síndrome De Liberación De Citoquinas Inducido Por Infección Por Sars-Cov-2 Abstract Introduction: cytokine storm syndrome (CSS) is a serious complication of COVID-19 patients. Treatment is tocilizumab. The use of glucocorticoids (GC) is controversial. In other very similar CSS, such as macrophage activation syndrome (MAS) and hemophagocytic syndrome (HFS), the main treatment are corticosteroids. Our objective is to evaluate the efficacy of GC in the CSS by COVID-19. Patients: we included 92 patients with CSS associated to COVID-19 who received GC, GC, and tocilizumab and only tocilizumab. We determine CSS markers. We evaluated mortality, intubation, and a combined variable. Results: in all cases the percentages of events were lower in the group of patients with GC was administered. The hazard ratio of the final variables with GC versus the group in which only tocilizumab was administered was lower as CGs were considered, with statistical significance for survival. Discussion: the early use of GC pulses could control SLC, with a lower requirement to use tocilizumab and a decrease in events such as intubation and death.

positive: The Biology of Lactoferrin, an Iron-Binding Protein That Can Help Defend Against Viruses and Bacteria Lactoferrin is a nutrient classically found in mammalian milk. It binds iron and is transferred via a variety of receptors into and between cells, serum, bile, and cerebrospinal fluid. It has important immunological properties, and is both antibacterial and antiviral. In particular, there is evidence that it can bind to at least some of the receptors used by coronaviruses and thereby block their entry. Of importance are Heparan Sulfate Proteoglycans (HSPGs) and the host receptor angiotensin-converting enzyme 2 (ACE2), as based on other activities lactoferrin might prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from attaching to the host cells. Lactoferrin (and more specifically enteric-coated LF because of increased bioavailability) may consequently be of preventive and therapeutic value during the present COVID-19 pandemic.

positive: Cytokine Storm Drugs Move from CAR T to COVID-19. Early reports suggest that tocilizumab, an IL6 receptor-blocking antibody used to manage toxicities associated with chimeric antigen receptor T-cell therapy, may help control cytokine storms in people infected with COVID-19. Preliminary data from randomized trials are less clear-cut.

positive: Low dose radiation therapy as a potential life saving treatment for COVID-19-induced acute respiratory distress syndrome (ARDS) Abstract The new coronavirus COVID-19 disease caused by SARS-CoV-2 was declared as global public health emergency by WHO on Jan 30, 2020. Despite massive efforts from various governmental, health and medical organizations, the disease continues to spread globally with increasing fatality rates. Several experimental drugs have been approved by FDA with unknown efficacy and potential adverse effects. The exponentially spreading pandemic of COVID-19 deserves prime public health attention to evaluate yet unexplored arenas of management. We opine that one of these treatment options is low dose radiation therapy for severe and most critical cases. There is evidence in literature that low dose radiation induces an anti-inflammatory phenotype that can potentially afford therapeutic benefit against COVID-19- related complications that are associated with significant morbidity and mortality. Herein, we review the effects and putative mechanisms of low dose radiation that may be viable, useful and of value in counter-acting the acute inflammatory state induced by critical stage COVID-19.

positive: Longitudinal COVID-19 profiling associates IL-1Ra and IL-10 with disease severity and RANTES with mild disease. Background Identifying immune correlates of COVID-19 disease severity is an urgent need for clinical management, vaccine evaluation and drug development. Here we present a temporal analysis of key immune mediators, cytokine and chemokines in blood of hospitalised COVID-19 patients from serial sampling and follow up over four weeks.Methods A total of 71 patients with laboratory-confirmed COVID-19 admitted to Beijing You'an hospital in China with either mild (53 patients) or severe disease (18 patients) were enrolled with 18 healthy volunteers. We measured 34 immune mediators, cytokines and chemokines in peripheral blood every 4-7 days over one month per patient using a bio-plex multiplex immunoassay.Results We found that the chemokine RANTES(CCL5) was significantly elevated, from an early stage of the infection, in patients with mild but not severe disease. We also found that early production of inhibitory mediators including IL-10 and IL-1RA were significantly associated with disease severity, and a combination of CCL5, IL-1Ra and IL-10 at week 1 may predict patient outcomes. The majority of cytokines that are known to be associated with the cytokine storm in virus infections such as IL-6 and IFN-gamma were only significantly elevated in the late stage of severe COVID-19 illness. TNF- alpha and GM-CSF showed no significant differences between severe and mild cases.Conclusion Together our data suggest early intervention to increase expression of CCL5 may prevent patients from developing severe illness. Our data also suggest that measurement of levels of CCL5, as well as IL-1Ra, IL-10 in blood individually and in combination might be useful prognostic bio-markers to guide treatment strategies.

positive: An interferon‐γ‐related cytokine storm in SARS patients Fourteen cytokines or chemokines were analyzed on 88 RT‐PCR‐confirmed severe acute respiratory syndrome (SARS) patients. IFN‐γ, IL‐18, TGF‐β, IL‐6, IP‐10, MCP‐1, MIG, and IL‐8, but not of TNF‐α, IL‐2, IL‐4, IL‐10, IL‐13, or TNFRI, were highly elevated in the acute phase sera of Taiwan SARS patients. IFN‐γ was significantly higher in the Ab(+) group than in the Ab(−) group. IFN‐γ, IL‐18, MCP‐1, MIG, and IP‐10 were already elevated at early days post fever onset. Furthermore, levels of IL‐18, IP‐10, MIG, and MCP‐1 were significantly higher in the death group than in the survival group. For the survival group, IFN‐γ and MCP‐1 were inversely associated with circulating lymphocytes count and monocytes count, but positively associated with circulating neutrophils count. It is concluded that an interferon‐γ‐related cytokine storm was induced post SARS coronavirus infection, and this cytokine storm might be involved in the immunopathological damage in SARS patients. J. Med. Virol. 75:185–194, 2005. © 2004 Wiley‐Liss, Inc.

positive: Hyperinflammation with Covid-19: the key to patient deterioration?()() BACKGROUND: The potential risk of cytokine storm in patients with coronavirus disease 2019 (Covid-19) has been described(1); we write to share our experience treating a 17-year-old male with haemophagocytic lymphohistiocytosis (HLH) secondary to Covid-19 infection. CASE REPORT: This patient presented with cough, sore throat, anorexia and pyrexia. On examination, he had gross cervical lymphadenopathy and palpable splenomegaly. Nose and throat swab for SARS-CoV-2 was positive and blood tests revealed pancytopaenia with very high ferritin, triglyceride and d-dimer levels. The patient’s HScore(2) was calculated at 220, suggesting probability of HLH of 93-96%. Considering Russell and colleagues’(3) comments about potential harm of corticosteroid use in patients with Covid-19 infection, the patient was commenced on treatment with the selective IL-1 receptor antagonist drug, Anakinra, and a two day course of intravenous immunoglobulin. RESULTS: The patient responded rapidly to treatment, becoming apyrexial after 24 hours. His lymph nodes and spleen began to normalise after the first 48 hours, at which time point the ferritin also started to decrease. He was discharged after 11 days feeling fit and well. CONCLUSION: This case certainly illustrates the importance of hyperinflammation syndromes in Covid-19. It also raises the question – is the severe pneumonitis seen in patients with Covid-19 an immunological phenomenon? We know that the viral load of patients with Covid-19 seems to peak in the early stages of illness(4, 5), however patients deteriorate later in the disease course, at around days 10-14. This patient, who had risk factors for deterioration (male, pancytopaenic), did not develop an oxygen requirement and clinically and biochemically improved rapidly on Anakinra with no adverse events. We might suggest Anakinra to the scientific community as a treatment option in Covid-19 infection.

positive: Paradigm Shift for COVID-19 Response: Identifying High-risk Individuals and Treating Inflammation

positive: COVID-19: A New Virus, but a Familiar Receptor and Cytokine Release Syndrome Summary Zhou et al. (Nature) and Hoffmann et al. (Cell) identify ACE2 as a SARS-CoV-2 receptor, and the latter show its entry mechanism depends on cellular serine protease TMPRSS2. These results may explain proinflammatory cytokine release via the associated angiotestin II pathway and a possible therapeutic target via the IL-6-STAT3 axis.

positive: Increased serum levels of soluble TNF-Î± receptor is associated with mortality of ICU COVID-19 patients Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has spread to almost 100 countries, infected over 10M patients and resulted in 505K deaths worldwide as of 30th June 2020. The major clinical feature of severe COVID-19 requiring ventilation is acute Respiratory Distress Syndrome (ARDS) with multi-functional failure as a result of a cytokine storm with increased serum levels of cytokines such as TNF- and IL-6 being reported. TNF- levels are increased during the cytokine storm in very ill patients and soluble receptors for IL-6 and IL-2 are present in the blood of COVID-19 patients, Objectives: To elucidate the involvement of serum levels of soluble TNF-Receptor of severe and mild COVID-19 patients to determine for severity of disease. Method: We recruited 16 severe COVID-19 patients in the ICU on ventilator support and 26 milder COVID-19 patients who were hospitalised but not within the intensive care unit (ICU) between March-May 2020 at the Masih Daneshvari Hospital Tehran, Iran. After harvesting of whole blood the serum was isolated and soluble TNF-Receptor levels measured by ELISA. Results: Serum levels of the usually inhibitory soluble TNF receptor 1 (sTNFaR1) were significantly elevated in severe COVID-19 patients at admission to ICU. High serum levels of sTNFaR1 were associated with mortality of severe COVID-19 patients treated within ICU. Conclusions: This pilot study demonstrates for role of STNF-aR1 receptor in severity of disease. Future studies should examine whether lower levels of systemic sTNFaR1 at admission may indicate a better disease outcome.

positive: A review of cardiac manifestations and predictors of outcome in patients with COVID – 19 Abstract Coronavirus disease (COVID-19) pandemic has so far involved 184 countries and more than 2.79 million patients worldwide. Over the past three months, it has attributed to more than 196, 000 deaths, with more than 50, 000 deaths in the United States alone. Pulmonary manifestations are predominant and have been well identified. Cardiac involvement is also common. Acute cardiac injury, the most common cardiac manifestation of this disease can be seen in patients even without prior cardiac comorbidities. Established cardiovascular risk factors such as diabetes mellitus, hypertension, and coronary artery disease predispose to cardiac injury, the severity of illness and mortality. Non-ischemic myocardial injury secondary to cytokine storm is thought to be the predominant mechanism of acute cardiac injury associated with COVID-19. Multiple mechanisms and processes contribute to cardiac injury resulting in a poor outcome. Some of these are not clearly understood. Clinical and diagnostic details of cardiovascular involvement in these patients are mostly limited to biochemical markers. Multiple therapeutic agents have been tried with questionable efficacy and without clinical evidence. Interactions of comorbidities, cardiovascular drugs, the cardiac effect of therapeutic agents on the illness continue to be under investigation. With an increasing number of patients, newer promising therapies, and ongoing clinical trials, the exact mechanisms and extent to which these risk factors contribute to outcomes will be clearer in the future.

positive: Clinical and laboratory predictors of in-hospital mortality in patients with COVID-19: a cohort study in Wuhan, China BACKGROUND: This study aimed to develop mortality-prediction models for patients with Coronavirus disease 2019 (COVID-19). METHODS: The training cohort were consecutive patients with COVID-19 in the First People’s Hospital of Jiangxia District in Wuhan from January 7, 2020 to February 11, 2020. We selected baseline clinical and laboratory data through the stepwise Akaike information criterion and ensemble XGBoost model to build mortality-prediction models. We then validated these models by randomly collecting COVID-19 patients in the Infection department of Union Hospital in Wuhan from January 1, 2020, to February 20, 2020. RESULTS: 296 patients with COVID-19 were enrolled in the training cohort, 19 of whom died during hospitalization and 277 were discharged from the hospital. The clinical model developed with age, history of hypertension and coronary heart disease showed AUC of 0.88 (95% CI, 0.80-0.95); threshold, -2.6551; sensitivity, 92.31%; specificity, 77.44% and negative predictive value (NPV), 99.34%. The laboratory model developed with age, high-sensitivity C-reactive protein (hsCRP), peripheral capillary oxygen saturation (SpO2), neutrophil and lymphocyte count, D-dimer, aspartate aminotransferase (AST) and glomerular filtration rate (GFR) had a significantly stronger discriminatory power than the clinical model (p=0.0157), with AUC of 0.98 (95% CI, 0.92-0.99); threshold, -2.998; sensitivity, 100.00%; specificity, 92.82% and NPV, 100.00%. In the subsequent validation cohort (N=44), the AUCs (95% CI) were 0.83 (0.68, 0.93) and 0.88 (0.75, 0.96) for clinical model and laboratory model, respectively. CONCLUSIONS: We developed two predictive models for the in-hospital mortality of patients with COVID-19 in Wuhan and validated in patients from another center.

positive: Understanding the cytokine storm during COVID-19: Contribution of preexisting chronic inflammation

positive: COVID-19, Renin-Angiotensin System and Endothelial Dysfunction. The newly emergent novel coronavirus disease 2019 (COVID-19) outbreak, which is caused by SARS-CoV-2 virus, has posed a serious threat to global public health and caused worldwide social and economic breakdown. Angiotensin-converting enzyme 2 (ACE2) is expressed in human vascular endothelium, respiratory epithelium, and other cell types, and is thought to be a primary mechanism of SARS-CoV-2 entry and infection. In physiological condition, ACE2 via its carboxypeptidase activity generates angiotensin fragments (Ang 1-9 and Ang 1-7), and plays an essential role in the renin-angiotensin system (RAS), which is a critical regulator of cardiovascular homeostasis. SARS-CoV-2 via its surface spike glycoprotein interacts with ACE2 and invades the host cells. Once inside the host cells, SARS-CoV-2 induces acute respiratory distress syndrome (ARDS), stimulates immune response (i.e., cytokine storm) and vascular damage. SARS-CoV-2 induced endothelial cell injury could exacerbate endothelial dysfunction, which is a hallmark of aging, hypertension, and obesity, leading to further complications. The pathophysiology of endothelial dysfunction and injury offers insights into COVID-19 associated mortality. Here we reviewed the molecular basis of SARS-CoV-2 infection, the roles of ACE2, RAS signaling, and a possible link between the pre-existing endothelial dysfunction and SARS-CoV-2 induced endothelial injury in COVID-19 associated mortality. We also surveyed the roles of cell adhesion molecules (CAMs), including CD209L/L-SIGN and CD209/DC-SIGN in SARS-CoV-2 infection and other related viruses. Understanding the molecular mechanisms of infection, the vascular damage caused by SARS-CoV-2 and pathways involved in the regulation of endothelial dysfunction could lead to new therapeutic strategies against COVID-19.

positive: Weathering the Cytokine Storm in COVID-19: Therapeutic Implications BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged in Wuhan, Hubei-China, as responsible for the coronavirus disease 2019 (COVID-19) and then spread rapidly worldwide. While most individuals remain asymptomatic or develop only mild symptoms, approximately 5% develop severe forms of COVID-19 characterized by acute respiratory distress syndrome (ARDS) and multiple-organ failure (MOF) that usually require intensive-care support and often yield a poor prognosis. SUMMARY: The pathophysiology of COVID-19 is far from being completely understood, and the lack of effective treatments leads to a sense of urgency to develop new therapeutic strategies based on pathophysiological assumptions. The exaggerated cytokine release in response to viral infection, a condition known as cytokine release syndrome (CRS) or cytokine storm, is emerging as the mechanism leading to ARDS and MOF in COVID-19, thus endorsing the hypothesis that properly timed anti-inflammatory therapeutic strategies could improve patients' clinical outcomes and prognosis. KEY MESSAGES: The objective of this article is to explore and comment on the potential role of the promising immunomodulatory therapies using pharmacological and nonpharmacological approaches to overcome the dysregulated proinflammatory response in COVID-19.

positive: Mesenchymal stem cell therapy in severe COVID-19: A retrospective study of short-term treatment efficacy and side effects

positive: Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2 To date, no vaccines or effective drugs have been approved to prevent or treat COVID-19 and the current standard care relies on supportive treatments. Therefore, based on the fast and global spread of the virus, urgent investigations are warranted in order to develop preventive and therapeutic drugs. In this regard, treatments addressing the immunopathology of SARS-CoV-2 infection have become a major focus. Notably, while a rapid and well-coordinated immune response represents the first line of defense against viral infection, excessive inflammatory innate response and impaired adaptive host immune defense may lead to tissue damage both at the site of virus entry and at systemic level. Several studies highlight relevant changes occurring both in innate and adaptive immune system in COVID-19 patients. In particular, the massive cytokine and chemokine release, the so-called "cytokine storm", clearly reflects a widespread uncontrolled dysregulation of the host immune defense. Although the prospective of counteracting cytokine storm is compelling, a major limitation relies on the limited understanding of the immune signaling pathways triggered by SARS-CoV-2 infection. The identification of signaling pathways altered during viral infections may help to unravel the most relevant molecular cascades implicated in biological processes mediating viral infections and to unveil key molecular players that may be targeted. Thus, given the key role of the immune system in COVID-19, a deeper understanding of the mechanism behind the immune dysregulation might give us clues for the clinical management of the severe cases and for preventing the transition from mild to severe stages.

positive: Adult-Onset Still’s Disease Adult-onset Still’s disease (AOSD) is a rare systemic, autoinflammatory disorder that often presents in adolescence and early adulthood with fever, rash, and polyarthritis. There are significant genetic and clinical similarities with systemic juvenile idiopathic arthritis (sJIA) with a different chronological disease onset. The disease can have many protean characteristics leading to delays in diagnosis. Treatment includes corticosteroids; traditional immunomodulators, such as methotrexate; and targeted biologic treatments that include IL-1 and IL-6 inhibitors.

positive: Elucidating the Pivotal Role of Immune Players in the Management of COVID-19: Focus on Mesenchymal Stem Cells and Inflammation The world is currently engulfed with a viral disease with no cure. So, far, millions of people are infected with the virus across the length and breadth of world with thousand losing their lives each passing day. The WHO is February 2020 classified the virus as a coronavirus and the name Coronavirus-19 (CoV-19) was offered to the virus. The disease caused by the virus was termed coronavirus disease-19 (COVID-19). The pathogenesis of COVID-19 is associated with elevation of several immune plays as well as inflammatory factors which contributes to cytokine storms. Currently, the detection of CoV-19 RNA is through reverse transcriptase polymerase chain reaction (RT-PCR). Mesenchymal stem cells (MSCs) are capable of suppressing several kinds of cytokines via the paracrine secretion system. Therefore, MSCs therapy could be game charges in the treatment of the current COVID-19 pandemic. Also, intravenous IG may be capable of suppressing the high expression of IL-6 by the CoV-19 resulting in lessen disease burden. Anti-inflammatory medications like, corticosteroids, tocilizumab, glycyrrhetinic acid, as well as etoposide may be very advantageous in decreasing the COVID-19 burden because, their mode of action targets the cytokine storms initiated by the CoV-19. It is important to indicate that, these medication does not target the virus itself. Therefore, potent CoV-19 anti-viral medications are needed to completely cure patients with COVID-19. Also, a vaccine is urgently needed to stop the spread of the virus. This review therefore elucidates the immune players in the management of COVID-19; focusing principally on MSCs and inflammatory mediators.

positive: Severe COVID-19: A Review of Recent Progress With a Look Toward the Future The novel coronavirus disease 2019 (COVID-19) is an acute infectious disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, the World Health Organization has confirmed that COVID-19 is a global infectious disease pandemic. This is the third acute infectious disease caused by coronavirus infection in this century, after sudden acute respirator syndrome and Middle East respiratory syndrome. The damage mechanism of SARS-CoV-2 is still unclear. It is possible that protein S binds to angiotensin-converting enzyme 2 receptors and invades alveolar epithelial cells, causing direct toxic effects and an excessive immune response. This stimulates a systemic inflammatory response, thus forming a cytokine storm, which leads to lung tissue injury. In severe cases, the disease can lead to acute respiratory distress syndrome, septic shock, metabolic acidosis, coagulation dysfunction, and multiple organ dysfunction syndromes. Patients with severe COVID-19 have a relatively high mortality rate. Currently, there are no specific antiviral drugs for the treatment of COVID-19. Most patients need to be admitted to the intensive care unit for intensive monitoring and supportive organ function treatments. This article reviews the epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment methods of severe COVID-19 and puts forward some tentative ideas, aiming to provide some guidance for the diagnosis and treatment of severe COVID-19.

positive: SARS-CoV-2 pandemic and research gaps: Understanding SARS-CoV-2 interaction with the ACE2 receptor and implications for therapy The COVID-19 pandemic is an emerging threat to global public health. While our current understanding of COVID-19 pathogenesis is limited, a better understanding will help us develop efficacious treatment and prevention strategies for COVID-19. One potential therapeutic target is angiotensin converting enzyme 2 (ACE2). ACE2 primarily catalyzes the conversion of angiotensin I (Ang I) to a nonapeptide angiotensin or the conversion of angiotensin II (Ang II) to angiotensin 1-7 (Ang 1-7) and has direct effects on cardiac function and multiple organs via counter-regulation of the renin-angiotensin system (RAS). Significant to COVID-19, ACE2 is postulated to serve as a major entry receptor for SARS-CoV-2 in human cells, as it does for SARS-CoV. Many infected individuals develop COVID-19 with fever, cough, and shortness of breath that can progress to pneumonia. Disease progression promotes the activation of immune cells, platelets, and coagulation pathways that can lead to multiple organ failure and death. ACE2 is expressed by epithelial cells of the lungs at high level, a major target of the disease, as seen in post-mortem lung tissue of patients who died with COVID-19, which reveals diffuse alveolar damage with cellular fibromyxoid exudates bilaterally. Comparatively, ACE2 is expressed at low level by vascular endothelial cells of the heart and kidney but may also be targeted by the virus in severe COVID-19 cases. Interestingly, SARS-CoV-2 infection downregulates ACE2 expression, which may also play a critical pathogenic role in COVID-19. Importantly, targeting ACE2/Ang 1-7 axis and blocking ACE2 interaction with the S protein of SARS-CoV-2 to curtail SARS-CoV-2 infection are becoming very attractive therapeutics potential for treatment and prevention of COVID-19. Here, we will discuss the following subtopics: 1) ACE2 as a receptor of SARS-CoV-2; 2) clinical and pathological features of COVID-19; 3) role of ACE2 in the infection and pathogenesis of SARS; 4) potential pathogenic role of ACE2 in COVID-19; 5) animal models for pathological studies and therapeutics; and 6) therapeutics development for COVID-19.

positive: The first case of COVID-19 treated with the complement C3 inhibitor AMY-101 Abstract Acute respiratory distress syndrome (ARDS) is a devastating clinical manifestation of COVID-19 pneumonia and is mainly based on an immune-driven pathology. Mounting evidence suggests that COVID-19 is fueled by a maladaptive host inflammatory response that involves excessive activation of innate immune pathways. While a “cytokine storm” involving IL-6 and other cytokines has been documented, complement C3 activation has been implicated as an initial effector mechanism that exacerbates lung injury in preclinical models of SARS-CoV infection. C3-targeted intervention may provide broader therapeutic control of complement-mediated inflammatory damage in COVID-19 patients. Herein, we report the clinical course of a patient with severe ARDS due to COVID-19 pneumonia who was safely and successfully treated with the compstatin-based complement C3 inhibitor AMY-101.

positive: A Promising Anti-Cytokine-Storm Targeted Therapy for COVID-19: The Artificial-Liver Blood-Purification System

positive: COVID-19 in the heart and the lungs: could we “Notch” the inflammatory storm? From January 2020, coronavirus disease (COVID-19) originated in China has spread around the world. The disease is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The presence of myocarditis, cardiac arrest, and acute heart failure in COVID-19 patients suggests the existence of a relationship between SARS-CoV-2 infection and cardiac disease. The Notch signalling is a major regulator of cardiovascular function and it is also implicated in several biological processes mediating viral infections. In this report we discuss the possibility to target Notch signalling to prevent SARS-CoV-2 infection and interfere with the progression of COVID-19- associated heart and lungs disease.

positive: Improved survival outcome in SARs-CoV-2 (COVID-19) Acute Respiratory Distress Syndrome patients with Tocilizumab administration ABSTRACT Background: The novel human coronavirus, severe acute respiratory syndrome coronavirus-2 (SARs-CoV-2), was declared a global pandemic by the World Health Organization on March 11, 2020. Hence, there is an urgency to find effective treatment. Of those patients afflicted in the United States, many have required treatment with ventilator secondary to acute respiratory distress syndrome (ARDS). Data are needed regarding the benefit of treatment and prevention of the cytokine storms in COVID-19 patients with Tocilizumab. Methods: Clinical outcomes data for patients admitted to Orange Regional Medical Center with confirmed COVID-19 from Mar 15, 2020 to Apr 20, 2020 were identified through electronic health record chart review. We conducted a retrospective case-control study in confirmed COVID 19 positive patients with ARDS requiring mechanical ventilation and compared outcome in terms of mortality and length of stay amongst those who received Tocilizumab as treatment modality opposed to those that did not. Results: A total of 94 patients with COVID-19 ARDS were analyzed. 44 were in the study group and 50 in the control group. We tried to match both group as close as possible in terms of age, sex, BMI and HS score- calculated using inflammatory markers- ferritin, triglycerides, AST and fibrinogen. The median age was 55.5 years in the study group and 66 in the control group, difference was not statistically significant. Average HS score was 114 in the Tocilizumab group and 92 in the control group, difference was statistically significant with P<0.0001. Also, the patients in the study group had elevated levels of IL-6, triglycerides, AST, ferritin which were statistically significant with p < 0.0001 when compared to the control group. Length of stay was longer, average 17.9 days in the Tocilizumab. Survival rate was much lower at 48 % in the control group and 61.36 % in patients who received Tocilizumab with significant P value of < 0.00001. The number needed to treat (NNT) was 7.48, if we treat 8 patients with Tocilizumab, 1 will not die. Conclusions: Cytokine Release Syndrome (CRS) occurs in a large number of patients with severe COVID-19, which is also an important cause of death. IL- 6 is the key molecule of CRS, so IL-6R antagonist Tocilizumab may be of value in improving outcomes. In our study Tocilizumab group seemed to have improved survival outcome. Results have to be interpreted with caution since this is a retrospective study and mortality is affected by multiple, confounding factors. We await the results of ongoing randomized controlled trials to definitely answer the question of whether Tocilizumab improves survival in COVID-19 ARDS patients.

positive: A Putative Role of de-Mono-ADP-Ribosylation of STAT1 by the SARS-CoV-2 Nsp3 Protein in the Cytokine Storm Syndrome of COVID-19. As more cases of COVID-19 are studied and treated worldwide, it had become apparent that the lethal and most severe cases of pneumonia are due to an out-of-control inflammatory response to the SARS-CoV-2 virus. I explored the putative causes of this specific feature through a detailed genomic comparison with the closest SARS-CoV-2 relatives isolated from bats, as well as previous coronavirus strains responsible for the previous epidemics (SARS-CoV and MERS-CoV). The high variability region of the nsp3 protein was confirmed to exhibit the most variations between closest strains. It was then studied in the context of physiological and molecular data available in the literature. A number of convergent findings suggest de-mono-ADP-ribosylation (de-MARylation) of STAT1 by the SARS-CoV-2 nsp3 as a putative cause of the cytokine storm observed in the most severe cases of COVID-19. This may suggest new therapeutic approaches and help in designing assays to predict the virulence of naturally circulating SARS-like animal coronaviruses.

positive: The immunology of COVID-19: is immune modulation an option for treatment? In December, 2019, an outbreak of COVID-19 emerged in Wuhan, China and quickly spread globally. As of May 7, 2020, there were 3 672 238 confirmed infections and 254 045 deaths attributed to COVID-19. Evidence has shown that there are asymptomatic carriers of COVID-19 who can transmit the disease to others. The virus incubation time shows a wide range (0–24 days) and the virus displays a high infectivity. It is therefore urgent to develop an effective therapy to treat patients with COVID-19 and to control the spread of the causative agent, severe respiratory syndrome coronavirus 2. Repurposing of approved drugs is widely adopted to fight newly emerged diseases such as COVID-19, as these drugs have known pharmacokinetic and safety profiles. As pathological examination has confirmed the involvement of immune hyperactivation and acute respiratory distress syndrome in fatal cases of COVID-19, several disease-modifying anti-rheumatic drugs (DMARDS), such as hydroxychloroquine and tocilizumab, have been proposed as potential therapies for the treatment of COVID-19. In this Review, we discuss the immunological aspects of COVID-19 and the potential implication of DMARDs in treating this disease.

positive: SGLT2 inhibition and COVID-19: The road not taken. The COVID-19 pandemic, caused by SARS-CoV-2, is an immense challenge for global healthcare. Diabetes mellitus, hypertension and obesity have been shown to portend poor prognosis in COVID-19 despite no greater susceptibility to the infection (1). Chronic hypertension is commonly associated with vasculopathy which can predispose to severe infection. In patients with diabetes, severity is attributable to impaired innate, adaptive immunity, upregulation of ACE2 (entry receptor for SARS-CoV2) by acute hyperglycemia and diabetic vasculopathy. The background of chronic low grade inflammation characterised by increased levels of IL-6 and CRP in diabetes and obesity can also lead to an enhanced 'cytokine storm' in COVID-19 (2). ACE2 expression on endothelial cells has been reported to cause viral mediated endothelitis and precipitate vascular dysfunction manifesting as acute respiratory distress syndrome as well as myocarditis, heart failure, arrhythmias, myocardial infarction and renal failure (3). In patients with pre-existing comorbidities like hypertension, diabetes, obesity and chronic kidney disease, this new-onset organ dysfunction can have deleterious additive effects.

positive: Tocilizumab Administration in Patients with SARS‐CoV‐2 Infection: Subcutaneous Injection versus Intravenous Infusion Recent studies have revealed that cytokine storm syndrome, which is caused by the activation of inflammatory cytokines, is a likely underlying pathophysiology in patients with severe COVID‐19 that has been associated with a high mortality rate(1). This article is protected by copyright. All rights reserved.

positive: Alpha-1 adrenergic receptor antagonists for preventing acute respiratory distress syndrome and death from cytokine storm syndrome. In severe viral pneumonias, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by a hyperinflammatory reaction ('cytokine storm syndrome') that leads to acute respiratory distress syndrome and death, despite maximal supportive care. Preventing hyperinflammation is key to avoiding these outcomes. We previously demonstrated that alpha-1 adrenergic receptor antagonists ($\alpha$-blockers) can prevent cytokine storm syndrome and death in mice. Here, we conduct a retrospective analysis of patients with acute respiratory distress or pneumonia (n = 13,125 and n = 108,956, respectively) from all causes; patients who were incidentally taking $\alpha$-blockers had a reduced risk of requiring ventilation (by 35% and 16%, respectively), and a reduced risk of being ventilated and dying (by 56% and 20%, respectively), compared to non-users. Beta-adrenergic receptor antagonists had no significant effects. These results highlight the urgent need for prospective trials testing whether prophylactic $\alpha$-blockers improve outcomes in diseases with a prominent hyperinflammatory component such as COVID-19.

positive: The Use of Non‐invasive Vagus Nerve Stimulation to Treat Respiratory Symptoms Associated With COVID‐19: A Theoretical Hypothesis and Early Clinical Experience OBJECTIVES: Coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), is a pandemic with no specific therapeutic agents and substantial mortality, and finding new treatments is critical. Most cases are mild, but a significant minority of patients develop moderate to severe respiratory symptoms, with the most severe cases requiring intensive care and/or ventilator support. This respiratory compromise appears to be due to a hyperimmune reaction, often called a cytokine storm. Vagus nerve stimulation has been demonstrated to block production of cytokines in sepsis and other medical conditions. We hypothesize that non‐invasive vagus nerve stimulation (nVNS) might provide clinical benefits in patients with respiratory symptoms similar to those associated with COVID‐19. MATERIALS AND METHODS: Information on two case reports was obtained via email correspondence and phone interviews with the patients. RESULTS: Both patients reported clinically meaningful benefits from nVNS therapy. In case 1, the patient used nVNS to expedite symptomatic recovery at home after hospital discharge and was able to discontinue use of opioid and cough suppressant medications. In case 2, the patient experienced immediate and consistent relief from symptoms of chest tightness and shortness of breath, as well as an improved ability to clear his lungs. CONCLUSIONS: Preliminary observations and a strong scientific foundation suggest that nVNS might provide clinical benefits in patients with COVID‐19 via multiple mechanisms.

positive: Insight into the relationship between obesity-induced low-level chronic inflammation and COVID-19 infection

positive: Tocilizumab in the treatment of a critical COVID-19 patient: a case report In December 2019, Coronavirus disease 2019 (COVID-19) emerged in Wuhan and rapidly spread throughout China and the rest of the world. COVID-19 is currently a global pandemic. There are cytokine storms in severe COVID-19 patients. Interleukin-6 plays an important role in cytokine storm. Tocilizumab is a blocker of interleukin-6 receptor, which is likely to become an effective drug for patients with severe COVID-19. Here, we reported a case in which tocilizumab was effective for a critical COVID-19 patient.

positive: Type 2 and interferon inflammation strongly regulate SARS-CoV-2 related gene expression in the airway epithelium Coronavirus disease 2019 (COVID-19) outcomes vary from asymptomatic infection to death. This disparity may reflect different airway levels of the SARS-CoV-2 receptor, ACE2, and the spike protein activator, TMPRSS2. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci (eQTL) for both ACE2 and TMPRSS2, that vary in frequency across world populations. Importantly, we find TMPRSS2 is part of a mucus secretory network, highly upregulated by T2 inflammation through the action of interleukin-13, and that interferon response to respiratory viruses highly upregulates ACE2 expression. Finally, we define airway responses to coronavirus infections in children, finding that these infections upregulate IL6 while also stimulating a more pronounced cytotoxic immune response relative to other respiratory viruses. Our results reveal mechanisms likely influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.

positive: Tocilizumab in a child with acute lymphoblastic leukaemia and COVID-19-related cytokine release syndrome()

positive: COVID-19-associated Hemophagocytic Lymphohistiocytosis and Coagulopathy: Targeting the Duumvirate CONTEXT: Preliminary data on coexistence of secondary hemophagocytic lymphohistiocytosis syndrome (HLH) and disseminated intravascular coagulation (DIC) in critically ill children with novel coronavirus disease (COVID-19) are emerging. Herein, we summarize the available literature and fill-in the gaps in this regard. EVIDENCE ACQUISITION: We have performed a literature search for articles in PubMed, EMBASE and Google Scholar databases till May 12, 2020, with following keywords: "COVID-19", "SARS-CoV-2", "HLH", "HScore", "coagulopathy", "D-dimer", "cytokine storm", "children" and "pediatrics" with interposition of Boolean operator "AND". RESULTS: Children presenting with moderate-severe COVID-19 and Kawasaki disease shock-like syndrome exhibit peripheral blood picture analogous to HLH. HScore, a validated tool to diagnose HLH, has been suggested to screen severe COVID-19 patients for cytokine storm. However, HScore faces certain limitations in this scenario. It may be more pragmatic to use 'high D-dimer' (> 3 µg/mL) instead of 'low fibrinogen' to facilitate early detection of cytokine storm. COVID-19 associated coagulopathy resembles hypercoagulable form of DIC with bleeding being rarely reported. Although the International Society on Thrombosis and Haemostasis (ISTH) interim guidance recommends low molecular weight heparin in all hospitalized patients, data is lacking in population below 14 years of age. However, in the presence of life-threatening thromboembolic event or symptomatic acro-ischemia, unfractionated heparin (UFH) should be used with caution. CONCLUSION: HScore can be used as a complement to clinical decision for initiating immunosuppression. Children with moderate-to-severe COVID-19, especially those with documented thrombocytopenia or chilblains, should be regularly monitored for coagulopathy.

positive: Blocking of the CD80/86 axis as a therapeutic approach to prevent progression to more severe forms of COVID-19 In its more severe forms, COVID-19 progresses towards an excessive immune response, leading to the systemic overexpression of proinflammatory cytokines like IL6, mostly from the infected lungs. This cytokine storm can cause multiple organ damage and death. Consequently, there is a pressing need to identify therapies to treat and prevent severe symptoms during COVID-19. Based on previous clinical evidence, we hypothesized that inhibiting T cell co-stimulation by blocking CD80/86 could be an effective therapeutic strategy against progression to severe proinflammatory states. To support this hypothesis, we performed an analysis integrating blood transcriptional data we generated from rheumatoid arthritis patients treated with abatacept -- a CD80/86 co-stimulation inhibitor -- with the pathological features associated with COVID-19, particularly in its more severe forms. We have found that many of the biological processes that have been consistently associated with COVID-19 pathology are reversed by CD80/86 co-stimulation inhibition, including the downregulation of IL6 production. Also, analysis of previous transcriptional data from blood of SARS-CoV-infected patients showed that the response to abatacept has a very high level of antagonism to that elicited by COVID-19. Finally, analyzing a recent single cell RNA-seq dataset from bronchoalveolar lavage fluid cells from COVID-19 patients, we found a significant correlation along the main elements of the C80/86 axis: CD86+/80+ antigen presenting cells, activated CD4+ T cells and IL6 production. Our in-silico study provides additional support to the hypothesis that blocking of the CD80/CD86 signaling axis may be protective of the excessive proinflammatory state associated with COVID-19 in the lungs.

positive: Advances in COVID-19: the virus, the pathogenesis, and evidence-based control and therapeutic strategies Since the outbreak of the COVID-19 pandemic in early December 2019, 81 174 confirmed cases and 3242 deaths have been reported in China as of March 19, 2020. The Chinese people and government have contributed huge efforts to combat this disease, resulting in significant improvement of the situation, with 58 new cases (34 were imported cases) and 11 new deaths reported on March 19, 2020. However, as of March 19, 2020, the COVID-19 pandemic continues to develop in 167 countries/territories outside of China, and 128 665 confirmed cases and 5536 deaths have been reported, with 16 498 new cases and 817 new deaths occurring in last 24 hours. Therefore, the world should work together to fight against this pandemic. Here, we review the recent advances in COVID-19, including the insights in the virus, the responses of the host cells, the cytokine release syndrome, and the therapeutic approaches to inhibit the virus and alleviate the cytokine storm. By sharing knowledge and deepening our understanding of the virus and the disease pathogenesis, we believe that the community can efficiently develop effective vaccines and drugs, and the mankind will eventually win this battle against this pandemic.

positive: COVID-19 and the elderly: insights into pathogenesis and clinical decision-making The elderly may represent a specific cluster of high-risk patients for developing COVID-19 with rapidly progressive clinical deterioration. Indeed, in older individuals, immunosenescence and comorbid disorders are more likely to promote viral-induced cytokine storm resulting in life-threatening respiratory failure and multisystemic involvement. Early diagnosis and individualized therapeutic management should be developed for elderly subjects based on personal medical history and polypharmacotherapy. Our review examines the pathogenesis and clinical implications of ageing in COVID-19 patients; finally, we discuss the evidence and controversies in the management in the long-stay residential care homes and aspects of end-of-life care for elderly patients with COVID-19.

positive: Effectiveness of Tocilizumab in a COVID-19 Patient with Cytokine Release Syndrome Cytokine release syndrome (CRS) is a systemic inflammatory response that can be triggered by many factors such as infections. CRS in patients with coronavirus disease 2019 (COVID-19) is life-threatening and can occur very rapidly after COVID-19 diagnosis. Tocilizumab (TCZ), an interleukin-6 (IL-6) inhibitor, may ameliorate the CRS associated with severe COVID-19 and thus improve clinical outcomes. We present a case of life-threatening CRS caused by COVID-19 infection successfully treated with TCZ. LEARNING POINTS: Cytokine release syndrome (CRS) is a systemic inflammatory response that can be triggered by COVID-19. CRS can be life-threatening in severe COVID-19. Tocilizumab may have a role in treating severe COVID-19 patients with CRS.

positive: The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status An acute respiratory disease, caused by a novel coronavirus (SARS-CoV-2, previously known as 2019-nCoV), the coronavirus disease 2019 (COVID-19) has spread throughout China and received worldwide attention. On 30 January 2020, World Health Organization (WHO) officially declared the COVID-19 epidemic as a public health emergency of international concern. The emergence of SARS-CoV-2, since the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, marked the third introduction of a highly pathogenic and large-scale epidemic coronavirus into the human population in the twenty-first century. As of 1 March 2020, a total of 87,137 confirmed cases globally, 79,968 confirmed in China and 7169 outside of China, with 2977 deaths (3.4%) had been reported by WHO. Meanwhile, several independent research groups have identified that SARS-CoV-2 belongs to β-coronavirus, with highly identical genome to bat coronavirus, pointing to bat as the natural host. The novel coronavirus uses the same receptor, angiotensin-converting enzyme 2 (ACE2) as that for SARS-CoV, and mainly spreads through the respiratory tract. Importantly, increasingly evidence showed sustained human-to-human transmission, along with many exported cases across the globe. The clinical symptoms of COVID-19 patients include fever, cough, fatigue and a small population of patients appeared gastrointestinal infection symptoms. The elderly and people with underlying diseases are susceptible to infection and prone to serious outcomes, which may be associated with acute respiratory distress syndrome (ARDS) and cytokine storm. Currently, there are few specific antiviral strategies, but several potent candidates of antivirals and repurposed drugs are under urgent investigation. In this review, we summarized the latest research progress of the epidemiology, pathogenesis, and clinical characteristics of COVID-19, and discussed the current treatment and scientific advancements to combat the epidemic novel coronavirus.

positive: Extracorporeal Blood Purification Treatment Options for COVID-19: The Role of Immunoadsorption Abstract The activation of theinnate and adaptive immune systems by SARS-CoV-2 causes the release of several inflammatory cytokines, including IL-6. The inflammatory hypercytokinemia causes immunopathological changes in the lungs including vascular leakage, and alveolar edema. As a result of these changes in the lungs, hypoxia and acute respiratory distress syndrome occur in patients with COVID-19. Even though there are clinical trials on the development of therapeutics and vaccines, there are currently no licensed vaccines or therapeutics for COVID-19. Pharmacological approaches have shown poor results in sepsis-like syndromes caused by the hypercytokinemia. Suppressing the cytokine storm is an important way to prevent the organ damage in patients with COVID-19. Extracorporeal blood purification could be proposed as an adjunctive therapy for sepsis, aiming to control the associated dysregulation of the immune system, which is known to protect organ functions. Several extracorporeal blood purification therapies are now available, and most of them target endotoxins and/or the cytokines and aim improving the immune response. For this purpose, plasmapheresis and immunoadsorption may be an important adjunctive treatment option to manage the complications caused by cytokine storm in critically ill patients with COVID-19.

positive: CytoResc - "CytoSorb" Rescue for critically ill patients undergoing the COVID-19 Cytokine Storm: A structured summary of a study protocol for a randomized controlled trial OBJECTIVES: Approximately 8 - 10 % of COVID-19 patients present with a serious clinical course and need for hospitalization, 8% of hospitalized patients need ICU-treatment. Currently, no causal therapy is available and treatment is purely supportive. The main reason for death in critically ill patients is acute respiratory failure. However, in a number of patients a severe hyperinflammatory response with excessively elevated proinflammatory cytokines causes vasoplegic shock resistant to vasopressor therapy. A new polystyrene-based hemoadsorber (CytoSorb®, Cytosorbents Inc., New Jersey, USA) has been shown to adsorb effectively cytokines and other middle molecular weight toxins this way reducing their blood concentrations. This has been routinely used in clinical practice in the EU for other conditions where a cytokine storm occurs and an observational study has just been completed on COVID-19 patients. We hypothesized that the extracorporeal elimination of cytokines in critically ill COVID-19 patients with suspected hyperinflammation and shock may stabilize hemodynamics and improve outcome. The primary endpoint is time until resolution of vasoplegic shock, which is a well implemented, clinically relevant endpoint in critical care studies. TRIAL DESIGN: Phase IIb, multicenter, prospective, open-label, randomized, 1:1 parallel group pilot study comparing the additional use of "CytoSorb" to standard of care without "CytoSorb". PARTICIPANTS: Patients are recruited from the Intensive Care Units (ICUs) of 7 participating centers in Germany (approximately 10 ICUs). All patients aged 18- 80 with positive polymerase chain reaction (PCR) test for SARS-CoV-2, a C-reactive protein (CRP) ≥ 100 mg/l, a Procalcitonin (PCT) < 2 ng/l, and suspected cytokine storm defined via a vasoplegic shock (Norepinephrine > 0.2 µg/min/kg to achieve a Mean Arterial Pressure ≥ 65mmHg). Patients are included irrespective of indication for renal replacement therapy. Suspected or proven bacterial cause for vasoplegic shock is a contraindication. INTERVENTION AND COMPARATOR: Within 24 hours after meeting the inclusion criteria patients will be randomized to receive either standard of care or standard of care and additional "CytoSorb" therapy via a shaldon catheter for 3-7 days. Filter exchange is done every 24 hours. If patients receive antibiotics, an additional dose of antibiotics is administered after each change of "CytoSorb" filter in order to prevent underdosing due to "CytoSorb" treatment. MAIN OUTCOMES: Primary outcome is time to resolution of vasoplegic shock (defined as no need for vasopressors for at least 8 hours in order to sustain a MAP ≥ 65mmHg) in days. Secondary outcomes are 7 day mortality after fulfilling the inclusion criteria, mortality until hospital discharge, Interleukin-6 (IL-6) measurement on day 1 and 3, need for mechanical ventilation, duration of mechanical ventilation, duration of ICU-stay, catecholamine dose on day 1/2/3 after start of "CytoSorb" and acute kidney injury. RANDOMIZATION: An electronic randomization will be performed using the study software secuTrial® administered by the Clinical Study Center (CSC) of the Charité - Universitätsmedizin Berlin, Germany. Randomization is done in blocks by 4 stratified by including center. BLINDING (MASKING): The trial will be non-blinded for the clinicians and patients. The statistician will receive a blinded data set, so that all analyses will be conducted blinded. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): As this is a pilot study with the goal to examine the feasibility of the study design as well as the intervention effect, no formal sample size calculation was conducted. A total number of approximately 80-100 patients is planned (40-50 patients per group). Safety assessment is done after the inclusion of each 10 patients per randomization group. TRIAL STATUS: Please see the study protocol version from April 24 2020. Recruitment of patients is still pending. TRIAL REGISTRATION: The study was registered on April 27 2020 in the German Registry of Clinical Trials (DRKS) under the number DRKS00021447. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

positive: COVID-19 pneumonia treated with Sarilumab: A clinical series of eight patients

positive: SARS-CoV-2, which induces COVID-19, causes kawasaki-like disease in children: role of pro-inflammatory and anti-inflammatory cytokines. Acute severe respiratory syndrome coronavirus-2 (SARS-CoV-2) caused a global pandemic coronavirus disease 2019 (COVID-19). In humans, SARS-CoV-2 infection leads to acute respiratory distress syndrome which presents edema, hemorrhage, intra-alveolar fibrin deposition, and vascular changes characterized by thrombus formation, micro-angiopathy and thrombosis. These clinical signs are mediated by pro-inflammatory cytokines. In recent studies it has been noted that COVID-19 pandemic can affect patients of all ages, including children (even if less severely) who were initially thought to be immune. Kawasaki disease is an autoimmune acute febrile inflammatory condition, which primarily affects young children. The disease can present immunodeficiency with the inability of the immune system to fight inflammatory pathogens and leads to fever, rash, alterations of the mucous membranes, conjunctiva infection, pharyngeal erythema, adenopathy, and inflammation. In the COVID-19 period, virus infection aggravates the condition of Kawasaki disease, but it has also been noted that children affected by SARS-V-2 may develop a disease similar to Kawasaki's illness. However, it is uncertain whether the virus alone can give Kawasaki disease-like forms. As in COVID-19, Kawasaki disease and its similar forms are mediated by pro-inflammatory cytokines produced by innate immunity cells such as macrophages and mast cells (MCs). In light of the above, it is therefore pertinent to think that by blocking pro-inflammatory cytokines with new anti-inflammatory cytokines, such as IL-37 and IL-38, it is possible to alleviate the symptoms of the disease and have a new available therapeutic tool. However, since Kawasaki and Kawasaki-like diseases present immunodeficiency, treatment with anti-inflammatory/immunosuppressant molecules must be applied very carefully.

positive: COVID-19: a new virus, but an old cytokine release syndrome Understanding the cell entry mechanism of pandemic coronavirus SARS-CoV-2 is crucial for treating the disease Zhou et al (Nature) and Hoffmann et al (Cell) identify ACE2 as a SARS-CoV-2 receptor, and the latter show its entry mechanism depends on cellular serine protease TMPRSS2 These results suggest several possible therapeutic targets, including the IL-6-STAT3 axis previously associated with cytokine release syndromes

positive: SARS-CoV-2 COVID-19 susceptibility and lung inflammatory storm by smoking and vaping The current pandemic of COVID-19 has caused severe morbidity and mortality across the globe. People with a smoking history have severe disease outcomes by COVID-19 infection. Epidemiological studies show that old age and pre-existing disease conditions (hypertension and diabetes) result in severe disease outcome and mortality amongst COVID-19 patients. Evidences suggest that the S1 domain of the SARS-CoV-2 (causative agent of COVID-19) membrane spike has a high affinity towards the angiotensin-converting enzyme 2 (ACE2) receptor found on the host’s lung epithelium. Likewise, TMPRSS2 protease has been shown to be crucial for viral activation thus facilitating the viral engulfment. The viral entry has been shown to cause ‘cytokine storm’ involving excessive production of pro-inflammatory cytokines/chemokines including IL-6, TNF-α, IFN-γ, IL-2, IL-7, IP-10, MCP-3 or GM-CSF, which is augmented by smoking. Future research could target these inflammatory-immunological responses to develop effective therapy for COVID-19. This mini-review provides a consolidated account on the role of inflammation and immune responses, proteases, and epithelial permeability by smoking and vaping during SARS-CoV2 infection with future directions of research, and provides a list of the potential targets for therapies particularly controlling cytokine storms in the lung.

positive: COVID 19: a clue from innate immunity The recent COVID-19 pandemic has had a significant impact on our lives and has rapidly expanded to reach more than 4 million cases worldwide by May 2020. These cases are characterized by extreme variability, from a mild or asymptomatic form lasting for a few days up to severe forms of interstitial pneumonia that may require ventilatory therapy and can lead to patient death. Several hypotheses have been drawn up to understand the role of the interaction between the infectious agent and the immune system in the development of the disease and the most severe forms; the role of the cytokine storm seems important. Innate immunity, as one of the first elements of guest interaction with different infectious agents, could play an important role in the development of the cytokine storm and be responsible for boosting more severe forms. Therefore, it seems important to study also this important arm of the immune system to adequately understand the pathogenesis of the disease. Research on this topic is also needed to develop therapeutic strategies for treatment of this disease.

positive: Cytokine Storm Drugs Move from CAR T to COVID-19 Early reports suggest that tocilizumab, an IL6 receptor-blocking antibody used to manage toxicities associated with chimeric antigen receptor T-cell therapy, may help control cytokine storms in people infected with COVID-19. Preliminary data from randomized trials are less clear-cut.

positive: Continuous Intravenous Anakinra Infusion to Calm the Cytokine Storm in Macrophage Activation Syndrome OBJECTIVE: The objective of this study was to report the benefit of a therapeutic approach consisting of intravenous (IV) continuous anakinra (recombinant human interleukin-1 receptor antagonist) infusions in treating severely ill adult patients with secondary hemophagocytic lymphohistiocytosis or macrophage activation syndrome (MAS). METHODS: A retrospective chart review of five patients treated at Regions Hospital from 2016 to 2019 was conducted. Demographic, clinical, and laboratory characteristics and outcomes were recorded. RESULTS: Continuous IV anakinra infusions up to 2400 mg/d resulted in rapid serologic, then clinical response in 4 of 5 severely ill patients who were refractory to all other therapies, including subcutaneous anakinra. Subsequently, 3 of 5 patients have been maintained on anakinra or canakinumab, with no recurrence of MAS. CONCLUSION: Continuous infusion of IV anakinra may result in rapid serologic and subsequent clinical improvement in adult patients with MAS. This method for treating cytokine storm should be considered in the current COVID-19 pandemic in the subgroup of patients with severe disease who have a cytokine storm presentation.

positive: Clinical outcomes in COVID-19 patients treated with tocilizumab: An individual patient data systematic review BACKGROUND: Current evidence suggests an important role of the interleukin-6 (IL-6) pathway in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related cytokine release storm in severely ill coronavirus disease 2019 (COVID-19) patients. Inhibition of the IL-6 pathway with tocilizumab has been employed successfully in some of these patients but the data is mostly consistent of case reports and series. METHODS: We performed a systematic search of PubMed, Embase, and Medline from 22nd April 2020 and again on 27th April 2020 using the following search terms alone or in combination: "COVID-19," "coronavirus," "SARS-CoV-2," "COVID," "anti-interleukin-6 receptor antibodies," "anti-IL-6," "tocilizumab," "sarilumab," "siltuximab." We included studies that reported individual patient data. We extracted and analyzed individual level data on baseline characteristics, laboratory findings, and clinical outcomes. The primary endpoint was in-hospital mortality. Secondary endpoints included in-hospital complications, recovery rates, effect of patient characteristics on the primary outcome and changes in levels of inflammatory markers. RESULTS: Three hundred fifty-two records were identified through a systematic search, of which 10 studies met the inclusion criteria. A single study currently under review was also added. Eleven observational studies encompassing 29 patients were included in the present review. There were more males (24 [82.8%]), and hypertension was the most common comorbidity (16 [48.3%]). Over an average of 5.4 hospital days, the primary endpoint occurred in 6 (20.7%) patients. Among surviving patients, about 10% had worsened disease and 17% recovered. The most common complication was acute respiratory distress syndrome (8 [27.6%]). The IL-6 level was significantly higher after the initiation of tocilizumab with median (interquartile range) of 376.6 (148-900.6) pg/mL compared to the baseline of 71.1 (31.9-122.8) pg/mL (P = .002). Mean (standard deviation) levels of C-reactive protein (CRP) were significantly decreased following treatment 24.6 (26.9) mg/L compared to baseline 140.4 (77) mg/L (P < .0001). Baseline demographics were not significantly different among survivors and nonsurvivors by Fisher's exact test. CONCLUSION: In COVID-19 patients treated with tocilizumab, IL-6 levels are significantly elevated, which are supportive of cytokine storm. Following initiation of tocilizumab, there is elevation in the IL-6 levels and CRP levels dramatically decrease, suggesting an improvement in this hyperinflammatory state. Ongoing randomized control trials will allow for further evaluation of this promising therapy. IMPORTANCE: Recent data indicate that severe COVID-19 causes a cytokine release storm and is associated with worse clinical outcomes and IL-6 plays an important role. It is suggestive that anti-IL-6 results in the improvement of this hyperinflammatory state. However, to our knowledge, there is no individual patient data systematic review performed to summarize baseline characteristics and clinical outcomes of COVID-19 patients who received tocilizumab.

positive: Elevated troponin in patients with Coronavirus Disease 2019 (COVID-19): possible mechanisms Abstract Coronavirus disease 2019 (COVID-19) is a pandemic that has affected more than 1.8 million people worldwide, overwhelmed health care systems due to the high proportion of critical presentations, and resulted in over 100,000 deaths. Since the first data analyses in China, elevated cardiac troponin has been noted in a substantial proportion of patients, implicating myocardial injury as a possible pathogenic mechanism contributing to severe illness and mortality. Accordingly, high troponin levels are associated with increased mortality in patients with COVID-19. This brief review explores the available evidence regarding the association between COVID-19 and myocardial injury.

positive: The cytokine storm of severe influenza and development of immunomodulatory therapy Severe influenza remains unusual in its virulence for humans. Complications or ultimately death arising from these infections are often associated with hyperinduction of proinflammatory cytokine production, which is also known as ‘cytokine storm'. For this disease, it has been proposed that immunomodulatory therapy may improve the outcome, with or without the combination of antiviral agents. Here, we review the current literature on how various effectors of the immune system initiate the cytokine storm and exacerbate pathological damage in hosts. We also review some of the current immunomodulatory strategies for the treatment of cytokine storms in severe influenza, including corticosteroids, peroxisome proliferator-activated receptor agonists, sphingosine-1-phosphate receptor 1 agonists, cyclooxygenase-2 inhibitors, antioxidants, anti-tumour-necrosis factor therapy, intravenous immunoglobulin therapy, statins, arbidol, herbs, and other potential therapeutic strategies.

positive: The COVID-19 Cytokine Storm; What We Know So Far COVID-19 is a rapidly spreading global threat that has been declared as a pandemic by the WHO. COVID-19 is transmitted via droplets or direct contact and infects the respiratory tract resulting in pneumonia in most of the cases and acute respiratory distress syndrome (ARDS) in about 15 % of the cases. Mortality in COVID-19 patients has been linked to the presence of the so-called “cytokine storm” induced by the virus. Excessive production of proinflammatory cytokines leads to ARDS aggravation and widespread tissue damage resulting in multi-organ failure and death. Targeting cytokines during the management of COVID-19 patients could improve survival rates and reduce mortality.

positive: Emergence of Low-density Inflammatory Neutrophils Correlates with Hypercoagulable State and Disease Severity in COVID-19 Patients Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel viral pathogen that causes a clinical disease called coronavirus disease 2019 (COVID-19). Approximately 20% of infected patients experience a severe manifestation of the disease, causing bilateral pneumonia and acute respiratory distress syndrome. Severe COVID-19 patients also have a pronounced coagulopathy with approximately 30% of patients experiencing thromboembolic complications. However, the etiology driving the coagulopathy remains unknown. Here, we explore whether the prominent neutrophilia seen in severe COVID-19 patients contributes to inflammation-associated coagulation. We found in severe patients the emergence of a CD16IntCD44lowCD11bInt low-density inflammatory band (LDIB) neutrophil population that trends over time with changes in disease status. These cells demonstrated spontaneous neutrophil extracellular trap (NET) formation, phagocytic capacity, enhanced cytokine production, and associated clinically with D-dimer and systemic IL-6 and TNF- levels, particularly for CD40+ LDIBs. We conclude that the LDIB subset contributes to COVID-19-associated coagulopathy (CAC) and could be used as an adjunct clinical marker to monitor disease status and progression. Identifying patients who are trending towards LDIB crisis and implementing early, appropriate treatment could improve all-cause mortality rates for severe COVID-19 patients.

positive: Intravenous Anakinra for Macrophage Activation Syndrome May Hold Lessons for Treatment of Cytokine Storm in the Setting of Coronavirus Disease 2019 Macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH) are increasingly recognized as being on a continuum of cytokine storm syndromes, with different initiating pathways culminating in cytotoxic dysfunction and uncontrolled activation and proliferation of T lymphocytes and macrophages. The activated immune cells produce large amounts of proinflammatory cytokines, including interleukin 1ß (IL)-1ß. Management depends on the recognized diagnosis. In the setting of a cytokine storm syndrome and infection, collaborative involvement of specialists, including infectious disease and rheumatology is ideal. Anakinra, a recombinant IL-1 receptor antagonist, has been used subcutaneously and intravenously in pediatric patients and is considered a first-line treatment for MAS and secondary HLH (sHLH) among many pediatric rheumatologists. Previous reports of anakinra used in adults for treatment of MAS or sHLH are limited to subcutaneous administration. In this issue, Moneagudo et al. present a series of adult patients with sHLH treated with intravenous anakinra, including patients in whom subcutaneous anakinra was insufficient. As the authors suggest, there is a potential therapeutic use for anakinra in sHLH or the cytokine storm syndrome triggered by COVID19. Trial design will be key, with the patient subpopulation, timing of intervention, and doses tested important.

positive: SARS-CoV-2 infection and overactivation of Nlrp3 inflammasome as a trigger of cytokine “storm” and risk factor for damage of hematopoietic stem cells The scientific community faces an unexpected and urgent challenge related to the SARS-CoV-2 pandemic and is investigating the role of receptors involved in entry of this virus into cells as well as pathomechanisms leading to a cytokine “storm,” which in many cases ends in severe acute respiratory syndrome, fulminant myocarditis and kidney injury. An important question is if it may also damage hematopoietic stem progenitor cells?

positive: Rheumatologists’ perspective on coronavirus disease 19 (COVID-19) and potential therapeutic targets The ongoing pandemic coronavirus disease 19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a matter of global concern. Environmental factors such as air pollution and smoking and comorbid conditions (hypertension, diabetes mellitus and underlying cardio-respiratory illness) likely increase the severity of COVID-19. Rheumatic manifestations such as arthralgias and arthritis may be prevalent in about a seventh of individuals. COVID-19 can result in acute interstitial pneumonia, myocarditis, leucopenia (with lymphopenia) and thrombocytopenia, also seen in rheumatic diseases like lupus and Sjogren’s syndrome. Severe disease in a subset of patients may be driven by cytokine storm, possibly due to secondary hemophagocytic lymphohistiocytosis (HLH), akin to that in systemic onset juvenile idiopathic arthritis or adult-onset Still’s disease. In the absence of high-quality evidence in this emerging disease, understanding of pathogenesis may help postulate potential therapies. Angiotensin converting enzyme 2 (ACE2) appears important for viral entry into pneumocytes; dysbalance in ACE2 as caused by ACE inhibitors or ibuprofen may predispose to severe disease. Preliminary evidence suggests potential benefit with chloroquine or hydroxychloroquine. Antiviral drugs like lopinavir/ritonavir, favipiravir and remdesivir are also being explored. Cytokine storm and secondary HLH might require heightened immunosuppressive regimens. Current international society recommendations suggest that patients with rheumatic diseases on immunosuppressive therapy should not stop glucocorticoids during COVID-19 infection, although minimum possible doses may be used. Disease-modifying drugs should be continued; cessation may be considered during infection episodes as per standard practices. Development of a vaccine may be the only effective long-term protection against this disease.

positive: COVID-19 infection induces readily detectable morphological and inflammation-related phenotypic changes in peripheral blood monocytes, the severity of which correlate with patient outcome Background: Excessive monocyte/macrophage activation with the development of a cytokine storm and subsequent acute lung injury, leading to acute respiratory distress syndrome (ARDS) is a feared consequence of infection with COVID-19. The ability to recognize and potentially intervene early in those patients at greatest risk of developing this complication could be of great clinical utility. Methods: We performed detailed flow cytometric analysis of peripheral blood samples from 28 COVID-19 patients treated at Xian No.8 Hospital and the First Affiliated Hospital of Xian Jiaotong University in early 2020 in an attempt to identify factors that could help predict severity of disease and patient outcome. Findings: While we did not detect significant differences in the number of monocytes between patients with COVID-19 and normal healthy individuals,we did identify significant morphological and functional differences, which are more pronounced in patients requiring prolonged hospitalization and ICU admission. Patients with COVID-19 have larger than normal monocytes, easily identified on forward scatter, side scatter analysis by routine flow cytometry,with the presence of a distinct population of monocytes with high forward scatter (FSC-high). On more detailed analysis, these FSC-high monocytes are CD11b+, CD14+, CD16+, CD68+, CD80+, CD163+, CD206+ and secrete IL-6, IL-10 and TNF-alpha, consistent with an inflammatory phenotype. Conclusions: The detection and serial monitoring of this subset of inflammatory monocytes using flow cytometry could be of great help in guiding the prognostication and treatment of patients with COVID-19 and merits further evaluation.

positive: Cytokine storm and leukocyte changes in mild versus severe SARS-CoV-2 infection: Review of 3939 COVID-19 patients in China and emerging pathogenesis and therapy concepts Clinical evidence indicates that the fatal outcome observed with severe acute respiratory syndrome-coronavirus-2 infection often results from alveolar injury that impedes airway capacity and multi-organ failure-both of which are associated with the hyperproduction of cytokines, also known as a cytokine storm or cytokine release syndrome. Clinical reports show that both mild and severe forms of disease result in changes in circulating leukocyte subsets and cytokine secretion, particularly IL-6, IL-1ß, IL-10, TNF, GM-CSF, IP-10 (IFN-induced protein 10), IL-17, MCP-3, and IL-1ra. Not surprising, therapies that target the immune response and curtail the cytokine storm in coronavirus 2019 (COVID-19) patients have become a focus of recent clinical trials. Here we review reports on leukocyte and cytokine data associated with COVID-19 disease in 3939 patients in China and describe emerging data on immunopathology. With an emphasis on immune modulation, we also look at ongoing clinical studies aimed at blocking proinflammatory cytokines; transfer of immunosuppressive mesenchymal stem cells; use of convalescent plasma transfusion; as well as immunoregulatory therapy and traditional Chinese medicine regimes. In examining leukocyte and cytokine activity in COVID-19, we focus in particular on how these levels are altered as the disease progresses (neutrophil NETosis, macrophage, T cell response, etc.) and proposed consequences to organ pathology (coagulopathy, etc.). Viral and host interactions are described to gain further insight into leukocyte biology and how dysregulated cytokine responses lead to disease and/or organ damage. By better understanding the mechanisms that drive the intensity of a cytokine storm, we can tailor treatment strategies at specific disease stages and improve our response to this worldwide public health threat.

positive: Recommendations for coronavirus infection in rheumatic diseases treated with biologic therapy Abstract The Coronavirus-associated disease, that was first identified in 2019 in China (CoViD-19), is a pandemic caused by a bat-derived beta-coronavirus, named SARS-CoV2. It shares homology with SARS and MERS-CoV, responsible for past outbreaks in China and in Middle East. SARS-CoV2 spread from China where the first infections were described in December 2019 and is responsible for the respiratory symptoms that can lead to acute respiratory distress syndrome. A cytokine storm has been shown in patients who develop fatal complications, as observed in past coronavirus infections. The management includes ventilatory support and broad-spectrum antiviral drugs, empirically utilized, as a targeted therapy and vaccines have not been developed. Based upon our limited knowledge on the pathogenesis of CoViD-19, a potential role of some anti-rheumatic drugs may be hypothesized, acting as direct antivirals or targeting host immune response. Antimalarial drugs, commonly used in rheumatology, may alter the lysosomal proteases that mediates the viral entry into the cell and have demonstrated efficacy in improving the infection. Anti-IL-1 and anti-IL-6 may interfere with the cytokine storm in severe cases and use of tocilizumab has shown good outcomes in a small cohort. Baricitinib has both antiviral and anti-inflammatory properties. Checkpoints inhibitors such as anti-CD200 and anti-PD1 could have a role in the treatment of CoViD-19. Rheumatic disease patients taking immunosuppressive drugs should be recommended to maintain the chronic therapy, prevent infection by avoiding social contacts and pausing immunosuppressants in case of infection. National and international registries are being created to collect data on rheumatic patients with CoViD-19.

positive: Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2 ACE2 (angiotensin-converting enzyme 2) has a multiplicity of physiological roles that revolve around its trivalent function: a negative regulator of the renin-angiotensin system, facilitator of amino acid transport, and the severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2 receptor. ACE2 is widely expressed, including, in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 has recently been identified as the SARS-CoV-2 receptor, the infective agent responsible for coronavirus disease 2019, providing a critical link between immunity, inflammation, ACE2, and cardiovascular disease. Although sharing a close evolutionary relationship with SARS-CoV, the receptor-binding domain of SARS-CoV-2 differs in several key amino acid residues, allowing for stronger binding affinity with the human ACE2 receptor, which may account for the greater pathogenicity of SARS-CoV-2. The loss of ACE2 function following binding by SARS-CoV-2 is driven by endocytosis and activation of proteolytic cleavage and processing. The ACE2 system is a critical protective pathway against heart failure with reduced and preserved ejection fraction including, myocardial infarction and hypertension, and against lung disease and diabetes mellitus. The control of gut dysbiosis and vascular permeability by ACE2 has emerged as an essential mechanism of pulmonary hypertension and diabetic cardiovascular complications. Recombinant ACE2, gene-delivery of Ace2, Ang 1–7 analogs, and Mas receptor agonists enhance ACE2 action and serve as potential therapies for disease conditions associated with an activated renin-angiotensin system. rhACE2 (recombinant human ACE2) has completed clinical trials and efficiently lowered or increased plasma angiotensin II and angiotensin 1-7 levels, respectively. Our review summarizes the progress over the past 20 years, highlighting the critical role of ACE2 as the novel SARS-CoV-2 receptor and as the negative regulator of the renin-angiotensin system, together with implications for the coronavirus disease 2019 pandemic and associated cardiovascular diseases.

positive: Rational Use of Tocilizumab in the Treatment of Novel Coronavirus Pneumonia Since December 2019, a novel coronavirus pneumonia (COVID-19) has broken out in Wuhan, China and spread rapidly. Recent studies have found that ⁓ 15.7% of patients develop severe pneumonia, and cytokine storm is an important factor leading to rapid disease progression. Currently, there are no specific drugs for COVID-19 and the cytokine storm it causes. IL-6 is one of the key cytokines involved in infection-induced cytokine storm. Tocilizumab, which is the IL-6 receptor antagonist, has been approved by the US FDA for the treatment of cytokine release syndrome (CRS), is expected to treat cytokine storm caused by COVID-19 and is now in clinical trials. In this paper, we will elaborate the role of cytokine storm in COVID-19, the mechanism of tocilizumab on cytokine storm and the key points of pharmaceutical care based on the actual clinical application for COVID-19 in our hospital, the latest research reports, clinical trial progress of tocilizumab, drug instruction from the US FDA, and “Diagnosis and Treatment Plan of Novel Coronavirus Pneumonia (seventh trial edition)” in China, so as to provide reference for the treatment of COVID-19.

positive: Serum protein profiling reveals a landscape of inflammation and immune signaling in early-stage COVID-19 infection Coronavirus disease 2019 (COVID-19) is a highly contagious infection and threating the human lives in the world. The elevation of cytokines in blood is crucial to induce cytokine storm and immunosuppression in the transition of severity in COVID-19 patients. However, the comprehensive changes of serum proteins in COVID-19 patients throughout the SARS-CoV-2 infection is unknown. In this work, we developed a high-density antibody microarray and performed an in-depth proteomics analysis of serum samples collected from early COVID-19 (n=15) and influenza (n=13) patients. We identified a large set of differentially expressed proteins (n=125) that participate in a landscape of inflammation and immune signaling related to the SARS-CoV-2 infection. Furthermore, the significant correlations of neutrophil and lymphocyte with the CCL2 and CXCL10 mediated cytokine signaling pathways was identified. These information are valuable for the understanding of COVID-19 pathogenesis, identification of biomarkers and development of the optimal anti-inflammation therapy.

positive: Anakinra for severe forms of COVID-19: a cohort study BACKGROUND: Coronaviruses can induce the production of interleukin (IL)-1β, IL-6, tumour necrosis factor, and other cytokines implicated in autoinflammatory disorders. It has been postulated that anakinra, a recombinant IL-1 receptor antagonist, might help to neutralise the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related hyperinflammatory state, which is considered to be one cause of acute respiratory distress among patients with COVID-19. We aimed to assess the off-label use of anakinra in patients who were admitted to hospital for severe forms of COVID-19 with symptoms indicative of worsening respiratory function. METHODS: The Ana-COVID study included a prospective cohort from Groupe Hospitalier Paris Saint-Joseph (Paris, France) and a historical control cohort retrospectively selected from the Groupe Hospitalier Paris Saint-Joseph COVID cohort, which began on March 18, 2020. Patients were included in the prospective cohort if they were aged 18 years or older and admitted to Groupe Hospitalier Paris Saint-Joseph with severe COVID-19-related bilateral pneumonia on chest x-ray or lung CT scan. The other inclusion criteria were either laboratory-confirmed SARS-CoV-2 or typical lung infiltrates on a lung CT scan, and either an oxygen saturation of 93% or less under oxygen 6 L/min or more, or aggravation (saturation ≤93% under oxygen 3 L/min) with a loss of 3% of oxygen saturation in ambient air over the previous 24 h. The historical control group of patients had the same inclusion criteria. Patients in the anakinra group were treated with subcutaneous anakinra (100 mg twice a day for 72 h, then 100 mg daily for 7 days) as well as the standard treatments at the institution at the time. Patients in the historical group received standard treatments and supportive care. The main outcome was a composite of either admission to the intensive care unit (ICU) for invasive mechanical ventilation or death. The main analysis was done on an intention-to-treat basis (including all patients in the anakinra group who received at least one injection of anakinra). FINDINGS: From March 24 to April 6, 2020, 52 consecutive patients were included in the anakinra group and 44 historical patients were identified in the Groupe Hospitalier Paris Saint-Joseph COVID cohort study. Admission to the ICU for invasive mechanical ventilation or death occurred in 13 (25%) patients in the anakinra group and 32 (73%) patients in the historical group (hazard ratio [HR] 0·22 [95% CI 0·11–0·41; p<0·0001). The treatment effect of anakinra remained significant in the multivariate analysis (HR 0·22 [95% CI 0·10–0·49]; p=0·0002). An increase in liver aminotransferases occurred in seven (13%) patients in the anakinra group and four (9%) patients in the historical group. INTERPRETATION: Anakinra reduced both need for invasive mechanical ventilation in the ICU and mortality among patients with severe forms of COVID-19, without serious side-effects. Confirmation of efficacy will require controlled trials. FUNDING: Groupe Hospitalier Paris Saint-Joseph.

positive: Rational Use of Tocilizumab in the Treatment of Novel Coronavirus Pneumonia Since December 2019, a novel coronavirus pneumonia (COVID-19) has broken out in Wuhan, China and spread rapidly. Recent studies have found that â 15.7% of patients develop severe pneumonia, and cytokine storm is an important factor leading to rapid disease progression. Currently, there are no specific drugs for COVID-19 and the cytokine storm it causes. IL-6 is one of the key cytokines involved in infection-induced cytokine storm. Tocilizumab, which is the IL-6 receptor antagonist, has been approved by the US FDA for the treatment of cytokine release syndrome (CRS), is expected to treat cytokine storm caused by COVID-19 and is now in clinical trials. In this paper, we will elaborate the role of cytokine storm in COVID-19, the mechanism of tocilizumab on cytokine storm and the key points of pharmaceutical care based on the actual clinical application for COVID-19 in our hospital, the latest research reports, clinical trial progress of tocilizumab, drug instruction from the US FDA, and "Diagnosis and Treatment Plan of Novel Coronavirus Pneumonia (seventh trial edition)" in China, so as to provide reference for the treatment of COVID-19.

positive: Treating COVID-19 with colchicine in community healthcare setting

positive: Lung under attack by COVID-19-induced cytokine storm: pathogenic mechanisms and therapeutic implications The lung is a key target of the cytokine storm that can be triggered by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for the widespread clinical syndrome known as coronavirus disease 2019 (COVID-19). Indeed, in some patients, SARS-CoV-2 promotes a dysfunctional immune response that dysregulates the cytokine secretory pattern. Hypercytokinemia underlies the hyperinflammatory state leading to injury of alveolar epithelial cells and vascular endothelial cells, as well as to lung infiltration sustained by neutrophils and macrophages. Within such a pathogenic context, interleukin-6 (IL-6) and other cytokines/chemokines play a pivotal pro-inflammatory role. Therefore, cytokines and their receptors, as well as cytokine-dependent intracellular signalling pathways can be targeted by potential therapies aimed to relieve the heavy burden of cytokine storm. In particular, the anti-IL-6-receptor monoclonal antibody tocilizumab is emerging as one of the most promising pharmacologic treatments. The reviews of this paper are available via the supplemental material section.

positive: The Efficacy of IL-6 Inhibitor Tocilizumab in Reducing Severe COVID-19 Mortality: A Systematic Review Without proven, targeted therapies against SARS-CoV-2, it is crucial to counter the known pathophysiological causes of severe COVID-19, potentially utilizing existing drugs. Severe COVID-19 is largely the result of a dysregulated immune response characterized by lymphocytopenia, neutrophilia and critical hypercytokinemia, also called a cytokine storm. The IL-6 inhibitor tocilizumab (TCZ) could potentially suppress effects of the pro-inflammatory cytokine which drives the cytokine storm and thereby lower mortality from the disease. This systematic analysis aimed to investigate and synthesize existing evidence for the efficacy of TCZ in reducing COVID-19 mortality. PubMed and SearchWorks searches were performed to locate clinical studies with primary data on TCZ treatment for severe COVID-19. 9 case-control studies comparing mortality between TCZ and standard of care (SOC) were identified for a qualitative synthesis. In all of the studies, the odds ratio of mortality from COVID-19 pointed towards lower fatality with TCZ versus the SOC and a combined random effects odds ratio calculation yielded an odds ratio of 0.482 (p<0.001, 95% CI 0.326-0.713). Additionally, 12 uncontrolled trials were identified for a qualitative analysis producing a raw combined mortality rate of 13.6%. Results from the systematic analysis provide positive evidence for the potential efficacy of TCZ, validating the merit and need for ongoing clinical trials of the drug to treat severe COVID-19.

positive: Overview of the COVID-19 and JAK/STAT Pathway Inhibition: Ruxolitinib Perspective Ruxolitinib is the first approved JAK1 and JAK2 inhibitor. It inhibits the JAK / STAT pathway which is one of the main cellular signaling pathways especially regulates inflammatory response. COVID-19 is an urgent pandemic situation caused by SARS-CoV-2 infection. This review firstly presents an overview of SARS-CoV-2 and COVID-19, and then it focuses on the potential efficacy of ruxolitinib in this infection. The possible targets of ruxolitinib are determined by using genetic alterations that have been reported in COVID-19 patients. The potential effectiveness of ruxolitinib is suggested by evaluating the interactions of these potential targets which are directly affected by the ruxolitinib or JAK/STAT pathway.

positive: Use of Toll-Like Receptor 3 Agonists Against Respiratory Viral Infections Respiratory RNA viruses are constantly evolving, thus requiring development of additional prophylactic and therapeutic strategies. Harnessing the innate immune system to non-specifically respond to viral infection has the advantage of being able to circumvent viral mutations that render the virus resistant to a particular therapeutic agent. Viruses are recognized by various cellular receptors, including Toll-like receptor (TLR) 3 which recognizes double-stranded (ds)RNA produced during the viral replication cycle. TLR3 agonists include synthetic dsRNA such as poly (IC), poly (ICLC) and poly (AU). These agents have been evaluated and found to be effective against a number of viral agents. One major limitation has been the toxicity associated with administration of these drugs. Significant time and effort have been spent to develop alternatives/modifications that will minimize these adverse effects. This review will focus on the TLR3 agonist, poly (IC)/(ICLC) with respect to its use in treatment/prevention of respiratory viral infections.

positive: Therapeutic Algorithm for Use of Melatonin in Patients With COVID-19 The coronavirus, COVID-19, has infected hundreds of thousands and killed tens of thousands of individuals worldwide. This highly infectious condition continues to ravage the world population and has yet to reach it peak infective rate in some countries. Many conventional drugs including hydroxychloroquine/chloroquine, lopinavir, remdesivir, etc., have been repurposed as treatments for this often deadly disease, but there is no specifically-designed effective drug available; also, the drugs mentioned have significant side effects and their efficacy is unknown. New drugs and vaccines are being designed as COVID-19 treatment, but their development and testing will require months to years. Time is not a luxury that this crisis has. Thus, there is a serious unmet need for the identification of currently-available and safe molecules which can be used to slow or treat COVID-19 disease. Here, we suggest melatonin be given consideration for prophylactic use or treatment alone or in combination with other drugs. Melatonin's multiple actions as an anti-inflammatory, anti-oxidant, and anti-viral (against other viruses) make it a reasonable choice for use. Melatonin is readily available, can be easily synthesized in large quantities, is inexpensive, has a very high safety profile and can be easily self-administered. Melatonin is endogenously-produced molecule in small amounts with its production diminishing with increased age. Under the current critical conditions, large doses of melatonin alone or in combination with currently-recommended drugs, e.g., hydroxychloroquine/chloroquine, to resist COVID-19 infection would seem judicious.

positive: COVID-19: a collision of complement, coagulation and inflammatory pathways COVID-19 is frequently accompanied by a hypercoagulable inflammatory state with microangiopathic pulmonary changes that can precede the diffuse alveolar damage characteristic of typical ARDS seen in other severe pathogenic infections. Parallels with systemic inflammatory disorders such as atypical haemolytic uraemic syndrome (aHUS) have implicated the complement pathway in the pathogenesis of COVID-19, and particularly the anaphylatoxins C3a and C5a released from cleavage of C3 and C5 respectively. C5a is a potent cell signalling protein that activates a cytokine storm - a hyper-inflammatory phenomenon - within hours of infection and the innate immune response. However, excess C5a can result in a pro-inflammatory environment orchestrated through a plethora of mechanisms, that propagates lung injury, lymphocyte exhaustion and an immune paresis. Furthermore, disruption of the homeostatic interactions between complement and extrinsic and intrinsic coagulation pathways contributes to a net pro-coagulant state in the microvasculature of critical organs. Fatal COVID-19 has been associated with a systemic inflammatory response accompanied by a pro-coagulant state and organ damage, particularly microvascular thrombi in the lungs and kidneys. Pathologic studies report strong evidence of complement activation. C5 blockade reduces inflammatory cytokines and their manifestations in animal studies, and has shown benefits in patients with aHUS, prompting investigation of this approach in the treatment of COVID-19. This review describes the role of the complement pathway and particularly C5a and its aberrations in highly pathogenic virus infections, and therefore its potential as a therapeutic target in COVID-19.

positive: SGLT2 inhibition and COVID-19: The road not taken The COVID-19 pandemic, caused by SARS-CoV-2, is an immense challenge for global healthcare. Diabetes mellitus, hypertension and obesity have been shown to portend poor prognosis in COVID-19 despite no greater susceptibility to the infection (1). Chronic hypertension is commonly associated with vasculopathy which can predispose to severe infection. In patients with diabetes, severity is attributable to impaired innate, adaptive immunity, upregulation of ACE2 (entry receptor for SARS-CoV2) by acute hyperglycemia and diabetic vasculopathy. The background of chronic low grade inflammation characterised by increased levels of IL-6 and CRP in diabetes and obesity can also lead to an enhanced 'cytokine storm' in COVID-19 (2). ACE2 expression on endothelial cells has been reported to cause viral mediated endothelitis and precipitate vascular dysfunction manifesting as acute respiratory distress syndrome as well as myocarditis, heart failure, arrhythmias, myocardial infarction and renal failure (3). In patients with pre-existing comorbidities like hypertension, diabetes, obesity and chronic kidney disease, this new-onset organ dysfunction can have deleterious additive effects.

positive: Statins as early therapy to mitigate COVID-19 (SARS-CoV-2)-associated ARDS and cytokine storm syndrome - time is of the essence.

positive: Inflammation resolution: a dual-pronged approach to averting cytokine storms in COVID-19? Severe coronavirus disease (COVID-19) is characterized by pulmonary hyper-inflammation and potentially life-threatening “cytokine storms”. Controlling the local and systemic inflammatory response in COVID-19 may be as important as anti-viral therapies. Endogenous lipid autacoid mediators, referred to as eicosanoids, play a critical role in the induction of inflammation and pro-inflammatory cytokine production. SARS-CoV-2 may trigger a cell death (“debris”)-induced “eicosanoid storm”, including prostaglandins and leukotrienes, which in turn initiates a robust inflammatory response. A paradigm shift is emerging in our understanding of the resolution of inflammation as an active biochemical process with the discovery of novel endogenous specialized pro-resolving lipid autacoid mediators (SPMs), such as resolvins. Resolvins and other SPMs stimulate macrophage-mediated clearance of debris and counter pro-inflammatory cytokine production, a process called inflammation resolution. SPMs and their lipid precursors exhibit anti-viral activity at nanogram doses in the setting of influenza without being immunosuppressive. SPMs also promote anti-viral B cell antibodies and lymphocyte activity, highlighting their potential use in the treatment of COVID-19. Soluble epoxide hydrolase (sEH) inhibitors stabilize arachidonic acid-derived epoxyeicosatrienoic acids (EETs), which also stimulate inflammation resolution by promoting the production of pro-resolution mediators, activating anti-inflammatory processes, and preventing the cytokine storm. Both resolvins and EETs also attenuate pathological thrombosis and promote clot removal, which is emerging as a key pathology of COVID-19 infection. Thus, both SPMs and sEH inhibitors may promote the resolution of inflammation in COVID-19, thereby reducing acute respiratory distress syndrome (ARDS) and other life-threatening complications associated with robust viral-induced inflammation. While most COVID-19 clinical trials focus on “anti-viral” and “anti-inflammatory” strategies, stimulating inflammation resolution is a novel host-centric therapeutic avenue. Importantly, SPMs and sEH inhibitors are currently in clinical trials for other inflammatory diseases and could be rapidly translated for the management of COVID-19 via debris clearance and inflammatory cytokine suppression. Here, we discuss using pro-resolution mediators as a potential complement to current anti-viral strategies for COVID-19.

positive: Vitamin D can prevent COVID-19 infection-induced multiple organ damage Vitamin D is an immunomodulator hormone with an anti-inflammatory and antimicrobial effect with a high safety profile. A lot of COVID-19 infected patients develop acute respiratory distress syndrome (ARDS), which may lead to multiple organ damage. These symptoms are associated with a cytokine storm syndrome. The aim of this letter is to note the 5 crucial points that vitamin D could have protective and therapeutic effects against COVID-19. For that reason, COVID-19 infection-induced multiple organ damage might be prevented by vitamin D.

positive: Use of Baricitinib in Patients with Moderate and Severe COVID-19 Cytokine storm and hyperinflammation are associated with increased mortality in COVID-19. In this small uncontrolled cohort of patients with moderate-severe COVID-19, treatment with baricitinib plus hydroxychloroquine was associated with recovery in 11 of 15 patients. Baricitinib for the treatment of COVID-19 should be further investigated in randomized controlled clinical trials.

positive: Biosensors for Managing the COVID-19 Cytokine Storm: Challenges Ahead [Image: see text] The global COVID-19 pandemic has oversaturated many intensive care units to the point of collapse, leading to enormous spikes in death counts. Before critical care becomes a necessity, identifying patients who are likely to become critically ill and providing prompt treatment is a strategy to avoid ICU oversaturation. There is a consensus that a hyperinflammatory syndrome or a “cytokine storm” is responsible for poor outcomes in COVID-19. Measuring cytokine levels at the point of care is required in order to better understand this process. In this Perspective, we summarize the main events behind the cytokine storm in COVID-19 as well as current experimental treatments. We advocate for a new biosensor-enabled paradigm to personalize the management of COVID-19 and stratify patients. Biosensor-guided dosing and timing of immunomodulatory therapies could maximize the benefits of these anti-inflammatory treatments while minimizing deleterious effects. Biosensors will also be essential in order to detect complications such as coinfections and sepsis, which are common in immunosuppressed patients. Finally, we propose the ideal features of these biosensors using some prototypes from the recent literature as examples. Multisensors, lateral flow tests, mobile biosensors, and wearable biosensors are seen as key players for precision medicine in COVID-19.

positive: COVID-19: Pathogenesis, Genetic Polymorphism, Clinical Features and Laboratory Findings. COVID-19 caused by a novel agent SARS-CoV-2 progressed to a pandemic condition and resulted in a major public health concern worldwide, leading to social and economic issues at the same time. The pathogenesis of COVID-19 starts with the bonding of the virus to ACE-2 receptors expressed in many tissues, and the triggered excessive immune response plays a critical role in the course of the disease. The cytokine storm that occurs upon excessive production of pro-inflammatory cytokines is considered responsible for the severe progression of the disease and the organ damage. However, the accurate pathophysiological mechanism of the disease, which progresses with various clinical presentations, is still substantially unknown. While various studies have been conducted on the effect of genetic polymorphism on the course and severity of the disease, the presence of a significant effect has not been proven yet. The clinical course of the disease is variable, with clinical representation ranging from 81% mild course to 14% severe course along with 5% critical course in patients. Asymptomatic course is considered to be higher than expected, although its frequency is not known exactly. Older adults and those with comorbidities are exposed to a more severe disease course. The disease progress with various symptoms, such as fever, cough, dyspnea, malaise, myalgia, taste and smell dysfunctions, diarrhea, and headache. A range of complications (Acute Respiratory Distress Syndrome, thromboembolic conditions, arrhythmia and cardiac events, secondary infections) could be seen during the course of the disease. Varied laboratory tests are vital to determine the severity and prognosis of the disease, along with the condition and exposure of the affected systems during the course of COVID-19.

positive: Consider Adjunctive Ketamine in Mechanically Ventilated COVID-19 Patients

positive: Should we unstress SARS-CoV-2 infected cells? [Figure: see text]

positive: Profile of natural anticoagulant, coagulant factor and anti-phospholipid antibody in critically ill COVID-19 patients The outbreak of novel coronavirus disease 2019 (COVID-19) has now become a global pandemic. Coagulopathy has been reported widely in critically ill COVID-19 patients and was related to high mortality. However, the comprehensive coagulation profiles have not been examined and the underlying mechanism of the coagulopathy in COVID-19 patients is unclear. To study the coagulation profiles of routine hemostasis tests, natural anticoagulants, coagulant factors and antiphospholipid antibodies in critically ill COVID-19 patients. This single-center and cross-section study included 19 patients with COVID-19, who were admitted to intensive care unit (ICU) at Tongji hospital in Wuhan, China, from Feb 23 to Mar 3, 2020. Demographic data, laboratory parameters, treatments and clinical outcomes of the patients were collected and analyzed. The final date of follow-up was Mar 31, 2020. In this study, 12 thrombotic events occurred in 9 patients, including 4 cerebral infarctions, 7 acro-ischemia and 1 internal jugular vein thrombosis. The common abnormalities of routine coagulation tests included evelated D-Dimer level (100%), prolonged prothrombin time (73.7%) and hyperfibrinogenemia (73.7%). The median activities of natural anticoagulants including protein C, protein S and antithrombin were all below the normal range. Factor VIII activities were significantly above normal range (median value 307%, IQR 198–441) in all patients. Factor V and factor VII activities were significantly lower in near-terminal stage patients. Anti-phospholipid antibodies were present in 10 patients. Strikingly, 4 cerebral infarction events were in patients had anti-phospholipid antibodies of multiple isotypes. Sustained hypercoagulable status and thrombotic events were common in critically ill patients with COVID-19. The low activities of natural anticoagulants, elevated factor VIII level and the presence of antiphospholipid antibodies, together, may contribute to the etiopathology of coagulopathy in COVID-19 patients.

positive: The potential insights of Traditional Chinese Medicine on treatment of COVID-19 Corona Virus Disease 2019 (COVID-19) broke out in 2019 and spread rapidly around the world. There is still no specific antiviral therapy to the current pandemic. In China, historical records show that Traditional Chinese Medicine (TCM) is effective in prevention and enhancing the resistance to pandemic with unique insights. To fight with COVID-19, National Health and Commission of PRC has recommended some TCM in the guideline, such as HuoxiangZhengqi, LianhuaQingwen ShufengJiedu and XueBijing, and actually displayed a remarkable effect in clinical treatment strategic for COVID-19. We review studies to provide an in-depth understanding into the effect of TCM, and also introduce the possible mechanism involved in COVID-19 treatment.

positive: Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases PURPOSE: Infection with COVID-19 potentially can result in severe outcomes and death from “cytokine storm syndrome”, resulting in novel coronavirus pneumonia (NCP) with severe dyspnea, acute respiratory distress syndrome (ARDS), fulminant myocarditis and multiorgan dysfunction with or without disseminated intravascular coagulation. No published treatment to date has been shown to adequately control the inflammation and respiratory symptoms associated with COVID-19, apart from oxygen therapy and assisted ventilation. We evaluated the effects of using high dose oral and/or IV glutathione in the treatment of 2 patients with dyspnea secondary to COVID-19 pneumonia. METHODS: Two patients living in New York City (NYC) with a history of Lyme and tick-borne co-infections experienced a cough and dyspnea and demonstrated radiological findings consistent with novel coronavirus pneumonia (NCP). A trial of 2 g of PO or IV glutathione was used in both patients and improved their dyspnea within 1 h of use. Repeated use of both 2000 mg of PO and IV glutathione was effective in further relieving respiratory symptoms. CONCLUSION: Oral and IV glutathione, glutathione precursors (N-acetyl-cysteine) and alpha lipoic acid may represent a novel treatment approach for blocking NF-κB and addressing “cytokine storm syndrome” and respiratory distress in patients with COVID-19 pneumonia.

positive: Pharmacological (or Synthetic) and Nutritional Agonists of PPAR-γ as Candidates for Cytokine Storm Modulation in COVID-19 Disease The cytokine storm is an abnormal production of inflammatory cytokines, due to the over-activation of the innate immune response. This mechanism has been recognized as a critical mediator of influenza-induced lung disease, and it could be pivotal for COVID-19 infections. Thus, an immunomodulatory approach targeting the over-production of cytokines could be proposed for viral aggressive pulmonary disease treatment. In this regard, the peroxisome proliferator-activated receptor (PPAR)-γ, a member of the PPAR transcription factor family, could represent a potential target. Beside the well-known regulatory role on lipid and glucose metabolism, PPAR-γ also represses the inflammatory process. Similarly, the PPAR-γ agonist thiazolidinediones (TZDs), like pioglitazone, are anti-inflammatory drugs with ameliorating effects on severe viral pneumonia. In addition to the pharmacological agonists, also nutritional ligands of PPAR-γ, like curcuma, lemongrass, and pomegranate, possess anti-inflammatory properties through PPAR-γ activation. Here, we review the main synthetic and nutritional PPAR-γ ligands, proposing a dual approach based on the strengthening of the immune system using pharmacological and dietary strategies as an attempt to prevent/treat cytokine storm in the case of coronavirus infection.

positive: COVID-19, Immuno-oncology and Cardiovascular Disease: Viewpoint from the Intersection

positive: Cytokine release syndrome in severe COVID-19

positive: Traditional Chinese medicine for treatment of COVID-19 based on literature mining of targeting cytokine storm/ 基于干预细胞因子风暴文献挖掘的中医药治疗重症新型冠状病毒肺炎探讨 The primary clinical manifestations of coronavirus disease 2019 (COVID-19) are fever, fatigue and dry cough. Several clinical studies reported that some patients with low or medium fever, or even without obvious symptom, rapidly progressed to severe or critical illness, including severe acute respiratory syndrome, septic shock, coagulation disorders and intractable metabolic acidosis. These patients were usually associated with significant elevated serum levels of a profile of cytokines, which is similar to SARS-2003 and MERS-2015, indicating the occurrence of cytokine storm. In the present review, we summarized previous advances in the treatment of severe cases of SARS by using traditional Chinese medicines (TCM), especially those TCM targeting cytokine storm, based on literature mining. By using data mining and network pharmacology, we also investigated underlying mechanisms and biological pathways involved in the inhibitory effects of TCM against cytokine storm. This review not only provides novel insights in the precise application of TCM, appropriate integrative use of TCM in combination with western medicine, but also contributes to the discovery of novel drugs or new therapeutic strategies targeting cytokine storm to suppress progression of COVID-19 and to improve clinical prognosis and outcomes.

positive: Hypertransaminasemia in the course of infection with SARS-CoV-2: Incidence and pathogenetic hypothesis In patients infected with severe acute respiratory syndrome coronavirus 2, the respiratory symptoms, such as fever, cough and dyspnea, are the most frequent clinical manifestations. These patients may also present with less well-defined symptoms like diarrhea, nausea, vomiting and/or abdominal discomfort both at the time of diagnosis and during the clinical course. In a few cases, these symptoms may also present before the appearance of respiratory symptoms. To penetrate the body, Severe acute respiratory syndrome coronavirus 2 uses ACE2 receptors, which are present not only in respiratory epithelium but also in gastrointestinal mucosa and liver cholangiocytes. In several cases, viral RNA is detectable in the stool of patients with coronavirus disease 2019 (COVID-19). The liver damage seems to show a multifactorial origin. About 2%-11% of patients with COVID-19 have known underlying hepatic pathologies. In 14%-53% of COVID-19 cases, there is an alteration of the indices of liver cytolysis and is more frequently observed in severe forms of COVID-19, especially during hospitalization.

positive: Vitamin intervention for cytokine storm in the patients with coronavirus disease 2019

positive: Steroid-Responsive Encephalitis in Coronavirus Disease 2019 Coronavirus disease 2019 (COVID-19) infection has the potential for targeting the central nervous system, and several neurological symptoms have been described in patients with severe respiratory distress. Here, we described the case of a 60-year-old patient with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but only mild respiratory abnormalities who developed an akinetic mutism attributable to encephalitis. Magnetic resonance imaging was negative, whereas electroencephalography showed generalized theta slowing. Cerebrospinal fluid analyses during the acute stage were negative for SARS-CoV-2, positive for pleocytosis and hyperproteinorrachia, and showed increased interleukin-8 and tumor necrosis factor-α concentrations. Other infectious or autoimmune disorders were excluded. A progressive clinical improvement along with a reduction of cerebrospinal fluid parameters was observed after high-dose steroid treatment, thus arguing for an inflammatory-mediated brain involvement related to COVID-19. ANN NEUROL 2020.

positive: Network pharmacology for treatment of COVID-19 with Renshen Baidu Powder based on cytokines/ 基于细胞因子的人参败毒散治疗新型冠状病毒肺炎（COVID-19）的网络药理学研究 Objective: To investigate the multi compound-target-pathway mechanism of Renshen Baidu Powder (RSBDS) in the treatment of COVID-19 from cytokine perspective. Methods: The active compounds of RSBDS were collected by TCMSP and the cytokine storm related targets were collected by the drug target database. The interaction network of RSBDS on single drug-active compounds-targets was established by Cytoscape. The interaction network, GO function and KEGG pathway of the targets were analyzed by String and DAVID databases. Results: The interaction network of RSBDS on single drug-active compounds-targets included 10 kinds of medicinal materials, 211 active compounds and 151 disease targets. Interaction network showed that the targets related to the inhibition to cytokine storm of RSBDS on COVID-19 might include STAT3, MAPK1, NFκB1, PIK3CA, MAPK3, TNF, CXCR4, VEGFA, IL-6, IL-2, etc. GO function showed that above targets in biological function involved chemotaxis and steroid metabolism; Molecular function entries involved heme binding, iron ion binding and oxygen binding; Cell composition entries involved cell surface and cell membrane. KEGG pathway showed that above targets participated in the regulation of Chagas disease, HIF-1 signaling pathway, TNF signaling pathway, etc. Conclusion: The multi compound-target-pathways effect of RSBDS on COVID-19 was realized by inhibiting cytokine storm, which through regulating chemotaxis, increasing blood oxygen saturation, inhibiting STAT, MAPK, NFκB, PIK3K and IL-6 signal pathways.

positive: Single-cell analysis of severe COVID-19 patients reveals a monocyte-driven inflammatory storm attenuated by Tocilizumab Despite the current devastation of the COVID-19 pandemic, several recent studies have suggested that the immunosuppressive drug Tocilizumab can powerfully treating inflammatory responses that occur in this disease. Here, by employing single-cell analysis of the immune cell composition of severe-stage COVID-19 patients and these same patients in post Tocilizumab-treatment remission, we have identified a monocyte subpopulation specific to severe disease that contributes to inflammatory storms in COVID-19 patients. Although Tocilizumab treatment attenuated the strong inflammatory immune response, we found that immune cells including plasma B cells and CD8+ T cells still exhibited an intense humoral and cell-mediated anti-virus immune response in COVID-19 patients after Tocilizumab treatment. Thus, in addition to providing a rich, very high-resolution data resource about the immune cell distribution at multiple stages of the COVID-19 disease, our work both helps explain Tocilizumab’s powerful therapeutic effects and defines a large number of potential new drug targets related to inflammatory storms.

positive: Obesity and COVID-19: immune and metabolic derangement as a possible link to adverse clinical outcomes Recent reports have shown a strong association between obesity and the severity of COVID-19 infection, even in the absence of other comorbidities. After infecting the host cells, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may cause a hyperinflammatory reaction through the excessive release of cytokines, a condition known as “cytokine storm,” while inducing lymphopenia and a disrupted immune response. Obesity is associated with chronic low-grade inflammation and immune dysregulation, but the exact mechanisms through which it exacerbates COVID-19 infection are not fully clarified. The production of increased amounts of cytokines such as TNFα, IL-1, IL-6, and monocyte chemoattractant protein (MCP-1) lead to oxidative stress and defective function of innate and adaptive immunity, whereas the activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome seems to play a crucial role in the pathogenesis of the infection. Endothelial dysfunction and arterial stiffness could favor the recently discovered infection of the endothelium by SARS-CoV-2, whereas alterations in cardiac structure and function and the prothrombotic microenvironment in obesity could provide a link for the increased cardiovascular events in these patients. The successful use of anti-inflammatory agents such as IL-1 and IL-6 blockers in similar hyperinflammatory settings, like that of rheumatoid arthritis, has triggered the discussion of whether such agents could be administrated in selected patients with COVID-19 disease.

positive: The COVID-19 Pandemic during the Time of the Diabetes Pandemic: Likely Fraternal Twins? An altered immune response to pathogens has been suggested to explain increased susceptibility to infectious diseases in patients with diabetes. Recent evidence has documented several immunometabolic pathways in patients with diabetes directly related to the COVID-19 infection. This also seems to be the case for prediabetic subjects with proinflammatory insulin resistance syndrome accompanied with prothrombotic hyperinsulinemic and dysglycemic states. Patients with frank hyperglycemia, dysglycemia and/or hyperinsulinemia develop systemic immunometabolic inflammation with higher levels of circulating cytokines. This deleterious scenario has been proposed as the underlying mechanism enhancing a cytokine storm-like hyperinflammatory state in diabetics infected with severe COVID-19 triggering multi-organ failure. Compared with moderately affected COVID-19 patients, diabetes was found to be highly prevalent among severely affected patients suggesting that this non-communicable disease should be considered as a risk factor for adverse outcomes. The COVID-19 pandemic mirrors with the diabetes pandemic in many pathobiological aspects. Our interest is to emphasize the ties between the immunoinflammatory mechanisms that underlie the morbidity and lethality when COVID-19 meets diabetes. This review brings attention to two pathologies of highly complex, multifactorial, developmental and environmentally dependent manifestations of critical importance to human survival. Extreme caution should be taken with diabetics with suspected symptoms of COVID-19 infection.

positive: Whole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early prognostic marker for severe COVID-19 SARS-CoV-2 is the novel coronavirus responsible for the current COVID-19 pandemic. Severe complications are observed only in a small proportion of infected patients but the cellular mechanisms underlying this progression are still unknown. Comprehensive flow cytometry of whole blood samples from 54 COVID-19 patients revealed a dramatic increase in the number of immature neutrophils. This increase strongly correlated with disease severity and was associated with elevated IL-6 and IP-10 levels, two key players in the cytokine storm. The most pronounced decrease in cell counts was observed for CD8 T-cells and VD2 γδ T-cells, which both exhibited increased differentiation and activation. ROC analysis revealed that the count ratio of immature neutrophils to CD8 or VD2 T-cells predicts pneumonia onset (0.9071) as well as hypoxia onset (0.8908) with high sensitivity and specificity. It would thus be a useful prognostic marker for preventive patient management and improved healthcare resource management.

positive: Role of oxidized LDL-induced “trained macrophages” in the pathogenesis of COVID-19 and benefits of pioglitazone: A hypothesis BACKGROUND AND AIMS: Older adults and people who have cardiovascular disorders (their common pathogenetic mechanism is progressive atherosclerosis) are at higher risk for severe illness from COVID-19 (coronavirus disease 2019). Their common pathogenetic mechanism is progressive atherosclerosis in which oxLDL (oxidized LDL) plays major role. Receptor-mediated uptake of oxLDL by the monocyte-derived macrophages activates the long-term epigenetic reprogramming of innate immunity, which is termed “trained immunity.” The aim of this work is to investigate the mechanisms and treatment possibilities that can control the activities of these specific macrophages. METHODS: Search in Medline and PubMed relevant articles on the trained immunity and cytokine storm of COVID-19. CONCLUSIONS: When oxLDL-trained macrophages encounter SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in the lung, it causes unregulated cytokine secretion, leading to the alveolar damage. Therefore, blocking macrophage training by pioglitazone, a thiazolidinedione, could control the hyperactivation that the virus would trigger.

positive: Mechanism of Dayuanyin in the treatment of coronavirus disease 2019 based on network pharmacology and molecular docking BACKGROUND: At present, coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2, is spreading all over the world, with disastrous consequences for people of all countries. The traditional Chinese medicine prescription Dayuanyin (DYY), a classic prescription for the treatment of plague, has shown significant effects in the treatment of COVID-19. However, its specific mechanism of action has not yet been clarified. This study aims to explore the mechanism of action of DYY in the treatment of COVID-19 with the hope of providing a theoretical basis for its clinical application. METHODS: First, the TCMSP database was searched to screen the active ingredients and corresponding target genes of the DYY prescription and to further identify the core compounds in the active ingredient. Simultaneously, the Genecards database was searched to identify targets related to COVID-19. Then, the STRING database was applied to analyse protein–protein interaction, and Cytoscape software was used to draw a network diagram. The R language and DAVID database were used to analyse GO biological processes and KEGG pathway enrichment. Second, AutoDock Vina and other software were used for molecular docking of core targets and core compounds. Finally, before and after application of DYY, the core target gene IL6 of COVID-19 patients was detected by ELISA to validate the clinical effects. RESULTS: First, 174 compounds, 7053 target genes of DYY and 251 genes related to COVID-19 were selected, among which there were 45 target genes of DYY associated with treatment of COVID-19. This study demonstrated that the use of DYY in the treatment of COVID-19 involved a variety of biological processes, and DYY acted on key targets such as IL6, ILIB, and CCL2 through signaling pathways such as the IL-17 signaling pathway, AGE-RAGE signaling pathway in diabetic complications, and cytokine–cytokine receptor interaction. DYY might play a vital role in treating COVID-19 by suppressing the inflammatory storm and regulating immune function. Second, the molecular docking results showed that there was a certain affinity between the core compounds (kaempferol, quercetin, 7-Methoxy-2-methyl isoflavone, naringenin, formononetin) and core target genes (IL6, IL1B, CCL2). Finally, clinical studies showed that the level of IL6 was elevated in COVID-19 patients, and DYY can reduce its levels. CONCLUSIONS: DYY may treat COVID-19 through multiple targets, multiple channels, and multiple pathways and is worthy of clinical application and promotion.

positive: Immunologic Features in Coronavirus Disease 2019: Functional Exhaustion of T Cells and Cytokine Storm

positive: COVID-19–Associated Collapsing Glomerulopathy: An Emerging Entity

positive: Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome The term cytokine storm syndromes describes conditions characterised by a life-threatening, fulminant hypercytokinaemia with high mortality. Cytokine storm syndromes can be genetic or a secondary complication of autoimmune or autoinflammatory disorders, infections, and haematological malignancies. These syndromes represent a key area of interface between rheumatology and general medicine. Rheumatologists often lead in management, in view of their experience using intensive immunosuppressive regimens and managing cytokine storm syndromes in the context of rheumatic disorders or infection (known as secondary haemophagocytic lymphohistiocytosis or macrophage activation syndrome [sHLH/MAS]). Interleukin (IL)-1 is pivotal in hyperinflammation. Anakinra, a recombinant humanised IL-1 receptor antagonist, is licenced at a dose of 100 mg once daily by subcutaneous injection for rheumatoid arthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, and cryopyrin-associated periodic syndromes. In cytokine storm syndromes, the subcutaneous route is often problematic, as absorption can be unreliable in patients with critical illness, and multiple injections are needed to achieve the high doses required. As a result, intravenous anakinra is used in clinical practice for sHLH/MAS, despite this being an off-licence indication and route of administration. Among 46 patients admitted to our three international, tertiary centres for sHLH/MAS and treated with anakinra over 12 months, the intravenous route of delivery was used in 18 (39%) patients. In this Viewpoint, we describe current challenges in the management of cytokine storm syndromes and review the pharmacokinetic and safety profile of intravenous anakinra. There is accumulating evidence to support the rationale for, and safety of, intravenous anakinra as a first-line treatment in patients with sHLH/MAS. Intravenous anakinra has important clinical relevance when high doses of drug are required or if patients have subcutaneous oedema, severe thrombocytopenia, or neurological involvement. Cross-speciality management and collaboration, with the generation of international, multi-centre registries and biobanks, are needed to better understand the aetiopathogenesis and improve the poor prognosis of cytokine storm syndromes.

positive: Emerging pharmacotherapies for COVID-19 Novel Corona-virus Disease 2019 (nCOVID 19) is caused by a novel virulent corona virus and leads to potentially fatal virulent pneumonia and severe respiratory distress syndrome. It was initially declared as public health emergency if international concern by WHO followed by Pandemic on 12(th) March 2020. As of 10(th) April 2020, more than 1.5 million people are affected globally with around 95000 deaths. Vaccines for this deadly virus are currently under development and many drugs used for other indications have been repurposed and investigated for prophylaxis and treatment of COVID 19. As per SOLIDARITY trial by WHO, some of the most promising candidates include chloroquine phosphate and hydroxychloroquine which are anti-malarial medications, Remdesivir, Lopinavir-Ritonavir combination with or without interferon which are anti-HIV drugs and convalescent plasma therapy. The current evidence of efficacy and ongoing research has been elaborated in the article. Besides, there has been evidence regarding inflammatory pathogenesis of this virus leading to cytokine storm in susceptible individuals. Thus, anti-proinflammatory cytokine drugs like Anakinra and Tocilizumab are undergoing multiple trials and some results are encouraging. Similarly, use of anti-inflammatory cytokines like IL-37 and IL-38 is hypothesised to be useful and is under research. The situation is still evolving and hence there is yet no definitive therapy but to conclude the use of repurposed medications can be a boon till a definitive therapy and vaccines are developed.

positive: COVID-Net: A Tailored Deep Convolutional Neural Network Design for Detection of COVID-19 Cases from Chest X-Ray Images The COVID-19 pandemic continues to have a devastating effect on the health and well-being of the global population. A critical step in the fight against COVID-19 is effective screening of infected patients, with one of the key screening approaches being radiology examination using chest radiography. Motivated by this and inspired by the open source efforts of the research community, in this study we introduce COVID-Net, a deep convolutional neural network design tailored for the detection of COVID-19 cases from chest X-ray (CXR) images that is open source and available to the general public. To the best of the authors' knowledge, COVID-Net is one of the first open source network designs for COVID-19 detection from CXR images at the time of initial release. We also introduce COVIDx, an open access benchmark dataset that we generated comprising of 13,975 CXR images across 13,870 patient patient cases, with the largest number of publicly available COVID-19 positive cases to the best of the authors' knowledge. Furthermore, we investigate how COVID-Net makes predictions using an explainability method in an attempt to not only gain deeper insights into critical factors associated with COVID cases, which can aid clinicians in improved screening, but also audit COVID-Net in a responsible and transparent manner to validate that it is making decisions based on relevant information from the CXR images. By no means a production-ready solution, the hope is that the open access COVID-Net, along with the description on constructing the open source COVIDx dataset, will be leveraged and build upon by both researchers and citizen data scientists alike to accelerate the development of highly accurate yet practical deep learning solutions for detecting COVID-19 cases and accelerate treatment of those who need it the most.

positive: Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19 BACKGROUND: The inflammatory response plays a critical role in coronavirus disease 2019 (COVID-19), and inflammatory cytokine storm increases the severity of COVID-19. OBJECTIVE: To investigate the ability of interleukin-6 (IL-6), C-reactive protein (CRP), and procalcitonin (PCT) to predict mild and severe cases of COVID-19. STUDY DESIGN: This retrospective cohort study included 140 patients diagnosed with COVID-19 from January 18, 2020, to March 12, 2020. The study population was divided into two groups according to disease severity: a mild group (MG) (n = 107) and a severe group (SG) (n = 33). Data on demographic characteristics, baseline clinical characteristics, and the levels of IL-6, CRP, and PCT on admission were collected. RESULTS: Among the 140 patients, the levels of IL-6, CRP, and PCT increased in 95 (67.9 %), 91 (65.0 %), and 8 (5.7 %) patients on admission, respectively. The proportion of patients with increased IL-6, CRP, and PCT levels was significantly higher in the SG than in the MG. Cox proportional hazard model showed that IL-6 and CRP could be used as independent factors to predict the severity of COVID-19. Furthermore, patients with IL-6 > 32.1 pg/mL or CRP > 41.8 mg/L were more likely to have severe complications. CONCLUSION: The serum levels of IL-6 and CRP can effectively assess disease severity and predict outcome in patients with COVID-19.

positive: Ursodeoxycholic acid as a candidate therapeutic to alleviate and/or prevent COVID-19-associated cytokine storm

positive: Immune alterations during SARS-CoV-2-related acute respiratory distress syndrome We report a longitudinal analysis of the immune response associated with a fatal case of COVID-19. This patient exhibited a rapid evolution towards multiorgan failure. SARS-CoV-2 was detected in multiple nasopharyngeal, blood, and pleural samples, despite antiviral and immunomodulator treatment. Clinical evolution in the blood was marked by an increase (2-3 fold) in differentiated effector T cells expressing exhaustion (PD-1) and senescence (CD57) markers, an expansion of antibody-secreting cells, a 15-fold increase in {gamma}{delta} T-cell and proliferating NK-cell populations, and the total disappearance of monocytes, suggesting lung trafficking. In the serum, waves of a proinflammatory cytokine storm, Th1 and Th2 activation, and markers of T-cell exhaustion, apoptosis, cell cytotoxicity, and endothelial activation were observed until the fatal outcome. This case underscores the need for well-designed studies to investigate complementary approaches to control viral replication, the source of the hyperinflammatory status, and immunomodulation to target the pathophysiological response.

positive: Regenerative Medicine in COVID-19 Treatment: Real Opportunities and Range of Promises Novel coronavirus disease (COVID-19) has attracted much attention around the world due to its rapid transmission among humans and relatively high mortality rate. Studies are increasing to find the best therapeutic approach for the disease and its management. Regenerative medicine offers various cell-tissue therapeutics and related products, such as stem cell therapy, natural killer (NK) cell therapy, Chimeric antigen receptor (CAR) T cell therapy, exosomes, and tissue products. Interestingly, mesenchymal stem cells (MSCs) can reduce inflammatory symptoms and protect against cytokine storm, which critically contributes to the COVID-19 progression. Notably, having the potentials to exert cytotoxic effects on infected cells and induce interferon production probably make NK cells a candidate for COVID-19 cell therapy. Besides, exosomes are one of the crucial products of cells that can exert therapeutic effects through the induction of immune responses and neutralizing antibody titers. The paper aims to briefly consider current options for COVID-19 therapy to show that there is no specific cure for COVID-19, and then assess the real opportunities and range of promises regenerative medicine can provide for specific treatment of COVID-19. [Figure: see text]

positive: Role of inflammatory markers in corona virus disease (COVID-19) patients: A review IMPACT STATEMENT: In late 2019, a novel virus called SARS-CoV-2, expanded globally from Wuhan, China and was declared a pandemic on 11 March 2020 by the WHO. The mechanism of virus entry inside the host cell depends upon the cellular proteases including cathepsins, HAT, and TMPRSS2, which splits up the spike protein and causes further penetration. MERS coronavirus uses DPP4, while coronavirus HCoV-NL63 and SARS-CoV and SARS-CoV-2 employ ACE-2 as the key receptor. Cytokine storm syndrome was analyzed in critically ill nCOVID-19 patients and it is presented with high inflammatory mediators, systemic inflammation, and multiple organ failure. Among various inflammatory mediators, the level of interleukins (IL-2, IL-7, IL-10), G-CSF, MIP1A, MCP1, and TNF-α was reported to be higher in critically ill patients. Understanding this molecular mechanism of ILs, T cells, and dendritic cells will be helpful to design immunotherapy and novel drugs for the treatment of nCOVID-19 infection.

positive: Pneumonia, Acute Respiratory Distress Syndrome, and Early Immune-Modulator Therapy Acute respiratory distress syndrome (ARDS) is caused by infectious insults, such as pneumonia from various pathogens or related to other noninfectious events. Clinical and histopathologic characteristics are similar across severely affected patients, suggesting that a common mode of immune reaction may be involved in the immunopathogenesis of ARDS. There may be etiologic substances that have an affinity for respiratory cells and induce lung cell injury in cases of ARDS. These substances originate not only from pathogens, but also from injured host cells. At the molecular level, these substances have various sizes and biochemical characteristics, classifying them as protein substances and non-protein substances. Immune cells and immune proteins may recognize and act on these substances, including pathogenic proteins and peptides, depending upon the size and biochemical properties of the substances (this theory is known as the protein-homeostasis-system hypothesis). The severity or chronicity of ARDS depends on the amount of etiologic substances with corresponding immune reactions, the duration of the appearance of specific immune cells, or the repertoire of specific immune cells that control the substances. Therefore, treatment with early systemic immune modulators (corticosteroids and/or intravenous immunoglobulin) as soon as possible may reduce aberrant immune responses in the potential stage of ARDS.

positive: Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions Abstract The coronavirus disease-19 pandemic (COVID-19), which appeared in China in December 2019 and rapidly spread throughout the world, has forced clinicians and scientists to take up extraordinary challenges. This unprecedented situation led to the inception of numerous fundamental research protocols and many clinical trials. It quickly became apparent that although COVID-19, in the vast majority of cases, was a benign disease, it could also develop a severe form with sometimes fatal outcomes. Cytokines are central to the pathophysiology of COVID-19; while some of them are beneficial (type-I interferon, interleukin-7), others appear detrimental (interleukin-1β, -6, and TNF-α) particularly in the context of the so-called cytokine storm. Yet another characteristic of the disease has emerged: concomitant immunodeficiency, notably involving impaired type-I interferon response, and lymphopenia. This review provides an overview of current knowledge on COVID-19 immunopathology. We discuss the defective type-I IFN response, the theoretical role of IL-7 to restore lymphocyte repertoire, as well as we mention the two patterns observed in severe COVID-19 (i.e. interleukin-1β-driven macrophage activation syndrome vs. interleukin-6-driven immune dysregulation). Next, reviewing current evidence drawn from clinical trials, we examine a number of cytokine and anti-cytokine therapies, including interleukin-1, -6, and TNF inhibitors, as well as less targeted therapies, such as corticosteroids, chloroquine, or JAK inhibitors.

positive: Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation: challenges and opportunities. The COVID-19 pandemic is a global public health crisis, with considerable mortality and morbidity exerting pressure on health-care resources, including critical care. An excessive host inflammatory response in a subgroup of patients with severe COVID-19 might contribute to the development of acute respiratory distress syndrome (ARDS) and multiorgan failure. Timely therapeutic intervention with immunomodulation in patients with hyperinflammation could prevent disease progression to ARDS and obviate the need for invasive ventilation. Granulocyte macrophage colony-stimulating factor (GM-CSF) is an immunoregulatory cytokine with a pivotal role in initiation and perpetuation of inflammatory diseases. GM-CSF could link T-cell-driven acute pulmonary inflammation with an autocrine, self-amplifying cytokine loop leading to monocyte and macrophage activation. This axis has been targeted in cytokine storm syndromes and chronic inflammatory disorders. Here, we consider the scientific rationale for therapeutic targeting of GM-CSF in COVID-19-associated hyperinflammation. Since GM-CSF also has a key role in homoeostasis and host defence, we discuss potential risks associated with inhibition of GM-CSF in the context of viral infection and the challenges of doing clinical trials in this setting, highlighting in particular the need for a patient risk-stratification algorithm.

positive: Evidence Supporting a Phased Immuno-physiological Approach to COVID-19 From Prevention Through Recovery This paper presents an evidence-based strategy for improving clinical outcomes in COVID-19 Recommendations are based on the phases of the disease, because optimal interventions for one phase may not be appropriate for a different phase The four phases addressed are: Prevention, Infection, Inflammation and Recovery Underlying this phased approach is recognition of emerging evidence for two different components of pathophysiology, early infection and late stage severe complications These two aspects of the disease suggest two different patterns of clinical emphasis that seem on the surface to be not entirely concordant We describe the application of therapeutic strategies and appropriate tactics that address four main stages of disease progression for COVID-19 Emerging evidence in COVID-19 suggests that the SARS-CoV-2 virus may both evade the innate immune response and kill macrophages Delayed innate immune response and a depleted population of macrophages can theoretically result in a blunted antigen presentation, delaying and diminishing activation of the adaptive immune response Thus, one clinical strategy involves supporting patient innate and adaptive immune responses early in the time course of illness, with the goal of improving the timeliness, readiness, and robustness of both the innate and adaptive immune responses At the other end of the disease pathology spectrum, risk of fatality in COVID-19 is driven by excessive and persistent upregulation of inflammatory mechanisms associated with cytokine storm Thus, the second clinical strategy is to prevent or mitigate excessive inflammatory response to prevent the cytokine storm associated with high mortality risk Clinical support for immune system pathogen clearance mechanisms involves obligate activation of immune response components that are inherently inflammatory This puts the goals of the first clinical strategy (immune activation) potentially at odds with the goals of the second strategy(mitigation of proinflammatory effects) This creates a need for discernment about the time course of the illness and with that, understanding of which components of an overall strategy to apply at each phase of the time course of the illness We review evidence from early observational studies and the existing literature on both outcomes and mechanisms of disease, to inform a phased approach to support the patient at risk for infection, with infection, with escalating inflammation during infection, and at risk of negative sequelae as they move into recovery

positive: Altered cytokine levels and immune responses in patients with SARS-CoV-2 infection and related conditions The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic in early 2020. The infection has been associated with a wide range of clinical symptoms. In the severely affected patients, it has caused dysregulation of immune responses including over-secretion of inflammatory cytokines and imbalances in the proportion of naïve helper T cells, memory helper T cells and regulatory T cells. Identification of the underlying mechanism of such aberrant function of immune system would help in the prediction of disease course and selection of susceptible patients for more intensive cares. In the current review, we summarize the results of studies which reported alterations in cytokine levels and immune cell functions in patients affected with SARS-CoV-2 and related viruses.

positive: Storm, typhoon, cyclone or hurricane in patients with COVID-19? Beware of the same storm that has a different origin Some of the articles being published during the severe acute respiratory syndrome–coronavirus (SARS-CoV)-2 pandemic highlight a link between severe forms of coronavirus disease 2019 (COVID-19) and the so-called cytokine storm, also with increased ferritin levels. However, this scenario is more complex than initially thought due to the heterogeneity of hyperinflammation. Some patients with coronavirus 2019 disease (COVID-19) develop a fully blown secondary haemophagocytic lymphohistiocytosis (sHLH), whereas others, despite a consistent release of pro-inflammatory cytokines, do not fulfil sHLH criteria but still show some features resembling the phenotype of the hyperferritinemic syndrome. Despite the final event (the cytokine storm) is shared by various conditions leading to sHLH, the aetiology, either infectious, autoimmune or neoplastic, accounts for the differences in the various phases of this process. Moreover, the evidence of a hyperinflammatory microenvironment provided the rationale to employ immunomodulating agents for therapeutic purposes in severe COVID-19. This viewpoint aims at discussing the pitfalls and issues to be considered with regard to the use of immunomodulating agents in COVID-19, such as timing of treatment based on the viral load and the extent of cytokine/ferritin overexpression. Furthermore, it encompasses recent findings in the paediatric field about a novel multisystem inflammatory disease resembling toxic shock syndrome and atypical Kawasaki disease observed in children with proven SARS-CoV2 infection. Finally, it includes arguments in favour of adding COVID-19 to the spectrum of the recently defined ‘hyperferritinemic syndrome’, which already includes adult-onset Still’s disease, macrophage activation syndrome, septic shock and catastrophic anti-phospholipid syndrome.

positive: Evidence Supporting a Phased Immuno-physiological Approach to COVID-19 From Prevention Through Recovery. This paper presents an evidence-based strategy for improving clinical outcomes in COVID-19. Recommendations are based on the phases of the disease, because optimal interventions for one phase may not be appropriate for a different phase. The four phases addressed are: Prevention, Infection, Inflammation and Recovery. Underlying this phased approach is recognition of emerging evidence for two different components of pathophysiology, early infection and late stage severe complications. These two aspects of the disease suggest two different patterns of clinical emphasis that seem on the surface to be not entirely concordant. We describe the application of therapeutic strategies and appropriate tactics that address four main stages of disease progression for COVID-19. Emerging evidence in COVID-19 suggests that the SARS-CoV-2 virus may both evade the innate immune response and kill macrophages. Delayed innate immune response and a depleted population of macrophages can theoretically result in a blunted antigen presentation, delaying and diminishing activation of the adaptive immune response. Thus, one clinical strategy involves supporting patient innate and adaptive immune responses early in the time course of illness, with the goal of improving the timeliness, readiness, and robustness of both the innate and adaptive immune responses. At the other end of the disease pathology spectrum, risk of fatality in COVID-19 is driven by excessive and persistent upregulation of inflammatory mechanisms associated with cytokine storm. Thus, the second clinical strategy is to prevent or mitigate excessive inflammatory response to prevent the cytokine storm associated with high mortality risk. Clinical support for immune system pathogen clearance mechanisms involves obligate activation of immune response components that are inherently inflammatory. This puts the goals of the first clinical strategy (immune activation) potentially at odds with the goals of the second strategy(mitigation of proinflammatory effects). This creates a need for discernment about the time course of the illness and with that, understanding of which components of an overall strategy to apply at each phase of the time course of the illness. We review evidence from early observational studies and the existing literature on both outcomes and mechanisms of disease, to inform a phased approach to support the patient at risk for infection, with infection, with escalating inflammation during infection, and at risk of negative sequelae as they move into recovery.

positive: COVID-19 gone bad: A new character in the spectrum of the hyperferritinemic syndrome? The severe form of COVID-19 share several clinical and laboratory features with four entities gathered under the term "hyperferritinemic syndromes" and including macrophage activation syndrome (MAS), adult-onset Still's disease (AOSD), catastrophic anti-phospholipid syndrome (CAPS) and septic shock. COVID-19 systemic inflammatory reaction and "hyperferritinemic syndromes" are all characterized by high serum ferritin and a life-threatening hyper-inflammation sustained by a cytokines storm which eventually leads to multi-organ failure. In this review, we analyze the possible epidemiological and molecular mechanisms responsible for hyper-inflammation in patients with severe COVID-19 and we underline the similarities between this condition and "hyperferritinemic syndromes" which would allow considering severe COVID-19 as a fifth member of this spectrum of inflammatory conditions.

positive: Rheumatologists and Pulmonologists at Temple University Weather the COVID-19 Storm Together In recent commentaries from Lancet Rheumatology and The Journal of Rheumatology 1,2, the authors eloquently illustrated the connection between the coronavirus disease 2019 (COVID-19) infection, the subsequent cytokine storm (CS) that ensues in a number of patients, and the potential efficacy of biologics that rheumatologists routinely use in their practices. Moreover, those biologics were originally investigated by rheumatologists for the treatment of numerous rheumatic conditions, including macrophage activating syndrome (MAS), a similar form of storm that resembles the one occurring in patients with COVID-193.

positive: Modulation of LPS-induced inflammatory cytokine production by a novel glycogen synthase kinase-3 inhibitor Sepsis is a serious condition that can lead to long-term organ damage and death. At the molecular level, the hallmark of sepsis is the elevated expression of a multitude of potent cytokines, i.e. a cytokine storm. For sepsis involving gram-negative bacteria, macrophages recognize lipopolysaccharide (LPS) shed from the bacteria, activating Toll-like-receptor 4 (TLR4), and triggering a cytokine storm. Glycogen synthase kinase-3 (GSK-3) is a highly active kinase that has been implicated in LPS-induced cytokine production. Thus, compounds that inhibit GSK-3 could be potential therapeutics for sepsis. Our group has recently described a novel and highly selective inhibitor of GSK-3 termed COB-187. In the present study, using THP-1 macrophages, we evaluated the ability of COB-187 to attenuate LPS-induced cytokine production. We found that COB-187 significantly reduced, at the protein and mRNA levels, cytokines induced by LPS (e.g. IL-6, TNF-α, IL-1β, CXCL10, and IFN-β). Further, the data suggest that the inhibition could be due, at least in part, to COB-187 reducing NF-κB (p65/p50) DNA binding activity as well as reducing IRF-3 phosphorylation at Serine 396. Thus, COB-187 appears to be a potent inhibitor of the cytokine storm induced by LPS.

positive: Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment COVID-19 infection has a heterogenous disease course; it may be asymptomatic or causes only mild symptoms in the majority of the cases, while immunologic complications such as macrophage activation syndrome also known as secondary hemophagocytic lymphohistiocytosis, resulting in cytokine storm syndrome and acute respiratory distress syndrome, may also occur in some patients. According to current literature, impairment of SARS-CoV-2 clearance due to genetic and viral features, lower levels of interferons, increased neutrophil extracellular traps, and increased pyroptosis and probable other unknown mechanisms create a background for severe disease course complicated by macrophage activation syndrome and cytokine storm. Various genetic mutations may also constitute a risk factor for severe disease course and occurrence of cytokine storm in COVID-19. Once, immunologic complications like cytokine storm occur, anti-viral treatment alone is not enough and should be combined with appropriate anti-inflammatory treatment. Anti-rheumatic drugs, which are tried for managing immunologic complications of COVID-19 infection, will also be discussed including chloroquine, hydroxychloroquine, JAK inhibitors, IL-6 inhibitors, IL-1 inhibitors, anti-TNF-α agents, corticosteroids, intravenous immunoglobulin (IVIG), and colchicine. Early recognition and appropriate treatment of immunologic complications will decrease the morbidity and mortality in COVID-19 infection, which requires the collaboration of infectious disease, lung, and intensive care unit specialists with other experts such as immunologists, rheumatologists, and hematologists.

positive: Analysis on application of Chinese materia medica in treatment of COVID-19 by suppressing cytokine storm/ 中药在抗新型冠状病毒肺炎（COVID-19）引起的细胞因子风暴中的应用分析 At the end of December, 2019, a novel coronavirus disease (COVID-19) outbreak was found in China. COVID-19 spreads all over 268 countries, and more than 70 000 people got infected till February 23th, 2020. COVID-19 can result in acute respiratory distress syndrome and multiple organ failure due to its strong infectivity and extensive spread. These severe complications are believed to be the consequence of cytokine storm caused by the virus infection. In the “Diagnosis and treatment of novel coronavirus pneumonia”, glucocorticoid is recommended as the immunosuppressive agents to prevent acute immune reaction in critical patients. However, the usage of glucocorticoid may bring severe residual effects such as superinfection risks, prolonged course of disease. Traditional Chinese medicine might have advantages in the moderation of immune system. Actually, TCM is now applied in the treatment of COVID-19 clinically, and exhibits excellent therapeutic effects. In this review, the potential usage of TCM or traditional prescriptions in inhibiting cytokine storm and treating in acute lung injury were analyzed, which would be an effective strategy for the treatment of COVID-19.

positive: Cytokine storm and leukocyte changes in mild versus severe SARS‐CoV‐2 infection: Review of 3939 COVID‐19 patients in China and emerging pathogenesis and therapy concepts Clinical evidence indicates that the fatal outcome observed with severe acute respiratory syndrome‐coronavirus‐2 infection often results from alveolar injury that impedes airway capacity and multi‐organ failure—both of which are associated with the hyperproduction of cytokines, also known as a cytokine storm or cytokine release syndrome. Clinical reports show that both mild and severe forms of disease result in changes in circulating leukocyte subsets and cytokine secretion, particularly IL‐6, IL‐1β, IL‐10, TNF, GM‐CSF, IP‐10 (IFN‐induced protein 10), IL‐17, MCP‐3, and IL‐1ra. Not surprising, therapies that target the immune response and curtail the cytokine storm in coronavirus 2019 (COVID‐19) patients have become a focus of recent clinical trials. Here we review reports on leukocyte and cytokine data associated with COVID‐19 disease in 3939 patients in China and describe emerging data on immunopathology. With an emphasis on immune modulation, we also look at ongoing clinical studies aimed at blocking proinflammatory cytokines; transfer of immunosuppressive mesenchymal stem cells; use of convalescent plasma transfusion; as well as immunoregulatory therapy and traditional Chinese medicine regimes. In examining leukocyte and cytokine activity in COVID‐19, we focus in particular on how these levels are altered as the disease progresses (neutrophil NETosis, macrophage, T cell response, etc.) and proposed consequences to organ pathology (coagulopathy, etc.). Viral and host interactions are described to gain further insight into leukocyte biology and how dysregulated cytokine responses lead to disease and/or organ damage. By better understanding the mechanisms that drive the intensity of a cytokine storm, we can tailor treatment strategies at specific disease stages and improve our response to this worldwide public health threat.

positive: Th17 serum cytokines in relation to laboratory‐confirmed respiratory viral infection: A pilot study BACKGROUND: Th17 cytokines are associated with modulation of inflammation and may be beneficial in clearing influenza infection in experimental models. The Th17 cytokine profile was evaluated in a pilot study of respiratory virus infections. METHODS: Consecutive patients with symptoms of respiratory tract infection visiting the emergency department of a tertiary care hospital during the winter influenza season of 2014 to 2015 were evaluated. CLART PneumoVir kit, (GENOMICA, Madrid, Spain) was used for viral detection of all known respiratory viruses. Th17 cytokine profile was evaluated with the MILLIPLEX MAP Human TH17 Magnetic Bead Panel (Millipore Corp., Billerica, MA). Correlation of the TH17 profile with viral detection was performed with univariate and multivariate analysis. RESULTS: Seventy‐six patients were evaluated (median age 56 years, 51.3% female); a respiratory virus was identified in 60 (78.9%) patients; 45% had confirmed influenza. Influenza A (H3N2) correlated with higher levels of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), interleukin 1β (IL‐1β), IL‐17A, IL‐17E, IL‐17F, IL‐21, IL‐22, and IL‐23 (P < 0.05 by analysis of variance [ANOVA]) compared with respiratory syncytial virus (RSV). Parainfluenza virus (PIV) similarly had higher levels of GM‐CSF, IL‐1b, IL‐17A, IL‐22 compared with those detected in RSV, influenza B and any other virus infection ( P < 0.05; ANOVA). Increasing age (β‐coefficient = 1.11, 95% CI, 1.04‐1.2, P < 0.01) as well as IL‐17A levels (β‐coefficient = 1.03, 95% CI, 1.001‐1.05, P = 0.04) predicted hospital admission. CONCLUSION: Main Th17 cell effector cytokines were upregulated in laboratory‐confirmed A(H3N2) influenza and PIV. Excessive amounts of Th17 cytokines may be implicated in the pathogenesis and immune control of acute influenza and PIV infection in humans and may predict the severity of disease.

positive: COVID-19: Immunology and treatment options Abstract The novel coronavirus SARS-CoV2 causes COVID-19, a pandemic threatening millions. As protective immunity does not exist in humans and the virus is capable of escaping innate immune responses, it can proliferate, unhindered, in primarily infected tissues. Subsequent cell death results in the release of virus particles and intracellular components to the extracellular space, which result in immune cell recruitment, the generation of immune complexes and associated damage. Infection of monocytes/macrophages and/or recruitment of uninfected immune cells can result in massive inflammatory responses later in the disease. Uncontrolled production of pro-inflammatory mediators contributes to ARDS and cytokine storm syndrome. Antiviral agents and immune modulating treatments are currently being trialled. Understanding immune evasion strategies of SARS-CoV2 and the resulting delayed massive immune response will result in the identification of biomarkers that predict outcomes as well as phenotype and disease stage specific treatments that will likely include both antiviral and immune modulating agents.

positive: A Digital Protein Microarray for COVID-19 Cytokine Storm Monitoring Despite widespread concern for cytokine storms leading to severe morbidity in COVID-19, rapid cytokine assays are not routinely available for monitoring critically ill patients. We report the clinical application of a machine learning-based digital protein microarray platform for rapid multiplex quantification of cytokines from critically ill COVID-19 patients admitted to the intensive care unit (ICU) at the University of Michigan Hospital. The platform comprises two low-cost modules: (i) a semi-automated fluidic dispensing/mixing module that can be operated inside a biosafety cabinet to minimize the exposure of technician to the virus infection and (ii) a 12-12-15 inch compact fluorescence optical scanner for the potential near-bedside readout. The platform enabled daily cytokine analysis in clinical practice with high sensitivity (<0.4pg/mL), inter-assay repeatability (~10% CV), and near-real-time operation with a 10 min assay incubation. A cytokine profiling test with the platform allowed us to observe clear interleukin-6 (IL-6) elevations after receiving tocilizumab (IL-6 inhibitor) while significant cytokine profile variability exists across all critically ill COVID-19 patients and to discover a weak correlation between IL-6 to clinical biomarkers, such as Ferritin and CRP. Our data revealed large subject-to-subject variability in a patient's response to anti-inflammatory treatment for COVID-19, reaffirming the need for a personalized strategy guided by rapid cytokine assays.

positive: Clinical Outcomes in COVID‐19 Patients Treated with Tocilizumab: An Individual Patient Data Systematic Review BACKGROUND: Current evidence suggests an important role of interleukin‐6 (IL‐6) pathway in SARS‐CoV‐2‐related cytokine release storm in severely ill COVID‐19 patients. Inhibition of the IL‐6 pathway with tocilizumab has been employed successfully in some of these patients but the data is mostly consistent of case reports and series. METHODS: We performed a systematic search of PubMed, Embase, and Medline from 22(nd) April 2020 and again on 27(th) April 2020 using the following search terms alone or in combination: “COVID‐19”, “coronavirus”, “SARS‐CoV‐2”, “COVID”, “anti‐interleukin 6 receptor antibodies”, “anti‐IL‐6”, “tocilizumab”, “sarilumab”, “siltuximab”. We included studies which reported individual patient data. We extracted and analyzed individual level data on baseline characteristics, laboratory findings, and clinical outcomes. Primary endpoint was in‐hospital mortality. Secondary endpoints included in‐hospital complications, recovery rates, effect of patient characteristics on the primary outcome and changes in levels of inflammatory markers. RESULTS: 352 records were identified through the systematic search of which 10 studies met the inclusion criteria. A single study currently under review was also added. Eleven observational studies encompassing 29 patients were included in the present review. There were more males (24 [82.8%]) and hypertension was the most common comorbidity (16 [48.3 %]). Over an average of 5.4 hospital days, the primary endpoint occurred in 6 (20.7%) patients. Among surviving patients, about 10% had worsened disease and 17% recovered. The most common complication was acute respiratory distress syndrome (8[27.6%]). IL‐6 level was significantly higher after the initiation of tocilizumab with median (IQR) of 376.6 (148‐900.6) pg/mL compared to the baseline of 71.1 (31.9‐122.8) pg/mL (p=0.002). Mean (SD) levels of c‐reactive protein (CRP) were significantly decreased following treatment 24.6 (26.9) mg/L compared to baseline 140.4 (77) mg/L (P< 0.0001). Baseline demographics were not significantly different amongst survivors and non‐survivors by Fisher's exact test. CONCLUSION: In COVID‐19 patients treated with tocilizumab, IL‐6 levels are significantly elevated which are supportive of cytokine storm. Following initiation of tocilizumab, there is elevation in the IL‐6 levels and CRP levels dramatically decrease suggesting an improvement in this hyper‐inflammatory state. Ongoing randomized control trials will allow for further evaluation of this promising therapy. IMPORTANCE: Recent data indicate that severe COVID 19 causes cytokine release storm and is associated with worse clinical outcomes and IL‐6 plays an important role. It is suggestive that anti‐IL6 results in the improvement of this hyperinflammatory state. However, to our knowledge, there is no individual patient data systematic review performed to summarize baseline characteristics and clinical outcomes of COVID 19 patients who received tocilizumab. This article is protected by copyright. All rights reserved.

positive: Highlight of Immune Pathogenic Response and Hematopathologic Effect in SARS-CoV, MERS-CoV, and SARS-Cov-2 Infection A sudden outbreak of COVID-19 caused by a novel coronavirus, SARS-CoV-2, in Wuhan, China in December 2019 quickly grew into a global pandemic, putting at risk not only the global healthcare system, but also the world economy. As the disease continues to spread rapidly, the development of prophylactic and therapeutic approaches is urgently required. Although some progress has been made in understanding the viral structure and invasion mechanism of coronaviruses that may cause severe cases of the syndrome, due to the limited understanding of the immune effects caused by SARS-CoV-2, it is difficult for us to prevent patients from developing acute respiratory distress syndrome (ARDS) and pulmonary fibrosis (PF), the major complications of coronavirus infection. Therefore, any potential treatments should focus not only on direct killing of coronaviruses and prevention strategies by vaccine development, but also on keeping in check the acute immune/inflammatory responses, resulting in ARDS and PF. In addition, potential treatments currently under clinical trials focusing on killing coronaviruses or on developing vaccines preventing coronavirus infection largely ignore the host immune response. However, taking care of SARS-CoV-2 infected patients with ARDS and PF is considered to be the major difficulty. Therefore, further understanding of the host immune response to SARS-CoV-2 is extremely important for clinical resolution and saving medication cost. In addition to a breif overview of the structure, infection mechanism, and possible therapeutic approaches, we summarized and compared the hematopathologic effect and immune responses to SARS-CoV, MERS-CoV, and SARS-CoV-2. We also discussed the indirect immune response caused by SARS and direct infection, replication, and destroying of immune cells by MERS-CoV. The molecular mechanisms of SARS-CoV and MERS-CoV infection-induced lymphopenia or cytokine storm may provide some hint toward fight against SARS-CoV-2, the novel coronavirus. This may provide guidance over using immune therapy as a combined treatment to prevent patients developing severe respiratory syndrome and largely reduce complications.

positive: Repositioning PARP inhibitors for SARS‐CoV‐2 infection (COVID‐19); a new multi‐pronged therapy for ARDS? Clinically approved PARP inhibitors (PARPi) have a mild adverse effect profile and are well‐tolerated as continuous daily oral therapy. We review the evidence that justifies the repurposing of PARPi to block the proliferation of SARS‐CoV‐2 and combat the life‐threatening sequelae of COVID‐19 by several mechanisms. PARPi’s can effectively decrease IL‐6, IL‐1 and TNFα levels (key interleukins in SARS‐CoV‐2‐induced cytokine storm) and can alleviate subsequent lung fibrosis, as demonstrated in murine experiments and clinical trials. PARPi can tune macrophages towards a tolerogenic phenotype. PARPi’s may also counteract SARS‐CoV‐2‐induced and inflammation‐induced cell death and support cell survival. PARPi’s had beneficial effects in animal models of acute respiratory distress syndrome (ARDS), asthma and ventilator‐induced lung injury. PARPi’s may potentiate the effectiveness of Tocilizumab, Anakinra, Sarilumab, Adalimumab, Canakinumab or Siltuximab therapy. In summary, the evidence suggests that PARPi therapy would benefit COVID‐19 patients and trials of these drugs should be undertaken.

positive: The trinity of COVID-19: immunity, inflammation and intervention Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Alongside investigations into the virology of SARS-CoV-2, understanding the fundamental physiological and immunological processes underlying the clinical manifestations of COVID-19 is vital for the identification and rational design of effective therapies. Here, we provide an overview of the pathophysiology of SARS-CoV-2 infection. We describe the interaction of SARS-CoV-2 with the immune system and the subsequent contribution of dysfunctional immune responses to disease progression. From nascent reports describing SARS-CoV-2, we make inferences on the basis of the parallel pathophysiological and immunological features of the other human coronaviruses targeting the lower respiratory tract — severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Finally, we highlight the implications of these approaches for potential therapeutic interventions that target viral infection and/or immunoregulation.

positive: Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality Since December 2019, a viral pneumonia, named coronavirus disease 2019 (COVID-19), from Wuhan, China, has swept the world. Although the case fatality rate is not high, the number of people infected is large and there is still a large number of patients dying. With the collation and publication of more and more clinical data, a large number of data suggest that there are mild or severe cytokine storms in severe patients, which is an important cause of death. Therefore, treatment of the cytokine storm has become an important part of rescuing severe COVID-19 patients. Interleukin-6 (IL-6) plays an important role in cytokine release syndrome. If it is possible to block the signal transduction pathway of IL-6, it is expected to become a new method for the treatment of severe COVID-19 patients. Tocilizumab is an IL-6 receptor (IL-6R) blocker that can effectively block the IL-6 signal transduction pathway and thus is likely to become an effective drug for patients with severe COVID-19.

positive: Weathering the Cytokine Storm in COVID-19: Therapeutic Implications BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged in Wuhan, Hubei-China, as responsible for the coronavirus disease 2019 (COVID-19) and then spread rapidly worldwide. While most individuals remain asymptomatic or develop only mild symptoms, approximately 5% develop severe forms of COVID-19 characterized by acute respiratory distress syndrome (ARDS) and multiple-organ failure (MOF) that usually require intensive-care support and often yield a poor prognosis. SUMMARY: The pathophysiology of COVID-19 is far from being completely understood, and the lack of effective treatments leads to a sense of urgency to develop new therapeutic strategies based on pathophysiological assumptions. The exaggerated cytokine release in response to viral infection, a condition known as cytokine release syndrome (CRS) or cytokine storm, is emerging as the mechanism leading to ARDS and MOF in COVID-19, thus endorsing the hypothesis that properly timed anti-inflammatory therapeutic strategies could improve patients' clinical outcomes and prognosis. Key Messages: The objective of this article is to explore and comment on the potential role of the promising immunomodulatory therapies using pharmacological and nonpharmacological approaches to overcome the dysregulated proinflammatory response in COVID-19.

positive: Longitudinal COVID-19 profiling associates IL-1Ra and IL-10 with disease severity and RANTES with mild disease Background Identifying immune correlates of COVID-19 disease severity is an urgent need for clinical management, vaccine evaluation and drug development. Here we present a temporal analysis of key immune mediators, cytokine and chemokines in blood of hospitalised COVID-19 patients from serial sampling and follow up over four weeks.Methods A total of 71 patients with laboratory-confirmed COVID-19 admitted to Beijing You'an hospital in China with either mild (53 patients) or severe disease (18 patients) were enrolled with 18 healthy volunteers. We measured 34 immune mediators, cytokines and chemokines in peripheral blood every 4-7 days over one month per patient using a bio-plex multiplex immunoassay.Results We found that the chemokine RANTES(CCL5) was significantly elevated, from an early stage of the infection, in patients with mild but not severe disease. We also found that early production of inhibitory mediators including IL-10 and IL-1RA were significantly associated with disease severity, and a combination of CCL5, IL-1Ra and IL-10 at week 1 may predict patient outcomes. The majority of cytokines that are known to be associated with the cytokine storm in virus infections such as IL-6 and IFN-gamma were only significantly elevated in the late stage of severe COVID-19 illness. TNF- alpha and GM-CSF showed no significant differences between severe and mild cases.Conclusion Together our data suggest early intervention to increase expression of CCL5 may prevent patients from developing severe illness. Our data also suggest that measurement of levels of CCL5, as well as IL-1Ra, IL-10 in blood individually and in combination might be useful prognostic bio-markers to guide treatment strategies.

positive: Potential Mechanisms of Cardiac Injury and Common Pathways of Inflammation in Patients With COVID-19 Due to the lack of prospective, randomized, controlled clinical studies on inflammation and cardiovascular involvement, the exact mechanism of cardiac injury among patients with Coronavirus Disease 2019 (COVID-19) still remains uncertain. It was demonstrated that there is a high and significantly positive linear correlation between troponin T and plasma high-sensitivity C-reactive protein levels, biomarkers of cardiac injury and systemic inflammation, respectively. Cardiac injury and inflammation is a relatively common association among patients hospitalized with COVID-19, and it is related to higher risk of in-hospital mortality. In our literature search, we identified several potential mechanisms of myocardial tissue damage, namely, coronavirus-associated acute myocarditis, angiotensin-converting enzyme 2 receptor binding affinity to the virus Spike protein, increased cytokine secretion, and hypoxia-induced cardiac myocyte apoptosis. Elucidation of the disease pathogenesis and prospective histopathological studies are crucial for future proper treatment in case of renewed outbreaks. Of interest is that with hundred of thousands of bodies available for autopsy studies, no prospective investigation has been reported so far. Strong efforts and continued research of the cardiovascular complications and identification of risk factors for poor prognosis in COVID-19 are steadily needed. The high morbidity and mortality of COVID-19, its monumental economic burden and social impact, the despair of a new pandemic outbreak, and the thread of potential utilization of novel severe acute respiratory syndrome coronavirus 2 as biologic weapons make it a preponderant necessity to better comprehend the therapeutic management of this lethal disease. Emerging as an acute infectious disease, COVID-19 may become a chronic epidemic because of genetic recombination. Therefore, we should be ready for the reemergence of COVID-19 or other coronaviruses.

positive: COVID-19 infection may increase the risk of parkinsonism – Remember the Spanish flu?

positive: Metformin and SARS-CoV-2: mechanistic lessons on air pollution to weather the cytokine/thrombotic storm in COVID-19 Pathological signaling in the lung induced by particulate matter (PM) air pollution partially overlaps with that provoked by COVID-19, the pandemic disease caused by infection with the novel coronavirus SARS-CoV-2. Metformin is capable of suppressing one of the molecular triggers of the proinflammatory and prothrombotic processes of urban PM air pollution, namely the mitochondrial ROS/Ca(2+) release-activated Ca(2+) channels (CRAC)/IL-6 cascade. Given the linkage between mitochondrial functionality, ion channels, and inflamm-aging, the ability of metformin to target mitochondrial electron transport and prevent ROS/CRAC-mediated IL-6 release might illuminate new therapeutic avenues to quell the raging of the cytokine and thrombotic-like storms that are the leading causes of COVID-19 morbidity and mortality in older people. The incorporation of infection rates, severity and lethality of SARS-CoV-2 infections as new outcomes of metformin usage in elderly populations at risk of developing severe COVID-19, together with the assessment of bronchial/serological titers of inflammatory cytokines and D-dimers, could provide a novel mechanistic basis for the consideration of metformin as a therapeutic strategy against the inflammatory and thrombotic states underlying the gerolavic traits of SARS-CoV-2 infection.

positive: CytoResc – “CytoSorb” Rescue for critically ill patients undergoing the COVID-19 Cytokine Storm: A structured summary of a study protocol for a randomized controlled trial OBJECTIVES: Approximately 8 - 10 % of COVID-19 patients present with a serious clinical course and need for hospitalization, 8% of hospitalized patients need ICU-treatment. Currently, no causal therapy is available and treatment is purely supportive. The main reason for death in critically ill patients is acute respiratory failure. However, in a number of patients a severe hyperinflammatory response with excessively elevated proinflammatory cytokines causes vasoplegic shock resistant to vasopressor therapy. A new polystyrene-based hemoadsorber (CytoSorb®, Cytosorbents Inc., New Jersey, USA) has been shown to adsorb effectively cytokines and other middle molecular weight toxins this way reducing their blood concentrations. This has been routinely used in clinical practice in the EU for other conditions where a cytokine storm occurs and an observational study has just been completed on COVID-19 patients. We hypothesized that the extracorporeal elimination of cytokines in critically ill COVID-19 patients with suspected hyperinflammation and shock may stabilize hemodynamics and improve outcome. The primary endpoint is time until resolution of vasoplegic shock, which is a well implemented, clinically relevant endpoint in critical care studies. TRIAL DESIGN: Phase IIb, multicenter, prospective, open-label, randomized, 1:1 parallel group pilot study comparing the additional use of “CytoSorb” to standard of care without “CytoSorb”. PARTICIPANTS: Patients are recruited from the Intensive Care Units (ICUs) of 7 participating centers in Germany (approximately 10 ICUs). All patients aged 18- 80 with positive polymerase chain reaction (PCR) test for SARS-CoV-2, a C-reactive protein (CRP) ≥ 100 mg/l, a Procalcitonin (PCT) < 2 ng/l, and suspected cytokine storm defined via a vasoplegic shock (Norepinephrine > 0.2 μg/min/kg to achieve a Mean Arterial Pressure ≥ 65mmHg). Patients are included irrespective of indication for renal replacement therapy. Suspected or proven bacterial cause for vasoplegic shock is a contraindication. INTERVENTION AND COMPARATOR: Within 24 hours after meeting the inclusion criteria patients will be randomized to receive either standard of care or standard of care and additional “CytoSorb” therapy via a shaldon catheter for 3-7 days. Filter exchange is done every 24 hours. If patients receive antibiotics, an additional dose of antibiotics is administered after each change of “CytoSorb” filter in order to prevent underdosing due to “CytoSorb” treatment. MAIN OUTCOMES: Primary outcome is time to resolution of vasoplegic shock (defined as no need for vasopressors for at least 8 hours in order to sustain a MAP ≥ 65mmHg) in days. Secondary outcomes are 7 day mortality after fulfilling the inclusion criteria, mortality until hospital discharge, Interleukin-6 (IL-6) measurement on day 1 and 3, need for mechanical ventilation, duration of mechanical ventilation, duration of ICU-stay, catecholamine dose on day 1/2/3 after start of “CytoSorb” and acute kidney injury. RANDOMIZATION: An electronic randomization will be performed using the study software secuTrial® administered by the Clinical Study Center (CSC) of the Charité – Universitätsmedizin Berlin, Germany. Randomization is done in blocks by 4 stratified by including center. BLINDING (MASKING): The trial will be non-blinded for the clinicians and patients. The statistician will receive a blinded data set, so that all analyses will be conducted blinded. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): As this is a pilot study with the goal to examine the feasibility of the study design as well as the intervention effect, no formal sample size calculation was conducted. A total number of approximately 80-100 patients is planned (40-50 patients per group). Safety assessment is done after the inclusion of each 10 patients per randomization group. TRIAL STATUS: Please see the study protocol version from April 24 2020. Recruitment of patients is still pending. TRIAL REGISTRATION: The study was registered on April 27 2020 in the German Registry of Clinical Trials (DRKS) under the number DRKS00021447. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

positive: The cytokine storm of COVID-19: a spotlight on prevention and protection INTRODUCTION: The cytokine release syndrome (CRS) of COVID-19 is associated with the development of critical illness requiring multi-organ support. Further research is required to halt progression of multi-organ injury induced by hyper-inflammation. AREAS COVERED: PubMed/MEDLINETM databases were accessed between May 9th-June 9th, 2020, to review the latest perspectives on the treatment and pathogenesis of CRS. EXPERT OPINION: Over-activity of chemotaxis triggers a macrophage activation syndrome (MAS) resulting in the release of pro-inflammatory cytokines. IL-6 and TNF- α are at the forefront of hyper-inflammation. The inflammatory cascade induces endothelial activation and capillary leak, leading to circulatory collapse and shock. As endothelial dysfunction persists, there is activation of the clotting cascade and microvascular obstruction. Continued endothelial activation results in multi-organ failure, regardless of pulmonary tissue damage. We propose that targeting the endothelium may interrupt this cycle. Immuno-modulating therapies have been suggested, however, further data is necessary to confirm that they do not jeopardize adaptive immunity. Inhibition of IL-6 and the Janus Kinase, signal transducer and activator of transcription proteins pathway (JAK/STAT), are favorable targets. Remote ischemic conditioning (RIC) reduces the inflammation of sepsis in animal models and should be considered as a low risk intervention, in combination with cardiovascular protection.

positive: The cytokine storm and COVID‐19 Coronavirus disease 2019 (COVID‐19), which began in Wuhan, China in December 2019 has caused a large global pandemic and poses a serious threat to public health. More than four million cases of COVID‐19, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), have been confirmed as of May 11, 2020. SARS‐CoV‐2 is a highly pathogenic and transmissible coronavirus that primarily spreads through respiratory droplets and close contact. A growing body of clinical data suggests that a cytokine storm is associated with COVID‐19 severity and is also a crucial cause of death from COVID‐19. In the absence of antivirals and vaccines for COVID‐19, there is an urgent need to understand the cytokine storm in COVID‐19. Here, we have reviewed the current understanding of the features of SARS‐CoV‐2 and the pathological features, pathophysiological mechanisms, and treatments of the cytokine storm induced by COVID‐19. Additionally, we suggest that the identification and treatment of the cytokine storm are important components for rescuing patients with severe COVID‐19. This article is protected by copyright. All rights reserved.

positive: Lessons Learned to Date on COVID-19 Hyperinflammatory Syndrome: Considerations for Interventions to Mitigate SARS-CoV-2 Viral Infection and Detrimental Hyperinflammation The first case of human transmission of SARS-CoV-2 was reported in China in December 2019. A few months later, this viral infection had spread worldwide and became a pandemic. The disease caused by SARS-CoV-2, termed COVID-19, is multifactorial and associated with both specific antiviral as well as inflammatory responses, the extent of which may determine why some individuals are asymptomatic while others develop serious complications. Here we review possible life-threating immune events that can occur during disease progression to uncover key factors behind COVID-19 severity and provide suggestions for interventions with repurposed drugs in well-controlled and randomized clinical trials. These drugs include therapeutics with potential to inhibit SARS-CoV-2 entry into host cells such as serine protease inhibitors of the cellular protease TMPS2 and drugs targeting the renin-angiotensin system; antivirals with potential to block SARS-CoV-2 replication or factors that could boost the antiviral response; monoclonal antibodies targeting pro-inflammatory cytokines that drive the hyperinflammatory response during COVID-19 progression toward the severe stage and therapeutics that could ameliorate the function of the lungs. Furthermore, in order to help make more informed decisions on the timing of the intervention with the drugs listed in this review, we have grouped these therapeutics according to the stage of COVID-19 progression that we considered most appropriate for their mechanism of action.

positive: Longitudinal COVID-19 profiling associates IL-1RA and IL-10 with disease severity and RANTES with mild disease BACKGROUND: Identifying immune correlates of COVID-19 disease severity is an urgent need for clinical management, vaccine evaluation, and drug development. Here, we present a temporal analysis of key immune mediators, cytokines, and chemokines in blood of hospitalized COVID-19 patients from serial sampling and follow-up over 4 weeks. METHODS: A total of 71 patients with laboratory-confirmed COVID-19 admitted to Beijing You'an Hospital in China with either mild (53 patients) or severe (18 patients) disease were enrolled with 18 healthy volunteers. We measured 34 immune mediators, cytokines, and chemokines in peripheral blood every 4-7 days over 1 month per patient using a bioplex multiplex immunoassay. RESULTS: We found that the chemokine RANTES (CCL5) was significantly elevated, from an early stage of the infection, in patients with mild but not severe disease. We also found that early production of inhibitory mediators including IL-10 and IL-1RA were significantly associated with disease severity, and a combination of CCL5, IL-1 receptor antagonist (IL-1RA), and IL-10 at week 1 may predict patient outcomes. The majority of cytokines that are known to be associated with the cytokine storm in virus infections such as IL-6 and IFN-Î³ were only significantly elevated in the late stage of severe COVID-19 illness. TNF-α and GM-CSF showed no significant differences between severe and mild cases. CONCLUSION: Together, our data suggest that early intervention to increase expression of CCL5 may prevent patients from developing severe illness. Our data also suggest that measurement of levels of CCL5, as well as IL-1RA and IL-10 in blood individually and in combination, might be useful prognostic biomarkers to guide treatment strategies.

positive: Absence of severe complications from SARS-CoV-2 infection in children with rheumatic diseases treated with biologic drugs. We read with interest the Editorial by Cron and Chatam (1) suggesting a cytokine storm syndrome (CSS) occurring in response to SARS-CoV-2 infection and, consequently, a possible role for targeted approaches to blocking inflammatory cytokines.

positive: Alveolar macrophage dysfunction and cytokine storm in the pathogenesis of two severe COVID-19 patients BACKGROUND: The novel coronavirus pneumonia COVID-19 caused by SARS-CoV-2 infection could lead to a series of clinical symptoms and severe illnesses, including acute respiratory distress syndrome (ARDS) and fatal organ failure. We report the fundamental pathological investigation in the lungs and other organs of fatal cases for the mechanistic understanding of severe COVID-19 and the development of specific therapy in these cases. METHODS: The autopsy and pathological investigations of specimens were performed on bodies of two deceased cases with COVID-19. Gross anatomy and histological investigation by Hematoxylin and eosin (HE) stained were reviewed on each patient. Alcian blue/periodic acid-Schiff (AB-PAS) staining and Masson staining were performed for the examinations of mucus, fibrin and collagen fiber in lung tissues. Immunohistochemical staining was performed on the slides of lung tissues from two patients. Real-time PCR was performed to detect the infection of SARS-CoV-2. Flow cytometry analyses were performed to detect the direct binding of S protein and the expression of ACE2 on the cell surface of macrophages. FINDINGS: The main pathological features in lungs included extensive impairment of type I alveolar epithelial cells and atypical hyperplasia of type II alveolar cells, with formation of hyaline membrane, focal hemorrhage, exudation and pulmonary edema, and pulmonary consolidation. The mucous plug with fibrinous exudate in the alveoli and the dysfunction of alveolar macrophages were characteristic abnormalities. The type II alveolar epithelial cells and macrophages in alveoli and pulmonary hilum lymphoid tissue were infected by SARS-CoV-2. S protein of SARS-CoV-2 directly bound to the macrophage via the S-protein-ACE2 interaction. INTERPRETATION: Infection of alveolar macrophage by SARS-CoV-2 might be drivers of the "cytokine storm", which might result in damages in pulmonary tissues, heart and lung, and lead to the failure of multiple organs . FUNDING: Shanghai Guangci Translational Medical Research Development Foundation, Shanghai, China.

positive: Diarrhea and altered inflammatory cytokine pattern in severe COVID-19: impact on disease course and in-hospital mortality BACKGROUND: Dynamic changes of immunocyte subsets and inflammatory profiles in coronavirus disease 2019(COVID-19) patients with gastrointestinal symptoms were undetermined. METHODS: A single center retrospective analysis of 409 severe hospitalized COVID-19 patients from Jan 20 to Feb 29, 2020 was performed. The longitudinal characteristics of immune inflammatory cytokines in patients with/without diarrhea were analyzed. The relations of diarrhea and immuno-inflammatory factors with illness course and clinical outcomes were further explored. RESULTS: Diarrhea was more common and more serious with longer duration (4.9 ± 1.5 days vs 4.2 ± 1.5 days, P=0.039) and higher frequency (5.5 ± 2.1 times/day vs 4.0 ± 2.0 times/day, P=0.001) in deceased patients than in the survivors. Also, diarrhea patients were more inclined to develop multi-organ damage, who had longer illness course (media 41.0 days vs 36.0 days, P=0.052) and hospital stays (media 27.0 days vs 23.0 days, P=0.041) in survivors, and higher mortality (33.0% vs 22.6%, P=0.045) and earlier death (media 20.0 days vs 25.0 days, P=0.038) in the deceased patients. Progressively neutrophilia and lymphopenia, especially the declined CD8+ T cells, were demonstrated in diarrhea patients relative to the non-diarrhea cases. The inflammatory cytokines including IL-6, IL-10 and TNF-α were intensively increased in patients with diarrhea. The multivariable logistic analysis showed longer duration of diarrhea (P=0.036), higher neutrophil counts (P=0.011) and lower lymphocyte counts (P<0.001) were independent risk factors of in-hospital death. The proportional hazards model indicated longer duration of diarrhea (P=0.002), higher frequency of diarrhea (P=0.058), higher neutrophil counts (P=0.001), lower lymphocyte counts (P=0.035) and decreased proportion of CD8+ T cells (P<0.001) were independently associated with longer illness course of the survivors. CONCLUSIONS: Diarrhea patients were more likely to present with neutrophilia, lymphopenia and cytokine storm, and to develop multi-organ damage. The inflammatory patterns were independent factors associated with illness course of the survivors and in-hospital death of severe COVID-19.

positive: Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome Severe acute respiratory syndrome (SARS) is a recently emerged infectious disease caused by a novel coronavirus, but its immunopathological mechanisms have not yet been fully elucidated. We investigated changes in plasma T helper (Th) cell cytokines, inflammatory cytokines and chemokines in 20 patients diagnosed with SARS. Cytokine profile of SARS patients showed marked elevation of Th1 cytokine interferon (IFN)-γ, inflammatory cytokines interleukin (IL)-1, IL-6 and IL-12 for at least 2 weeks after disease onset, but there was no significant elevation of inflammatory cytokine tumour necrosis factor (TNF)-α, anti-inflammatory cytokine IL-10, Th1 cytokine IL-2 and Th2 cytokine IL-4. The chemokine profile demonstrated significant elevation of neutrophil chemokine IL-8, monocyte chemoattractant protein-1 (MCP-1), and Th1 chemokine IFN-γ-inducible protein-10 (IP-10). Corticosteroid reduced significantly IL-8, MCP-1 and IP-10 concentrations from 5 to 8 days after treatment (all P < 0·001). Together, the elevation of Th1 cytokine IFN-γ, inflammatory cytokines IL-1, IL-6 and IL-12 and chemokines IL-8, MCP-1 and IP-10 confirmed the activation of Th1 cell-mediated immunity and hyperinnate inflammatory response in SARS through the accumulation of monocytes/macrophages and neutrophils.

positive: Temporal clinical and laboratory response to interleukin-6 receptor blockade with Tocilizumab in 89 hospitalized patients with COVID-19 pneumonia Abstract: Background:. Emerging evidence links morbidity and mortality of pandemic COVID-19 pneumonia to an inflammatory cytokine storm. Methods: Eighty nine patients with COVID-19 pneumonia and heightened systemic inflammation (elevated serum C reactive protein and interleukin-6 levels) were treated with Tocilizumab (TCZ), a human monoclonal IgG1 antibody to the interleukin-6 receptor. Results: Clinical and laboratory improvement was seen comparing baseline and 1-2 day post-infusion indices. Among 72 patients not receiving mechanical ventilation, NEWS2 scores fell from 5 to 2 (p <0.001) C reactive protein levels fell from 95 to 14 mg/L (p <0.001) and lymphocyte counts rose from 900 to 1000/uL (p=0.036). Sixty three of 72 patients were discharged from hospital, one patient died, and 8 remained in hospital at time of writing. Among 17 patients receiving mechanical ventilation, despite a rapid decrease in CRP levels from 89 to 35 mg/L (p = 0.014) and early improvements in NEWS2 scores in 10 of 17, ten patients died and seven remain in hospital at time of writing. Overall, mortality was only seen in patients who had markedly elevated CRP levels (>30 mg/L) and low lymphocyte counts (<1000/uL) before TCZ administration. Conclusions: Inflammation and lymphocytopenia are linked to mortality in COVID-19. Inhibition of IL-6 activity by administration of Tocilizumab, an anti IL-6 receptor antibody is associated with rapid improvement in both CRP and lymphocyte counts and in clinical indices. Controlled clinical trials are needed to confirm the utility of IL-6 blockade in this setting. Additional interventions will be needed for patients requiring mechanical ventilation.

positive: Cytokine biomarkers of COVID-19 We used a new strategy to screen cytokines associated with SARS-CoV-2 infection. Cytokines that can classify populations in different states of SARS-CoV-2 infection were first screened in cross-sectional serum samples from 184 subjects by 2 statistical analyses. The resultant cytokines were then analyzed for their interrelationships and fluctuating features in sequential samples from 38 COVID-19 patients. Three cytokines, M-CSF, IL-8 and SCF, which were clustered into 3 different correlation groups and had relatively small fluctuations during SARS-CoV-2 infection, were selected for the construction of a multiclass classification model. This model discriminated healthy individuals and asymptomatic and nonsevere patients with accuracy of 77.4% but was not successful in classifying severe patients. Further searching led to a single cytokine, hepatocyte growth factor (HGF), which classified severe from nonsevere COVID-19 patients with a sensitivity of 84.6% and a specificity of 97.9% under a cutoff value of 1128 pg/ml. The level of this cytokine did not increase in nonsevere patients but was significantly elevated in severe patients. Considering its potent antiinflammatory function, we suggest that HGF might be a new candidate therapy for critical COVID-19. In addition, our new strategy provides not only a rational and effective way to focus on certain cytokine biomarkers for infectious diseases but also a new opportunity to probe the modulation of cytokines in the immune response.

positive: Free DNA, a reason for severe COVID-19 infection? The fast-growing outbreak of 2019 novel coronaviruses (SARS-CoV-2) reached all continents except the Antarctica in merely three months. Severe SARS-CoV-2 infection (COVID-19) has a bad clinical outcome, and some reports emphasized the role of cytokine storm and dysfunctions of multiple organs. However, the etiology of severe COVID-19 has been largely unknown. Similar as SARS-CoV and MERS-CoV, SARS-CoV-2 is also thought derived from bat coronaviruses. However, it is not pathogenic for bat at all, because free DNA in cytoplasm or blood cannot bring up violent immune response in bat; but it can produce severe inflammations in human. I hypothesized that the damage induced by free DNA is a reason for severe COVID-19, which can explain many symptoms of this disease, such as cytokine storm, acute respiratory distress syndrome (ARDS) and muscus plug, acute injuries of heart, liver and kidney, and some special symptoms of COVID-19. My hypothesis will be helpful for better understand the etiology of severe COVID-19.

positive: Elevation of Intact and Proteolytic Fragments of Acute Phase Proteins Constitutes the Earliest Systemic Antiviral Response in HIV-1 Infection The earliest immune responses activated in acute human immunodeficiency virus type 1 infection (AHI) exert a critical influence on subsequent virus spread or containment. During this time frame, components of the innate immune system such as macrophages and DCs, NK cells, β-defensins, complement and other anti-microbial factors, which have all been implicated in modulating HIV infection, may play particularly important roles. A proteomics-based screen was performed on a cohort from whom samples were available at time points prior to the earliest positive HIV detection. The ability of selected factors found to be elevated in the plasma during AHI to inhibit HIV-1 replication was analyzed using in vitro PBMC and DC infection models. Analysis of unique plasma donor panels spanning the eclipse and viral expansion phases revealed very early alterations in plasma proteins in AHI. Induction of acute phase protein serum amyloid A (A-SAA) occurred as early as 5–7 days prior to the first detection of plasma viral RNA, considerably prior to any elevation in systemic cytokine levels. Furthermore, a proteolytic fragment of alpha–1-antitrypsin (AAT), termed virus inhibitory peptide (VIRIP), was observed in plasma coincident with viremia. Both A-SAA and VIRIP have anti-viral activity in vitro and quantitation of their plasma levels indicated that circulating concentrations are likely to be within the range of their inhibitory activity. Our results provide evidence for a first wave of host anti-viral defense occurring in the eclipse phase of AHI prior to systemic activation of other immune responses. Insights gained into the mechanism of action of acute-phase reactants and other innate molecules against HIV and how they are induced could be exploited for the future development of more efficient prophylactic vaccine strategies.

positive: In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) BACKGROUND: The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) first broke out in Wuhan (China) and subsequently spread worldwide. Chloroquine has been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late-phase in critically ill SARS-CoV-2 infected patients. Currently, there is no evidence to support the use of hydroxychloroquine in SARS-CoV-2 infection. METHODS: The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2 infected Vero cells. Physiologically-based pharmacokinetic models (PBPK) were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen whilst considering the drug’s safety profile. RESULTS: Hydroxychloroquine (EC(50)=0.72 μM) was found to be more potent than chloroquine (EC(50)=5.47 μM) in vitro. Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached three times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance. CONCLUSIONS: Hydroxychloroquine was found to be more potent than chloroquine to inhibit SARS-CoV-2 in vitro.

positive: Immune environment modulation in pneumonia patients caused by coronavirus: SARS-CoV, MERS-CoV and SARS-CoV-2 Currently, we are on a global pandemic of Coronavirus disease-2019 (COVID-19) which causes fever, dry cough, fatigue and acute respiratory distress syndrome (ARDS) that may ultimately lead to the death of the infected. Current researches on COVID-19 continue to highlight the necessity for further understanding the virus-host synergies. In this study, we have highlighted the key cytokines induced by coronavirus infections. We have demonstrated that genes coding interleukins (Il-1α, Il-1ß, Il-6, Il-10), chemokine (Ccl2, Ccl3, Ccl5, Ccl10), and interferon (Ifn-α2, Ifn-ß1, Ifn2) upsurge significantly which in line with the elevated infiltration of T cells, NK cells and monocytes in SARS-Cov treated group at 24 hours. Also, interleukins (IL-6, IL-23α, IL-10, IL-7, IL-1α, IL-1ß) and interferon (IFN-α2, IFN2, IFN-Î³) have increased dramatically in MERS-Cov at 24 hours. A similar cytokine profile showed the cytokine storm served a critical role in the infection process. Subsequent investigation of 463 patients with COVID-19 disease revealed the decreased amount of total lymphocytes, CD3+, CD4+, and CD8+ T lymphocytes in the severe type patients which indicated COVID-19 can impose hard blows on human lymphocyte resulting in lethal pneumonia. Thus, taking control of changes in immune factors could be critical in the treatment of COVID-19.

positive: COVID-19 – Considerations for the paediatric rheumatologist Abstract The novel coronavirus SARS-CoV2 is a threat to the health and well-being of millions of lifes across the globe. A significant proportion of adult patients require hospitalisation and may develop severe life-threatening complications. Children, on the other hand, can carry and transmit the virus, but usually do not develop severe disease. Mortality in the paediatric age-group is relatively low. Differences in virus containment and clearance, as well as reduced inflammation-related tissue and organ damage may be caused by age-specific environmental and host factors. Since severe complications in adults are frequently caused by uncontrolled immune responses and a resulting “cytokine storm” that may be controlled by targeted blockade of cytokines, previously established treatment with immunosuppressive treatments may indeed protect children from complications.

positive: Use of Tocilizumab for COVID-19-Induced Cytokine Release Syndrome: A Cautionary Case Report Novel coronavirus disease 2019 (COVID-19) emerged in late December 2019 in Wuhan, China. Since then, COVID-19 has become a pandemic affecting more than 1.5 million people worldwide. Patients with COVID-19 have a wide spectrum of manifestations, one being cytokine release syndrome (CRS) and its fatal correlate, secondary hemophagocytic lymphohistiocytosis (sHLH). Anti-cytokine therapy such as tocilizumab, an IL-6 receptor antagonist, is a potential treatment for COVID-19; however, data regarding the efficacy of this anti-IL-6 therapy are currently lacking. We report two cases of patients who received a diagnosis of COVID-19 complicated by CRS and were treated with tocilizumab. Both patients progressed to sHLH despite treatment with tocilizumab, and one developed viral myocarditis, challenging the safety and clinical usefulness of tocilizumab in the treatment of COVID-19-induced CRS. These cases highlight the need for clinical trials to determine optimal patient selection and timing for the use of tocilizumab during this disease process.

positive: Pathophysiology of Acute Illness and Injury The pathophysiology of acute illness and injury recognizes three main effectors: infection, trauma, and ischemia-reperfusion injury. Each of them can act by itself or in combination with the other two in developing a systemic inflammatory reaction syndrome (SIRS) that is a generalized reaction to the morbid event. The time course of SIRS is variable and influenced by the number and severity of subsequent insults (e.g., reparative surgery, acquired hospital infections). It occurs simultaneously with a complex of counter-regulatory mechanisms (compensatory anti-inflammatory response syndrome, CARS) that limit the aggressive effects of SIRS. In adjunct, a progressive dysfunction of the acquired (lymphocytes) immune system develops with increased risk for immunoparalysis and associated infectious complications. Both humoral and cellular effectors participate to the development of SIRS and CARS. The most important humoral mediators are pro-inflammatory (IL-1β, IL-6, IL-8, IL-12) and anti-inflammatory (IL-4, IL-10) cytokines and chemokines, complement, leukotrienes, and PAF. Effector cells include neutrophils, monocytes, macrophages, lymphocytes, and endothelial cells. The endothelium is a key factor for production of remote organ damage as it exerts potent chemo-attracting effects on inflammatory cells, allows for leukocyte trafficking into tissues and organs, and promotes further inflammation by cytokines release. Moreover, the loss of vasoregulatory properties and the increased permeability contribute to the development of hypotension and tissue edema. Finally, the disseminated activation of the coagulation cascade causes the widespread deposition of microthrombi with resulting maldistribution of capillary blood flow and ultimately hypoxic cellular damage. This mechanism together with increased vascular permeability and vasodilation is responsible for the development of the multiple organ dysfunction syndrome (MODS).

positive: Literature-based review of the drugs used for the treatment of COVID-19 COVID-19 is primarily a respiratory disease caused by a newly discovered SARS-CoV-2 virus and identified in the city of Wuhan, China in December 2019. WHO has declared this disease as a pandemic, and warned other countries. Presently this has affected 216 countries, areas or territories worldwide, spreading of this disease is very fast in USA, Brazil, and Russia than in the country of its origin, China. Like other coronaviruses, this may develop respiratory tract infections in the patients range from mild to fatal illness like pneumonia and acute respiratory distress syndrome (ARDS). As of now, no effective drug, vaccine, or any procedure is available and experiments are underway. However, empirical therapy is being followed to manage and save the lives of the patients. There is a need for pharmacological alternatives to combat this deadly virus and its complications. Based on the previous experiences with similar coronavirus management and present preliminary data from uncontrolled studies, drugs like chloroquine, hydroxychloroquine, remdesivir, lopinavir/ritonavir, and favipiravir have been recommended by the researchers to manage COVID-19. This review had assessed the potential mechanisms, safety profile, availability and cost of these drugs. This review concludes that the drugs mentioned above are having different properties and act differently in combating the COVID-19 viruses. Instead of single drug, combination of antivirals with different mechanism of action may be more effective and at the same time their adverse events should not be underestimated.

positive: Increased serum levels of sCD14 and sCD163 indicate a preponderant role for monocytes in COVID-19 immunopathology Background. Emerging evidence indicates a potential role for monocyte in COVID-19 immunopathology. We investigated two soluble markers of monocyte activation, sCD14 and sCD163, in covid19 patients with the aim of characterizing their potential role in monocyte-macrophage disease immunopathology. To the best of our knowledge, this is the first study of its kind. Methods. Fifty-nine SARS-Cov-2 positive hospitalized patients, classified according to ICU or non-ICU admission requirement, were prospectively recruited and analyzed by ELISA for levels of sCD14 and sCD163, along with other laboratory parameters, and compared to a healthy control group. Results. sCD14 and sCD163 levels were significantly higher among COVID-19 patients, independently of ICU admission requirement, compared to the control group. We found a significant correlation between sCD14 levels and other inflammatory markers, particularly Interleukin-6, in the non-ICU patients group. sCD163 showed a moderate positive correlation with the time at sampling from admission, increasing its value over time, independently of severity group. Conclusions. Monocyte-macrophage activation markers are increased and correlate with other inflammatory markers in SARS-Cov-2 infection, in association to hospital admission. These data suggest a potentially preponderant role for monocyte-macrophage activation in the development of immunopathology of covid19 patients.

positive: Myocardial injury and COVID-19: Possible mechanisms Coronavirus Disease 2019 (COVID-19) has quickly progressed to a global health emergency. Respiratory illness is the major cause of morbidity and mortality in these patients with the disease spectrum ranging from asymptomatic subclinical infection, to severe pneumonia progressing to acute respiratory distress syndrome. There is growing evidence describing pathophysiological resemblance of SARS-CoV-2 infection with other coronavirus infections such as Severe Acute Respiratory Syndrome coronavirus and Middle East Respiratory Syndrome coronavirus (MERS-CoV). Angiotensin Converting Enzyme-2 receptors play a pivotal role in the pathogenesis of the virus. Disruption of this receptor leads to cardiomyopathy, cardiac dysfunction, and heart failure. Patients with cardiovascular disease are more likely to be infected with SARS-CoV-2 and they are more likely to develop severe symptoms. Hypertension, arrhythmia, cardiomyopathy and coronary heart disease are amongst major cardiovascular disease comorbidities seen in severe cases of COVID-19. There is growing literature exploring cardiac involvement in SARS-CoV-2. Myocardial injury is one of the important pathogenic features of COVID-19. As a surrogate for myocardial injury, multiple studies have shown increased cardiac biomarkers mainly cardiac troponins I and T in the infected patients especially those with severe disease. Myocarditis is depicted as another cause of morbidity amongst COVID-19 patients. The exact mechanisms of how SARS-CoV-2 can cause myocardial injury are not clearly understood. The proposed mechanisms of myocardial injury are direct damage to the cardiomyocytes, systemic inflammation, myocardial interstitial fibrosis, interferon mediated immune response, exaggerated cytokine response by Type 1 and 2 helper T cells, in addition to coronary plaque destabilization, and hypoxia.

positive: Therapeutic Potential of B-1a Cells in COVID-19. Coronavirus disease 2019 (COVID-19) is a life-threatening respiratory illness caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Its clinical presentation can vary from the asymptomatic state to acute respiratory distress syndrome (ARDS) and multi-organ dysfunction. Due to our insufficient understanding of its pathophysiology and lack of effective treatment, the morbidity and mortality of severe COVID-19 patients are high. Patients with COVID-19 develop ARDS fueled by exaggerated neutrophil influx into the lungs and cytokine storm. B-1a cells represent a unique subpopulation of B lymphocytes critical for circulating natural antibodies, innate immunity, and immunoregulation. These cells spontaneously produce natural IgM, interleukin (IL)-10, and granulocyte-monocyte colony stimulating factor (GM-CSF). Natural IgM neutralizes viruses and opsonizes bacteria, IL-10 attenuates the cytokine storm, and GM-CSF induces IgM production by B-1a cells in an autocrine manner. Indeed, B-1a cells have been shown to ameliorate influenza virus infection, sepsis, and pneumonia, all of which are similar to COVID-19. The recent discovery of B-1a cells in humans further reinforces their potentially critical role in the immune response against SARS-CoV-2 and their anticipated translational applications against viral and microbial infections. Given that B-1a cells protect against ARDS via immunoglobulin production and the anti-COVID-19 effects of convalescent plasma treatment, we recommend that studies be conducted to further examine the role of B-1a cells in the pathogenesis of COVID-19 and explore their therapeutic potential to treat COVID-19 patients.

positive: Cytokines and the still-baffling clinical biology of COVID-19

positive: Mesenchymal stem cell therapy in severe COVID-19: a retrospective study of short-term treatment efficacy and side effects

positive: COVID-19: A New Virus, but a Familiar Receptor and Cytokine Release Syndrome Zhou et al. (Nature) and Hoffmann et al. (Cell) identify ACE2 as a SARS-CoV-2 receptor, and the latter show its entry mechanism depends on cellular serine protease TMPRSS2. These results may explain proinflammatory cytokine release via the associated angiotestin II pathway and a possible therapeutic target via the IL-6-STAT3 axis.

positive: The unique characteristics of COVID-19 coagulopathy Thrombotic complications and coagulopathy frequently occur in COVID-19. However, the characteristics of COVID-19-associated coagulopathy (CAC) are distinct from those seen with bacterial sepsis-induced coagulopathy (SIC) and disseminated intravascular coagulation (DIC), with CAC usually showing increased D-dimer and fibrinogen levels but initially minimal abnormalities in prothrombin time and platelet count. Venous thromboembolism and arterial thrombosis are more frequent in CAC compared to SIC/DIC. Clinical and laboratory features of CAC overlap somewhat with a hemophagocytic syndrome, antiphospholipid syndrome, and thrombotic microangiopathy. We summarize the key characteristics of representative coagulopathies, discussing similarities and differences so as to define the unique character of CAC.

positive: Is Adipose Tissue a Reservoir for Viral Spread, Immune Activation, and Cytokine Amplification in Coronavirus Disease 2019? Coronavirus disease 2019 (COVID-19), the worst pandemic in more than a century, has claimed >125,000 lives worldwide to date. Emerging predictors for poor outcomes include advanced age, male sex, preexisting cardiovascular disease, and risk factors including hypertension, diabetes, and, more recently, obesity. This article posits new obesity-driven predictors of poor COVID-19 outcomes, over and above the more obvious extant risks associated with obesity, including cardiometabolic disease and hypoventilation syndrome in intensive care patients. This article also outlines a theoretical mechanistic framework whereby adipose tissue in individuals with obesity may act as a reservoir for more extensive viral spread, with increased shedding, immune activation, and cytokine amplification. This paper proposes studies to test this reservoir concept with a focus on specific cytokine pathways that might be amplified in individuals with obesity and COVID-19. Finally, this paper underscores emerging therapeutic strategies that might benefit subsets of patients in which cytokine amplification is excessive and potentially fatal.

positive: Inflammation resolution: a dual-pronged approach to averting cytokine storms in COVID-19? Severe coronavirus disease (COVID-19) is characterized by pulmonary hyper-inflammation and potentially life-threatening "cytokine storms". Controlling the local and systemic inflammatory response in COVID-19 may be as important as anti-viral therapies. Endogenous lipid autacoid mediators, referred to as eicosanoids, play a critical role in the induction of inflammation and pro-inflammatory cytokine production. SARS-CoV-2 may trigger a cell death ("debris")-induced "eicosanoid storm", including prostaglandins and leukotrienes, which in turn initiates a robust inflammatory response. A paradigm shift is emerging in our understanding of the resolution of inflammation as an active biochemical process with the discovery of novel endogenous specialized pro-resolving lipid autacoid mediators (SPMs), such as resolvins. Resolvins and other SPMs stimulate macrophage-mediated clearance of debris and counter pro-inflammatory cytokine production, a process called inflammation resolution. SPMs and their lipid precursors exhibit anti-viral activity at nanogram doses in the setting of influenza without being immunosuppressive. SPMs also promote anti-viral B cell antibodies and lymphocyte activity, highlighting their potential use in the treatment of COVID-19. Soluble epoxide hydrolase (sEH) inhibitors stabilize arachidonic acid-derived epoxyeicosatrienoic acids (EETs), which also stimulate inflammation resolution by promoting the production of pro-resolution mediators, activating anti-inflammatory processes, and preventing the cytokine storm. Both resolvins and EETs also attenuate pathological thrombosis and promote clot removal, which is emerging as a key pathology of COVID-19 infection. Thus, both SPMs and sEH inhibitors may promote the resolution of inflammation in COVID-19, thereby reducing acute respiratory distress syndrome (ARDS) and other life-threatening complications associated with robust viral-induced inflammation. While most COVID-19 clinical trials focus on "anti-viral" and "anti-inflammatory" strategies, stimulating inflammation resolution is a novel host-centric therapeutic avenue. Importantly, SPMs and sEH inhibitors are currently in clinical trials for other inflammatory diseases and could be rapidly translated for the management of COVID-19 via debris clearance and inflammatory cytokine suppression. Here, we discuss using pro-resolution mediators as a potential complement to current anti-viral strategies for COVID-19.

positive: Effect of HA330 resin-directed hemoadsorption on a porcine acute respiratory distress syndrome model BACKGROUND: Blood purification is an emerging approach to dampening the cytokine storm. This study aims to assess the efficacy of HA330 resin-directed hemoadsorption (HA) on endotoxin-induced porcine acute respiratory distress syndrome (ARDS) model. METHODS: Twenty-four Chinese domestic pigs were allocated into saline group receiving intravenous infusion of saline (N = 6) and endotoxin group receiving intravenous infusion of LPS (N = 18). When ALI model was initially diagnosed, six pigs in the LPS and saline group were killed for BALF and histopathological analysis. The remaining 12 pigs in LPS group received 3-h HA (N = 6) or HA-sham (N = 6) treatment, respectively. Following another 5-h observation, animals were killed. Variables on hemodynamics, blood gases and lung mechanics were recorded at a series of time points. Differentially expressed cytokines and proteins were determined by ELISA and proteomics. RESULTS: HA treatment significantly improved injured oxygenation induced by LPS. HA also partially improved the barrier permeability and reduced lung edema and inflammation/injury induced by LPS infusion. Proteomic analysis showed the differentially expressed proteins between HA- and HA-sham-treated groups mostly belonged to the categories of acute inflammation/immune response, and proteolysis. CONCLUSIONS: Hemoadsorption improved ARDS possibly by blunting the cytokine storm and by restoring homeostasis of the disordered proteome milieu in the exudative phase. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13613-017-0287-0) contains supplementary material, which is available to authorized users.

positive: Rationale for Evaluating PDE4 Inhibition for Mitigating against Severe Inflammation in COVID-19 Pneumonia and Beyond. BACKGROUND In the absence of definitive anti-viral therapy, there is considerable interest in mitigating against severe inflammatory reactions in coronavirus disease-2019 (COVID-19) pneumonia to improve survival. These reactions are sometimes termed cytokine storm. PDE4 inhibitors (PDE4i) have anti-inflammatory properties with approved indications in inflammatory skin and joint diseases as well as chronic obstructive pulmonary disease (COPD). Furthermore, multiple animal models demonstrate strong anti-inflammatory effects of PDE4i in respiratory models of viral and bacterial infection and also after chemically mediated lung injury. The rationale for PDE4i use in COVID-19 patients comes from the multimodal mechanism of action with cytokine, chemokine, and other key pathway inhibition all achieved with an excellent safety profile. We highlight how PDE4i could be an overlooked treatment from the rheumatologic and respiratory armamentarium, which has potential beneficial immune-modulation for treating severe COVID-19 pneumonia associated with cytokine storms. The proposed use of PDE4i is also supported by age-related immune changes in inflammation severity in PDE4i modifiable pathways in primate coronavirus disease. In conclusion, over-exuberant anti-viral immune responses in older patients with COVID-19 may pose a substantial risk to patient survival and mitigation against such hyper-inflammation with PDE4i, especially with anti-viral agents, is a strategy that need to be pursed, especially in older patients.

positive: Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients Infection caused by SARS-CoV-2 can result in severe respiratory complications and death. Patients with a compromised immune system are expected to be more susceptible to a severe disease course. In this report we suggest that patients with systemic lupus erythematous might be especially prone to severe COVID-19 independent of their immunosuppressed state from lupus treatment. Specially, we provide evidence in lupus to suggest hypomethylation and overexpression of ACE2, which is located on the X chromosome and encodes a functional receptor for the SARS-CoV-2 spike glycoprotein. Oxidative stress induced by viral infections exacerbates the DNA methylation defect in lupus, possibly resulting in further ACE2 hypomethylation and enhanced viremia. In addition, demethylation of interferon-regulated genes, NF{kappa}B, and key cytokine genes in lupus patients might exacerbate the immune response to SARS-CoV-2 and increase the likelihood of cytokine storm. These arguments suggest that inherent epigenetic dysregulation in lupus might facilitate viral entry, viremia, and an excessive immune response to SARS-CoV-2. Further, maintaining disease remission in lupus patients is critical to prevent a vicious cycle of demethylation and increased oxidative stress, which will exacerbate susceptibility to SARS-CoV-2 infection during the current pandemic. Epigenetic control of the ACE2 gene might be a target for prevention and therapy in COVID-19.

positive: Eficacia de los pulsos de corticoides en pacientes con síndrome de liberación de citocinas inducido por infección por SARS-CoV-2 INTRODUCTION: Cytokine storm syndrome (CSS) is a serious complication of COVID-19 patients Treatment is tocilizumab The use of glucocorticoids (GC) is controversial In other very similar CSS, such as macrophage activation syndrome (MAS) and hemophagocytic syndrome (HFS), the main treatment are corticosteroids Our objective is to evaluate the efficacy of GC in the CSS by COVID-19 PATIENTS: We included 92 patients with CSS associated to COVID-19 who received GC, GC, and tocilizumab and only tocilizumab We determine CSS markers We evaluated mortality, intubation, and a combined variable RESULTS: In all cases the percentages of events were lower in the group of patients with GC was administered The hazard ratio of the final variables with GC versus the group in which only tocilizumab was administered was lower as CGs were considered, with statistical significance for survival DISCUSSION: The early use of GC pulses could control SLC, with a lower requirement to use tocilizumab and a decrease in events such as intubation and death

positive: Myocardial injury and COVID-19: Possible mechanisms Abstract Coronavirus Disease 2019 (COVID-19) has quickly progressed to a global health emergency. Respiratory illness is the major cause of morbidity and mortality in these patients with the disease spectrum ranging from asymptomatic subclinical infection, to severe pneumonia progressing to acute respiratory distress syndrome. There is growing evidence describing pathophysiological resemblance of SARS-CoV-2 infection with other coronavirus infections such as Severe Acute Respiratory Syndrome coronavirus and Middle East Respiratory Syndrome coronavirus (MERS-CoV). Angiotensin Converting Enzyme-2 receptors play a pivotal role in the pathogenesis of the virus. Disruption of this receptor leads to cardiomyopathy, cardiac dysfunction, and heart failure. Patients with cardiovascular disease are more likely to be infected with SARS-CoV-2 and they are more likely to develop severe symptoms. Hypertension, arrhythmia, cardiomyopathy and coronary heart disease are amongst major cardiovascular disease comorbidities seen in severe cases of COVID-19. There is growing literature exploring cardiac involvement in SARS-CoV-2. Myocardial injury is one of the important pathogenic features of COVID-19. As a surrogate for myocardial injury, multiple studies have shown increased cardiac biomarkers mainly cardiac troponins I and T in the infected patients especially those with severe disease. Myocarditis is depicted as another cause of morbidity amongst COVID-19 patients. The exact mechanisms of how SARS-CoV-2 can cause myocardial injury are not clearly understood. The proposed mechanisms of myocardial injury are direct damage to the cardiomyocytes, systemic inflammation, myocardial interstitial fibrosis, interferon mediated immune response, exaggerated cytokine response by Type 1 and 2 helper T cells, in addition to coronary plaque destabilization, and hypoxia.

positive: Editorial: Nicotine and SARS-CoV-2: COVID-19 may be a disease of the nicotinic cholinergic system

positive: Novel paediatric presentation of COVID-19 with ARDS and cytokine storm syndrome without respiratory symptoms

positive: SARS-CoV-2 infection: The role of cytokines in COVID-19 disease COVID-19 disease, caused by infection with SARS-CoV-2, is related to a series of physiopathological mechanisms that mobilize a wide variety of biomolecules, mainly immunological in nature. In the most severe cases, the prognosis can be markedly worsened by the hyperproduction of mainly proinflammatory cytokines, such as IL-1, IL-6, IL-12, IFN-Î³, and TNF-α, preferentially targeting lung tissue. This study reviews published data on alterations in the expression of different cytokines in patients with COVID-19 who require admission to an intensive care unit. Data on the implication of cytokines in this disease and their effect on outcomes will support the design of more effective approaches to the management of COVID-19.

positive: Authors’ Reply to: Tocilizumab, Adipokines and Severe Complications of COVID-19

positive: Convalescent plasma in Covid-19: Possible mechanisms of action Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible of the coronavirus disease 2019 (COVID-19) pandemic. Therapeutic options including antimalarials, antivirals, and vaccines are under study. Meanwhile the current pandemic has called attention over old therapeutic tools to treat infectious diseases. Convalescent plasma (CP) constitutes the first option in the current situation, since it has been successfully used in other coronaviruses outbreaks. Herein, we discuss the possible mechanisms of action of CP and their repercussion in COVID-19 pathogenesis, including direct neutralization of the virus, control of an overactive immune system (i.e., cytokine storm, Th1/Th17 ratio, complement activation) and immunomodulation of a hypercoagulable state. All these benefits of CP are expected to be better achieved if used in non-critically hospitalized patients, in the hope of reducing morbidity and mortality.

positive: THE “PERFECT CYTOKINE STORM” OF COVID-19

positive: New understanding of the damage of SARS-CoV-2 infection outside the respiratory system Abstract Since early December 2019, a number of pneumonia cases associated with unknown coronavirus infection were identified in Wuhan, China, and many additional cases were identified in other regions of China and in other countries within 3 months. Currently, more than 80,000 cases have been diagnosed in China, including more than 3,000 deaths. The epidemic is spreading to the rest of the world, posing a grave challenge to prevention and control. On February 12, 2020, the International Committee on Taxonomy of Viruses and the World Health Organization officially named the novel coronavirus and associated pneumonia as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19), respectively. According to the recent research on SARS-CoV-2, the virus mainly infects the respiratory system but may cause damage to other systems. In this paper, we will systematically review the pathogenic features, transmission routes, and infection mechanisms of SARS-CoV-2, as well as any adverse effects on the digestive system, urogenital system, central nervous system, and circulatory system, in order to provide a theoretical and clinical basis for the diagnosis, classification, treatment, and prognosis assessment of SARS-CoV-2 infection.

positive: Potential Factors for Prediction of Disease Severity of COVID-19 Patients Abstract: Objective: Coronavirus disease 2019 (COVID-19) is an escalating global epidemic caused by SARS-CoV-2, with a high mortality in critical patients. Effective indicators for predicting disease severity in SARS-CoV-2 infected patients are urgently needed. Methods: In this study, 43 COVID-19 patients admitted in Chongqing Public Health Medical Center were involved. Demographic data, clinical features, and laboratory examinations were obtained through electronic medical records. Peripheral blood specimens were collected from COVID-19 patients and examined for lymphocyte subsets and cytokine profiles by flow cytometry. Potential contributing factors for prediction of disease severity were further analyzed. Results: A total of 43 COVID-19 patients were included in this study, including 29 mild patients and 14 sever patients. Severe patients were significantly older (61.9+/-9.4 vs 44.4+/-15.9) and had higher incidence in co-infection with bacteria compared to mild group (85.7%vs27.6%). Significantly more severe patients had the clinical symptoms of anhelation (78.6%) and asthma (71.4%). For laboratory examination, 57.1% severe cases showed significant reduction in lymphocyte count. The levels of Interluekin-6 (IL6), IL10, erythrocyte sedimentation rate (ESR) and D-Dimer (D-D) were significantly higher in severe patients than mild patients, while the level of albumin (ALB) was remarkably lower in severe patients. Further analysis demonstrated that ESR, D-D, age, ALB and IL6 were the major contributing factors for distinguishing severe patients from mild patients. Moreover, ESR was identified as the most powerful factor to predict disease progression of COVID-19 patients. Conclusion: Age and the levels of ESR, D-D, ALB and IL6 are closely related to the disease severity of COVID-19 patients. ESR can be used as a valuable indicator for distinguishing severe COVID-19 patients in early stage, so as to increase the survival of severe patients. Keyword: COVID-19, erythrocyte sedimentation rate, cytokines, lymphocytes

positive: TLR4 antagonist FP7 inhibits LPS-induced cytokine production and glycolytic reprogramming in dendritic cells, and protects mice from lethal influenza infection Dysregulated Toll-like receptor (TLR)-4 activation is involved in acute systemic sepsis, chronic inflammatory diseases, such as atherosclerosis and diabetes, and in viral infections, such as influenza infection. Thus, therapeutic control of the TLR4 signalling pathway is of major interest. Here we tested the activity of the small-molecule synthetic TLR4 antagonist, FP7, in vitro on human monocytes and monocyte-derived dendritic cells (DCs) and in vivo during influenza virus infection of mice. Our results indicate that FP7 antagonized the secretion of proinflammatory cytokines (IL-6, IL-8, and MIP-1β) by monocytes and DCs (IC(50) < 1 μM) and prevented DC maturation upon TLR4 activation by ultrapure lipopolysaccharide (LPS). FP7 selectively blocked TLR4 stimulation, but not TLR1/2, TLR2/6, or TLR3 activation. TLR4 stimulation of human DCs resulted in increased glycolytic activity that was also antagonized by FP7. FP7 protected mice from influenza virus-induced lethality and reduced both proinflammatory cytokine gene expression in the lungs and acute lung injury (ALI). Therefore, FP7 can antagonize TLR4 activation in vitro and protect mice from severe influenza infection, most likely by reducing TLR4-dependent cytokine storm mediated by damage-associated molecular patterns (DAMPs) like HMGB1.

positive: A strategy targeting monocyte-macrophage differentiation to avoid pulmonary complications in SARS-Cov2 infection

positive: The role of interleukin‐6 in monitoring severe case of coronavirus disease 2019 Progression to severe disease is a difficult problem in treating coronavirus disease 2019 (COVID‐19). The purpose of this study is to explore changes in markers of severe disease in COVID‐19 patients. Sixty‐nine severe COVID‐19 patients were included. Patients with severe disease showed significant lymphocytopenia. Elevated level of lactate dehydrogenase (LDH), C‐reactive protein (CRP), ferritin, and D‐dimer was found in most severe cases. Baseline interleukin‐6 (IL‐6) was found to be associated with COVID‐19 severity. Indeed, the significant increase of baseline IL‐6 was positively correlated with the maximal body temperature during hospitalization and with the increased baseline of CRP, LDH, ferritin, and D‐dimer. High baseline IL‐6 was also associated with more progressed chest computed tomography (CT) findings. Significant decrease in IL‐6 and improved CT assessment was found in patients during recovery, while IL‐6 was further increased in exacerbated patients. Collectively, our results suggest that the dynamic change in IL‐6 can be used as a marker for disease monitoring in patients with severe COVID‐19.

positive: Why does COVID-19 disproportionately affect older people? The severity and outcome of coronavirus disease 2019 (COVID-19) largely depends on a patient’s age. Adults over 65 years of age represent 80% of hospitalizations and have a 23-fold greater risk of death than those under 65. In the clinic, COVID-19 patients most commonly present with fever, cough and dyspnea, and from there the disease can progress to acute respiratory distress syndrome, lung consolidation, cytokine release syndrome, endotheliitis, coagulopathy, multiple organ failure and death. Comorbidities such as cardiovascular disease, diabetes and obesity increase the chances of fatal disease, but they alone do not explain why age is an independent risk factor. Here, we present the molecular differences between young, middle-aged and older people that may explain why COVID-19 is a mild illness in some but life-threatening in others. We also discuss several biological age clocks that could be used in conjunction with genetic tests to identify both the mechanisms of the disease and individuals most at risk. Finally, based on these mechanisms, we discuss treatments that could increase the survival of older people, not simply by inhibiting the virus, but by restoring patients’ ability to clear the infection and effectively regulate immune responses.

positive: Iron: Innocent bystander or vicious culprit in COVID-19 pathogenesis? The coronavirus 2 (SARS-CoV-2) pandemic is viciously spreading through the continents with rapidly increasing mortality rates. Current management of COVID-19 is based on that respiratory failure is the leading cause of mortality. However, mounting evidence link accelerated pathogenesis in gravely ill COVID-19 patients to a hyper-inflammatory state involving a cytokine storm. Several components of the heightened inflammatory state were addressed as therapeutic targets. Another key component of the heightened inflammatory state is hyper-ferritinemia which reportedly identifies patients with increased mortality risk. In spite of its strong association with mortality, it is not yet clear if hyper-ferritinemia in COVID-19 patients is merely a systemic marker of disease progression, or a key modulator in disease pathogenesis. Here we address implications of a possible role for hyper-ferritinemia, and altered iron homeostasis in COVID-19 pathogenesis, and potential therapeutic targets in this regard.

positive: Favorable COVID‐19 course despite significant comorbidities in a ruxolitinib‐treated patient with primary myelofibrosis COVID‐19 carries a high risk of severe disease course, particularly in patients with comorbidities. Therapy of severe COVID‐19 infection has relied on supportive intensive care measures. More specific approaches including drugs that limit the detrimental “cytokine storm”, such as Janus‐activated kinase (JAK) inhibitors, are being discussed. Here, we report a compelling case of a 55‐yo patient with proven COVID‐19 pneumonia, who was taking the JAK1/2 inhibitor ruxolitinib in‐label for co‐existing primary myelofibrosis for 15 months prior to coronavirus infection. The patient had significant comorbidities, including chronic kidney disease, arterial hypertension, and obesity, and our previous cohort suggested that he was thus at high risk for acute respiratory distress syndrome (ARDS) and death from COVID‐19. Since abrupt discontinuation of ruxolitinib may cause fatal cytokine storm and ARDS, ruxolitinib treatment was continued and was well tolerated, and the patient´s condition remained stable, without the need for mechanical ventilation or vasopressors. The patient became negative for SARS‐CoV‐2 and was discharged home after 15 days. In conclusion, our report provides clinical evidence that ruxolitinib treatment is feasible and can be beneficial in patients with COVID‐19 pneumonia, preventing cytokine storm and ARDS.

positive: Platelet-to-lymphocyte ratio is associated with prognosis in patients with coronavirus disease-19 Since December 2019, novel coronavirus infected pneumonia emerged in Wuhan city and rapidly spread throughout China. In severe novel coronavirus pneumonia cases, the number of platelets, their dynamic changes during the treatment, platelet-to-lymphocyte ratio (PLR) were a concern. We sought to describe the platelet feature of these cases. Single-center case series of the 30 hospitalized patients with confirmed coronavirus disease (COVID)-19 in Huizhou municipal central hospital from January 2020 to February 2020 were retrospectively analyzed. Demographic, clinical, blood routine results, other laboratory results, and treatment data were collected and analyzed. Outcomes of severe patients and nonsevere patients were compared. Univariate analysis showed that: age, platelet peaks, and PLR at peak platelet were the influencing factors in severe patients, multivariate analysis showed that the PLR value at peak platelet during treatment was an independent influencing factor in severe patients. The average hospitalization day of patients with platelet peaks during treatment was longer than those without platelet peaks (P < .05). The average age of patients with platelet peaks during treatment was older than those without platelet peaks (P < .05). The patients with significantly elevated platelets during treatment had longer average hospitalization days. And the higher PLR of patients during treatment had longer average hospitalization days. Single-center case series of the 30 hospitalized patients with confirmed COVID-19 in Huizhou Municipal Central Hospital, presumed that the number of platelets and their dynamic changes during the treatment may have a suggestion on the severity and prognosis of the disease. The patient with markedly elevated platelets and longer average hospitalization days may be related to the cytokine storm. The PLR of patients means the degree of cytokine storm, which might provide a new indicator in the monitoring in patients with COVID-19.

positive: Severe COVID-19 and aging: are monocytes the key? The ongoing pandemic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes a disproportionate number of severe cases and deaths in older adults. Severe SARS-CoV-2-associated disease (coronavirus disease 2019 (COVID-19)) was declared a pandemic by the World Health Organization in March 2020 and is characterized by cytokine storm, acute respiratory distress syndrome, and in some cases by systemic inflammation-related pathology. Currently, our knowledge of the determinants of severe COVID-19 is primarily observational. Here, I review emerging evidence to argue that monocytes, a circulating innate immune cell, are principal players in cytokine storm and associated pathologies in COVID-19. I also describe changes in monocyte function and phenotype that are characteristic of both aging and severe COVID-19, which suggests a potential mechanism underlying increased morbidity and mortality due to SARS-CoV-2 infection in older adults. The innate immune system is therefore a potentially important target for therapeutic treatment of COVID-19, but experimental studies are needed, and SARS-CoV-2 presents unique challenges for pre-clinical and mechanistic studies in vivo. The immediate establishment of colonies of SARS-CoV-2-susceptible animal models for aging studies, as well as strong collaborative efforts in the geroscience community, will be required in order to develop the therapies needed to combat severe COVID-19 in older adult populations.

positive: Indomethacin and resveratrol as potential treatment adjuncts for SARS‐CoV‐2/COVID‐19 The ongoing pandemic due to severe acute respiratory syndrome coronavirus type 2 (SARS‐CoV‐2, also known as COVID‐19) has led to unprecedented challenges for the global healthcare system. This novel coronavirus disease phenotype ranges from asymptomatic carriage to fulminant cytokine storm with respiratory failure, polyorgan dysfunction, and death. Severe disease is characterized by exuberant inflammation resulting from high circulating cytokines such as interleukin‐6 (IL‐6) and tumor necrosis factor (TNF). These inflammatory mediators are responsible for the detrimental effects on the immune, hematologic, respiratory, renal, gastrointestinal and other body systems. In addition to inhibition of viral replication, blunting this inflammatory response before overt cytokine storm is important to improve outcomes. Although there are upcoming promising agents such as remdesivir and convalescent plasma, inexpensive, safe, and widely available adjunct treatments to ameliorate disease burden would be welcome. Two potential antiinflammatory agents include indomethacin, which has been shown in experimental models to decrease canine coronavirus (CCoV) levels in dogs and exhibit antiviral activity against several other viruses, and the polyphenol, resveratrol, a potent antioxidant that has shown antiviral activity against several viruses.

positive: Pathophysiological Characteristics and Therapeutic Approaches for Pulmonary Injury and Cardiovascular Complications of Coronavirus Disease 2019 Abstract The pandemic of coronavirus disease 2019 (COVID-19) has emerged as a major health crisis, with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) having infected over a million people around the world within a few months of its identification as a human pathogen. Initially, SARS-CoV-2 infects cells in the respiratory system and causes inflammation and cell death. Subsequently, the virus spreads out and damages other vital organs and tissues, triggering a complicated spectrum of pathophysiological changes and symptoms, including cardiovascular complications. Acting as the receptor for SARS-CoV entering mammalian cells, angiotensin converting enzyme-2 (ACE2) plays a pivotal role in the regulation of cardiovascular cell function. Diverse clinical manifestations and laboratory abnormalities occur in patients with cardiovascular injury in COVID-19, characterizing the development of this complication, as well as providing clues to diagnosis and treatment. This review provides a summary of the rapidly appearing laboratory and clinical evidence for the pathophysiology and therapeutic approaches to COVID-19 pulmonary and cardiovascular complications.

positive: A current review of COVID-19 for the cardiovascular specialist Although coronavirus disease 2019 (COVID-19) predominantly disrupts the respiratory system, there is accumulating experience that the disease, particularly in its more severe manifestations, also affects the cardiovascular system. Cardiovascular risk factors and chronic cardiovascular conditions are prevalent among patients affected by COVID-19 and associated with adverse outcomes. However, whether pre-existing cardiovascular disease is an independent determinant of higher mortality risk with COVID-19 remains uncertain. Acute cardiac injury, manifest by increased blood levels of cardiac troponin, electrocardiographic abnormalities, or myocardial dysfunction, occurs in up to ~60% of hospitalized patients with severe COVID-19. Potential contributors to acute cardiac injury in the setting of COVID-19 include (1) acute changes in myocardial demand and supply due to tachycardia, hypotension, and hypoxemia resulting in type 2 myocardial infarction; (2) acute coronary syndrome due to acute atherothrombosis in a virally induced thrombotic and inflammatory milieu; (3) microvascular dysfunction due to diffuse microthrombi or vascular injury; (4) stress-related cardiomyopathy (Takotsubo syndrome); (5) nonischemic myocardial injury due to a hyperinflammatory cytokine storm; or (6) direct viral cardiomyocyte toxicity and myocarditis. Diffuse thrombosis is emerging as an important contributor to adverse outcomes in patients with COVID-19. Practitioners should be vigilant for cardiovascular complications of COVID-19. Monitoring may include serial cardiac troponin and natriuretic peptides, along with fibrinogen, D-dimer, and inflammatory biomarkers. Management decisions should rely on the clinical assessment for the probability of ongoing myocardial ischemia, as well as alternative nonischemic causes of injury, integrating the level of suspicion for COVID-19.

positive: An update on SARS-CoV-2/COVID-19 with particular reference to its clinical pathology, pathogenesis, immunopathology and mitigation strategies Coronavirus Disease 2019 (COVID-19), emerged in early December 2019 in China and became a pandemic situation worldwide by its rapid spread to more than 200 countries or territories. Bats are considered as the reservoir host, and the search of a probable intermediate host is still going on. The severe form of the infection is associated with death is mainly reported in older and immune-compromised patients with pre-existing disease history. Death in severe cases is attributed to respiratory failure associated with hyperinflammation. Cytokine storm syndrome associated with inflammation in response to SARS-CoV-2 infection is considered as the leading cause of mortality in COVID-19 patients. COVID-19 patients have thus higher levels of many proinflammatory cytokines and chemokines. The blood laboratory profile of the COVID-19 patients exhibits lymphopenia, leukopenia, thrombocytopenia, and RNAaemia, along with increased levels of aspartate aminotransferase. SARS-CoV-2 infection in pregnant women does not lead to fetus mortality, unlike other zoonotic coronaviruses such as SARS-CoV and MERS-CoV, and there is, to date, no evidence of intrauterine transmission to neonates. Rapid diagnostics have been developed, and significant efforts are being made to develop effective vaccines and therapeutics. In the absence of any virus-specific therapy, internationally, health care authorities are recommending the adoption of effective community mitigation measures to counter and contain this pandemic virus. This paper is an overview of this virus and the disease with a particular focus on SARS-CoV-2/COVID-19 clinical pathology, pathogenesis, and immunopathology, along with recent research developments.

positive: Vascular Endothelial Growth Factor (VEGF) as a Vital Target for Brain Inflammation during the COVID-19 Outbreak. The coronavirus disease 19 (COVID-19) pandemic has brought a great threat to global public health. Currently, mounting evidence has shown the occurrence of neurological symptoms in patients with COVID-19. However, the detailed mechanism by which the SARS-CoV-2 attacks the brain is not well characterized. Recent investigations have revealed that a cytokine storm contributes to brain inflammation and subsequently triggers neurological manifestations during the COVID-19 outbreak. Targeting brain inflammation may provide significant clues to the treatment of neurologic complications caused by SARS-CoV-2. Vascular growth factor (VEGF), which is widely distributed in the brain, probably plays a crucial role in brain inflammation via facilitating the recruitment of inflammatory cells and regulating the level of angiopoietins II (Ang II). Also, Ang II is considered as the products of SARS-CoV-2-attacking target, angiotensin-converting enzyme 2 (ACE2). Further investigation of the therapeutic potential and the underlying mechanisms of VEGF-targeted drugs on the neurological signs of COVID-19 are warranted. In any case, VEGF is deemed a promising therapeutic target in suppressing inflammation during SARS-CoV-2 infection with neurological symptoms.

positive: Countermeasures to COVID-19: Are immunomodulators rational treatment options — a critical review of the evidence Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with higher concentrations of pro-inflammatory cytokines which leads to lung damage, respiratory failure, and resultant increased mortality. Immunomodulatory therapy has the potential to inhibit cytokines and quell the immune dysregulation. Controversial data found improved oxygenation after treatment with tocilizumab, an IL-6 inhibitor, sparking a wave of interest and resultant clinical trials evaluating immunomodulatory therapies. The purpose of this article is to assess potential pro-inflammatory targets and review the safety and efficacy of immunomodulatory therapies in managing patients with acute respiratory distress syndrome associated with COVID-19.

positive: Thalidomide-Revisited: Are COVID-19 Patients Going to Be the Latest Victims of Yet Another Theoretical Drug-Repurposing? The coronavirus disease 2019 (COVID-19) pandemic is a worldwide threatening health issue. The progression of this viral infection occurs in the airways of the lungs with an exaggerated inflammatory response referred to as the “cytokine storm” that can lead to lethal lung injuries. In the absence of an effective anti-viral molecule and until the formulation of a successful vaccine, anti-inflammatory drugs might offer a complementary tool for controlling the associated complications of COVID-19 and thus decreasing the subsequent fatalities. Drug repurposing for several molecules has emerged as a rapid temporary solution for COVID-19. Among these drugs is Thalidomide; a historically emblematic controversial molecule that harbors an FDA approval for treating erythema nodosum leprosum (ENL) and multiple myeloma (MM). Based on just one-case report that presented positive outcomes in a patient treated amongst others with Thalidomide, two clinical trials on the efficacy and safety of Thalidomide in treating severe respiratory complications in COVID-19 patients were registered. Yet, the absence of substantial evidence on Thalidomide usage in that context along with the discontinued studies on the efficiency of this drug in similar pulmonary diseases, might cause a significant obstacle for carrying out further clinical evaluations. Herein, we will discuss the theoretical effectiveness of Thalidomide in attenuating inflammatory complications that are encountered in COVID-19 patients while pinpointing the lack of the needed evidences to move forward with this drug.

positive: [Advances in the research of cytokine storm mechanism induced by Corona Virus Disease 2019 and the corresponding immunotherapies]. Corona Virus Disease 2019 (COVID-19) has seriously affected the treatment of patients and social stability. In the later stage of disease, some COVID-19 patients may develop into acute respiratory distress syndrome or even multiple organ failure. However, one of the most important mechanism underlying the deterioration of disease is cytokine storm. At present, some therapies such as interleukin-6 antibody blocker, stem cell therapy, and transfusion of convalescent plasma have been applied to counteract the cytokine storm and have made some progress. This article reviews the influences of cytokine storm syndrome on the COVID-19 and the corresponding immunotherapies to resist cytokine storm.

positive: Cannabinoid Receptor Type 2: A Possible Target in SARS-CoV-2 (CoV-19) Infection? In late December 2019, a novel coronavirus (SARS-CoV-2 or CoV-19) appeared in Wuhan, China, causing a global pandemic. SARS-CoV-2 causes mild to severe respiratory tract inflammation, often developing into lung fibrosis with thrombosis in pulmonary small vessels and causing even death. COronaVIrus Disease (COVID-19) patients manifest exacerbated inflammatory and immune responses, cytokine storm, prevalence of pro-inflammatory M1 macrophages and increased levels of resident and circulating immune cells. Men show higher susceptibility to SARS-CoV-2 infection than women, likely due to estrogens production. The protective role of estrogens, as well as an immune-suppressive activity that limits the excessive inflammation, can be mediated by cannabinoid receptor type 2 (CB2). The role of this receptor in modulating inflammation and immune response is well documented in fact in several settings. The stimulation of CB2 receptors is known to limit the release of pro-inflammatory cytokines, shift the macrophage phenotype towards the anti-inflammatory M2 type and enhance the immune-modulating properties of mesenchymal stromal cells. For these reasons, we hypothesize that CB2 receptor can be a therapeutic target in COVID-19 pandemic emergency.

positive: The CoV-2 outbreak: how hematologists could help to fight Covid-19 Abstract COVID-19 is a medical emergency, with 20 % of patients presenting with severe clinical manifestations. From the pathogenetic point of view, COVID-19 mimics two other well-known diseases characterized by cytokine storm and hyper-activation of the immune response, with consequent organ damage: acute graft-versus-host disease (aGVHD) and macrophage activation syndrome (MAS). Hematologists are confident with these situations requiring a prompt therapeutic approach for switching off the uncontrolled cytokine release; here, we discuss pros and cons of drugs that are already employed in hematology in the light of their possible application in COVID-19. The most promising drugs might be: Ruxolitinib, a JAK1/2 inhibitor, with a rapid and powerful anti-cytokine effect, tyrosine kinase inhibitors (TKIs), with their good anti-inflammatory properties, and perhaps the anti-Cd26 antibody Begelomab. We also present immunological data from gene expression experiments where TKIs resulted effective anti-inflammatory and pro-immune drugs. A possible combined treatment algorithm for COVID-19 is here proposed.

positive: Tocilizumab treatment in COVID-19: A single center experience Tocilizumab (TCZ), a monoclonal antibody against interleukin-6 (IL-6), emerged as an alternative treatment for COVID-19 patients with a risk of cytokine storms recently. In the present study, we aimed to discuss the treatment response of TCZ therapy in COVID-19 infected patients. The demographic, treatment, laboratory parameters of C-reactive protein (CRP) and IL-6 before and after TCZ therapy and clinical outcome in the 15 COVID-19 patients were retrospectively assessed. Totally 15 patients with COVID-19 were included in this study. Two of them were moderately ill, six were seriously ill and seven were critically ill. The TCZ was used in combination with methylprednisolone in eight patients. Five patients received the TCZ administration twice or more. Although TCZ treatment ameliorated the increased CRP in all patients rapidly, for the four critically ill patients who received an only single dose of TCZ, three of them (No. 1, 2, and 3) still dead and the CRP level in the rest one patient (No. 7) failed to return to normal range with a clinical outcome of disease aggravation. Serum IL-6 level tended to further spiked firstly and then decreased after TCZ therapy in 10 patients. A persistent and dramatic increase of IL-6 was observed in these four patients who failed treatment. TCZ appears to be an effective treatment option in COVID-19 patients with a risk of cytokine storms. And for these critically ill patients with elevated IL-6, the repeated dose of the TCZ is recommended.

positive: The novel immunomodulatory biologic LMWF5A for pharmacological attenuation of the “cytokine storm” in COVID-19 patients: a hypothesis BACKGROUND: A common complication of viral pulmonary infections, such as in the ongoing COVID-19 pandemic, is a phenomenon described as a “cytokine storm”. While poorly defined, this hyperinflammatory response results in diffuse alveolar damage. The low molecular weight fraction of commercial human serum albumin (LMWF5A), a novel biologic in development for osteoarthritis, demonstrates beneficial in vitro immunomodulatory effects complimentary to addressing inflammation, thus, we hypothesize that LMWF5A could improve the clinical outcomes of COVID-19 by attenuating hyperinflammation and the potential development of a cytokine storm. PRESENTATION OF THE HYPOTHESIS: A variety of human in vitro immune models indicate that LMWF5A reduces the production of pro-inflammatory cytokines implicated in cytokine storm associated with COVID-19. Furthermore, evidence suggests LMWF5A also promotes the production of mediators required for resolving inflammation and enhances the barrier function of endothelial cultures. TESTING THE HYPOTHESIS: A randomized controlled trial, to evaluate the safety and efficacy of nebulized LMWF5A in adults with Acute Respiratory Distress Syndrome (ARDS) secondary to COVID-19 infection, was developed and is currently under review by the Food and Drug Administration. IMPLICATIONS OF HYPOTHESIS: If successful, this therapy may attenuate the cytokine storm observed in these patients and potentially reduce mortality, increase ventilation free days, improve oxygenation parameters and consequently lessen the burden on patients and the intensive care unit. CONCLUSIONS: In conclusion, in vitro findings suggest that the immunomodulatory effects of LMWF5A make it a viable candidate for treating cytokine storm and restoring homeostasis to the immune response in COVID-19.

positive: Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? The emergent outbreak of coronavirus disease 2019 (COVID-19) has caused a global pandemic. Acute respiratory distress syndrome (ARDS) and multiorgan dysfunction are among the leading causes of death in critically ill patients with COVID-19. The elevated inflammatory cytokines suggest that a cytokine storm, also known as cytokine release syndrome (CRS), may play a major role in the pathology of COVID-19. However, the efficacy of corticosteroids, commonly utilized antiinflammatory agents, to treat COVID-19-induced CRS is controversial. There is an urgent need for novel therapies to treat COVID-19-induced CRS. Here, we discuss the pathogenesis of severe acute respiratory syndrome (SARS)-induced CRS, compare the CRS in COVID-19 with that in SARS and Middle East respiratory syndrome (MERS), and summarize the existing therapies for CRS. We propose to utilize interleukin-6 (IL-6) blockade to manage COVID-19-induced CRS and discuss several factors that should be taken into consideration for its clinical application.

positive: Intravenous Vitamin C for reduction of cytokines storm in Acute Respiratory Distress Syndrome Abstract The recent outbreak of Covid19 has required urgent treatments for numerous patients. No suitable vaccines or antivirals are available for Covid19. The efficiency against Covid19 of WHO therapies of choice, that are two antivirals developed for other pathologies, is controversial. Therefore, alternative approaches are required. Intravenous (IV) Vitamin C (Vit-C) has emerged as one of the other alternatives for this purpose. Here we review the effects of IV Vit-C on the immune system response, the antiviral properties of IV Vit-C, and finally the antioxidant properties of IV Vit-C to specifically address the cytokines' storm characteristic of the Acute Respiratory Distress Syndrome (ARDS) that occur in the later cycle of the Covid19 infectious disease.

positive: Hyperferritinemia in critically ill COVID-19 patients – Is ferritin the product of inflammation or a pathogenic mediator?

positive: Coronavirus disease 2019 (COVID-19) and cardiovascular complications Abstract The coronavirus disease 2019 (COVID-19) has become a global pandemic. It has been spread to more than 100 countries and more than 1 million patients have been confirmed. Although coronavirus causes severe respiratory infections in human, accumulating data have demonstrated cardiac complications and poor outcome in patients with coronavirus disease 2019. A large percent of patients have underlying cardiovascular disease and they are at a high risk of developing cardiac complications. We review the basics of the virus, the clinical manifestation, and the possible mechanisms of cardiac complications in patients with coronavirus disease 2019. Before the effective vaccine or medicine is available, supportive therapy and identifying patients who are at high risk of cardiac complications are important.

positive: Immunomodulatory therapy for the management of severe COVID-19. Beyond the anti-viral therapy: A comprehensive review Severe Acute Respiratory Syndrome related to Coronavirus-2 (SARS-CoV-2), coronavirus disease-2019 (COVID-19) may cause severe illness in 20% of patients. This may be in part due to an uncontrolled immune-response to SARS-CoV-2 infection triggering a systemic hyperinflammatory response, the so-called “cytokine storm”. The reduction of this inflammatory immune-response could be considered as a potential therapeutic target against severe COVID-19. The relationship between inflammation and clot activation must also be considered. Furthermore, we must keep in mind that currently, no specific antiviral treatment is available for SARS-CoV-2. While moderate-severe forms need in-hospital surveillance plus antivirals and/or hydroxychloroquine; in severe and life-threating subsets a high intensity anti-inflammatory and immunomodulatory therapy could be a therapeutic option. However, right data on the effectiveness of different immunomodulating drugs are scarce. Herein, we discuss the pathogenesis and the possible role played by drugs such as: antimalarials, anti-IL6, anti-IL-1, calcineurin and JAK inhibitors, corticosteroids, immunoglobulins, heparins, angiotensin-converting enzyme agonists and statins in severe COVID-19.

positive: Tocilizumab plus glucocorticoids in severe and critically COVID-19 patients. A single center experience

positive: COMPLEMENT ACTIVATION IN PATIENTS WITH COVID-19: A NOVEL THERAPEUTIC TARGET The pathophysiology of the severe complications of COVID-19 is still unclear. We report preliminary data providing evidence of complement activation in patients with COVID-19 with different degrees of respiratory failure.

positive: A rationale for targeting the P2X7 receptor in Coronavirus disease 19 (Covid‐19) Severe pneumonia which shares several of the features of acute respiratory distress syndrome (ARDS) is the main cause of morbidity and mortality in Coronavirus disease 19 (Covid‐19) for which as of now there is no effective treatment. ARDS is caused and sustained by an uncontrolled inflammatory activation characterized by a massive release of cytokines (cytokine storm), diffuse lung edema, inflammatory cell infiltraton and disseminated coagulation. Macrophage and T lymphocyte dysfunction plays a central role in this syndrome. In several experimental in vitro and in vivo models, many of these pathophysiological changes are triggered by stimulation of the P2X7 receptor. We hypothesize that this receptor might be an ideal candidate to target in Covid‐19‐associated severe pneumonia.

positive: Effects of hypertension, diabetes and coronary heart disease on COVID-19 diseases severity: a systematic review and meta-analysis Background: COVID-19 patients with chronic diseases such as hypertension, diabetes and coronary heart diseases is more likely to worsen, but with mixed results for COVID-19 severity. This meta-analysis is to analyze the correlation between hypertension, diabetes, coronary heart disease and COVID-19 disease severity. Methods: Available data from PubMed, Web of Science, China National Knowledge Infrastructure Database, WanFang Database and VIP Database, were analyzed using a fixed effects model meta-analysis to derive overall odds ratios (OR) with 95% CIs. Funnel plots and Begg's were used to assess publication bias. Findings: Of 182 articles found following our initial search, we assessed 34 full-text articles, of which 9 articles with 1936 COVID-19 patients met all selection criteria for our meta-analysis. No significant heterogeneity between studies. There were significant correlations between COVID-19 severity and hypertension [OR=2.3 [95% CI (1.76, 3.00), P<0.01], diabetes [OR=2.67, 95% CI (1.91, 3.74), P<0.01], coronary heart disease [OR=2.85 [95% CI (1.68, 4.84), P<0.01]. Most of the studies in the funnel plot are on the upper part and few on the base part, and are roughly symmetrical left and right. Begg's test: hypertension (Z=-0.1, P=1.0), diabetes (Z=0.73, P=0.466), coronary heart disease (Z=0.38, P=0.707), all found no publication bias. Interpretation: Hypertension, diabetes, and coronary heart disease can affect the severity of COVID-19. It may be related to the imbalance of angiotensin-converting enzyme 2 (ACE2) and the cytokine storm induced by Glucolipid metabolic disorders (GLMD).

positive: COVID-19 gone bad: A new character in the spectrum of the hyperferritinemic syndrome? Abstract The severe form of COVID-19 share several clinical and laboratory features with four entities gathered under the term “hyperferritinemic syndrome” and including macrophage activation syndrome (MAS), adult-onset Still's disease (AOSD), catastrophic anti-phospholipid syndrome (CAPS) and septic shock. COVID-19 systemic inflammatory reaction and “hyperferritinemic syndromes” are all characterized by high serum ferritin and a life-threatening hyper-inflammation sustained by a cytokines storm which eventually leads to multi-organ failure. In this review, we analyze the possible epidemiological and molecular mechanisms responsible for hyper-inflammation in patients with severe COVID-19 and we underline the similarities between this condition and “hyperferritinemic syndromes” which would allow considering this entity as the fifth member of the spectrum of inflammatory conditions.

positive: Cytochrome P450-mediated drug interactions in COVID-19 patients: current findings and possible mechanisms At the end of 2019, the entire world has witnessed the birth of a new member of coronavirus family in Wuhan, China. Ever since, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has swiftly invaded every corner on the planet. By the end of April 2020, almost 3.5 million cases have been reported worldwide, with a death toll of about 250000 deaths. It is currently well-recognized that patient’s immune response plays a pivotal role in the pathogenesis of Coronavirus Disease 2019 (COVID-19). This inflammatory element was evidenced by its elevated mediators that, in severe cases, reach their peak in a cytokine storm. Together with the reported markers of liver injury, such hyperinflammatory state may trigger significant derangements in hepatic cytochrome P450 metabolic machinery, and subsequent modulation of drug clearance that may result in unexpected therapeutic/toxic response. We hypothesize that COVID-19 patients are potentially vulnerable to a significant disease-drug interaction, and therefore, suitable dosing guidelines with therapeutic drug monitoring should be implemented to assure optimal clinical outcomes.

positive: Dipeptidyl peptidase-4 (DPP4) inhibition in COVID-19 AIMS: SARS–CoV-2 causes severe respiratory syndrome (COVID-19) with high mortality due to a direct cytotoxic viral effect and a severe systemic inflammation. We are herein discussing a possible novel therapeutic tool for COVID-19. METHODS: Virus binds to the cell surface receptor ACE2; indeed, recent evidences suggested that SARS–CoV-2 may be using as co-receptor, when entering the cells, the same one used by MERS–Co-V, namely the DPP4/CD26 receptor. The aforementioned observation underlined that mechanism of cell entry is supposedly similar among different coronavirus, that the co-expression of ACE2 and DPP4/CD26 could identify those cells targeted by different human coronaviruses and that clinical complications may be similar. RESULTS: The DPP4 family/system was implicated in various physiological processes and diseases of the immune system, and DPP4/CD26 is variously expressed on epithelia and endothelia of the systemic vasculature, lung, kidney, small intestine and heart. In particular, DPP4 distribution in the human respiratory tract may facilitate the entrance of the virus into the airway tract itself and could contribute to the development of cytokine storm and immunopathology in causing fatal COVID-19 pneumonia. CONCLUSIONS: The use of DPP4 inhibitors, such as gliptins, in patients with COVID-19 with, or even without, type 2 diabetes, may offer a simple way to reduce the virus entry and replication into the airways and to hamper the sustained cytokine storm and inflammation within the lung in patients diagnosed with COVID-19 infection.

positive: Unraveling the mystery of Covid-19 Cytokine storm: From skin to organ systems COVID-19 is a global pandemic that emerged from Wuhan, China. Besides pneumonia and acute respiratory distress syndrome, the disease leads to multisystem involvement in the form of myocarditis, arrhythmias, cardiac arrest, gastrointestinal symptoms, hypoxemic brain injury, acute liver and renal function impairment. There are also reports of cutaneous lesions in form of urticarial and maculopapular rashes, chilblain like fingers and toes (covid feet), livedoid vasculopathy and chicken-pox like or varicelliform vesicles. Clinically, many of these skin lesions are likely secondary to occlusion of small to medium blood vessels due to microthrombi formation or due to viral laden antigen-antibody immune complexes; and same explanation may hold true for possible hypoxemic injury simultaneously occurring in other vital organs like lungs, heart, brain and kidneys. The histopathology, immunoflorescence and RT-PCR analysis of skin biopsies can provide useful insights for ascertaining the pathogenesis of this complex viral syndrome. Apparently, it is interplay of disarmed cellular immunity and over-activated humoral immunity that culminates in end-organ changes. The morbidity and mortality can be significantly reduced by upgrading the cellular immunity and downgrading the humoral response; along with prevention of hypoxemic and reperfusion injuries by using antivirals, immunomodulators, antioxidants, anti-platelets and anticoagulants in judicious and phased manner. This article is protected by copyright. All rights reserved.

positive: Traditional Chinese medicine contributes to the treatment of COVID-19 patients

positive: Anti-coagulation for COVID-19 treatment: both anti-thrombotic and anti-inflammatory? Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been linked to a higher risk of mortality compared to influenza, which is mainly due to severe secondary diseases, such as acute respiratory distress syndrome (ARDS). In turn, ARDS is characterized by an acute inflammation and an excessive activity of the coagulation cascade, rising the vulnerability for venous thromboembolic events. In order to investigate the relation of inflammation and the influence of coagulation factors on their release, human peripheral mononuclear blood cells (PBMCs) were treated with autologous serum, heparinized plasma and different doses of fibrin. Thereafter, the concentration of pro-inflammatory cytokines and chemokines in the secretome of PBMCs was measured by enzyme-linked immunosorbent assay. Our analyses revealed autologous serum to significantly increase the secretion of cytokines and chemokines after 24 h of incubation time. Furthermore, the addition of fibrin markedly increased the secretion of cytokines and chemokines by PBMCs in a dose-dependent manner. Consequently, in accordance with previous studies, our study outlines that anti-coagulation may constitute a promising tool for the treatment of SARS-CoV-2, reducing both, the cytokine storm, as well as the risk for thrombotic complications.

positive: Leukemia inhibitory factor protects the lung during respiratory syncytial viral infection BACKGROUND: Respiratory syncytial virus (RSV) infects the lung epithelium where it stimulates the production of numerous host cytokines that are associated with disease burden and acute lung injury. Characterizing the host cytokine response to RSV infection, the regulation of host cytokines and the impact of neutralizing an RSV-inducible cytokine during infection were undertaken in this study. METHODS: A549, primary human small airway epithelial (SAE) cells and wild-type, TIR-domain-containing adapter-inducing interferon-β (Trif) and mitochondrial antiviral-signaling protein (Mavs) knockout (KO) mice were infected with RSV and cytokine responses were investigated by ELISA, multiplex analysis and qPCR. Neutralizing anti-leukemia inhibitory factor (LIF) IgG or control IgG was administered to a group of wild-type animals prior to RSV infection. RESULTS AND DISCUSSION: RSV-infected A549 and SAE cells release a network of cytokines, including newly identified RSV-inducible cytokines LIF, migration inhibitory factor (MIF), stem cell factor (SCF), CCL27, CXCL12 and stem cell growth factor beta (SCGF-β). These RSV-inducible cytokines were also observed in the airways of mice during an infection. To identify the regulation of RSV inducible cytokines, Mavs and Trif deficient animals were infected with RSV. In vivo induction of airway IL-1β, IL-4, IL-5, IL-6, IL-12(p40), IFN-γ, CCL2, CCL5, CCL3, CXCL1, IP-10/CXCL10, IL-22, MIG/CXCL9 and MIF were dependent on Mavs expression in mice. Loss of Trif expression in mice altered the RSV induction of IL-1β, IL-5, CXCL12, MIF, LIF, CXCL12 and IFN-γ. Silencing of retinoic acid–inducible gene-1 (RIG-I) expression in A549 cells had a greater impact on RSV-inducible cytokines than melanoma differentiation-associated protein 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2), and Trif expression. To evaluate the role of LIF in the airways during RSV infection, animals were treated with neutralizing anti-LIF IgG, which enhanced RSV pathology observed with increased airspace protein content, apoptosis and airway hyperresponsiveness compared to control IgG treatment. CONCLUSIONS: RSV infection in the epithelium induces a network of immune factors to counter infection, primarily in a RIG-I dependent manner. Expression of LIF protects the lung from lung injury and enhanced pathology during RSV infection. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12865-014-0041-4) contains supplementary material, which is available to authorized users.

positive: Facing SARS-CoV-2 outbreak in immunotherapy era Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread represents a sanitary emergency all over the world. Viral biology is only partially known with some aspects in common with other CoV and the damage observed in most severe cases is due to intense inflammation. Immunotherapy restores immunological activity against cancer cells and it has become a standard treatment for several cancers. We carried out an examination of available data concerning with the effects exerted by both SARS-CoV-2 and the most widespread immunotherapy treatments on the immune system in order to hypothesize mechanisms underlying potential and mutual interaction. We provided an analysis of laboratory, clinical and therapeutic data related with severe acute respiratory syndrome coronavirus. We finally focused on implications of immunotherapy treatments in clinical practice.

positive: Immunopathology and immunotherapeutic strategies in severe acute respiratory syndrome coronavirus 2 infection. The outbreak of coronavirus disease 2019 (COVID-19) and pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a major concern globally. As of 14 April 2020, more than 1.9 million COVID-19 cases have been reported in 185 countries. Some patients with COVID-19 develop severe clinical manifestations, while others show mild symptoms, suggesting that dysregulation of the host immune response contributes to disease progression and severity. In this review, we have summarized and discussed recent immunological studies focusing on the response of the host immune system and the immunopathology of SARS-CoV-2 infection as well as immunotherapeutic strategies for COVID-19. Immune evasion by SARS-CoV-2, functional exhaustion of lymphocytes, and cytokine storm have been discussed as part of immunopathology mechanisms in SARS-CoV-2 infection. Some potential immunotherapeutic strategies to control the progression of COVID-19, such as passive antibody therapy and use of interferon αβ and IL-6 receptor (IL-6R) inhibitor, have also been discussed. This may help us to understand the immune status of patients with COVID-19, particularly those with severe clinical presentation, and form a basis for further immunotherapeutic investigations.

positive: Role of Interleukin-6 in Lung Complications in Patients With COVID-19: Therapeutic Implications. COVID-19 is viral respiratory infection with frequently fatal lung complications in the elderly or in people with serious comorbidities. Lung destruction appears to be associated with a cytokine storm related to an increased level of interleukin-6 (IL6). Therapeutic targeting of the interleukin-6 signaling pathway can attenuate such a cytokine storm and can be beneficial for patients with COVID-19 in danger of pulmonary failure. This article demonstrates the importance of IL6 in progression of disease and the possibility of inhibition of IL6 signaling in COVID-19 therapy.

positive: Corticosteroids for critically ill COVID-19 patients with cytokine release syndrome: a limited case series

positive: The amount of cytokine-release defines different shades of Sars-Cov2 infection The recent outbreak of coronavirus disease (COVID 19), spreading from China all around the world in early 2020, has led scientists to investigate the immuno-mediated mechanisms underlying the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) infection. Depending on the amount of cytokines released as the result of the immunological activation induced by SARS-CoV2, three major clinical phenotypes can be identified: "mild",symbolized as a "drizzle" of cytokines, severe as a "storm", and critical as a "hurricane". In patients with mild symptoms, the release of pro-inflammatory cytokines is balanced to obtain a defense response against the virus which is often self-limiting and overcomes without tissue damage. In severe phenotype, resembling a "cytokine-release syndrome", SARS-CoV2 causes the lysis of the immune-mediators leading to a cytokine storm able to induce lung epithelium damage and acute respiratory distress syndrome. In critical patients, the immune response may become uncontrolled, thus the cytokine burst resembles a form of secondary hemophagocytic lymphohistiocytosis which may result in a multi organ failure. In addition to the standard of care, an immune-modulatory therapy tailored to each one of the different phenotypes should be used in order to prevent or reduce the release of cytokines responsible for organ damage and disease progression.

positive: The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality Abstract Since December 2019, a viral pneumonia (COVID-19) from Wuhan, China has swept the world. Although the case fatality rate is not high, the number of people infected is large, and there are still a large number of patients dying. With the collation and publication of more and more clinical data, a large number of data suggest that there are mild or severe cytokine storms in severe patients, which is also an important cause of death. Therefore, the treatment of cytokine storm has become an important part of rescuing severe patients. Interleukin-6 (IL-6) plays an important role in cytokine release syndrome (CRS). If it can block the signal transduction pathway of IL-6, it is expected to become a new method for the treatment of severe patients. Tocilizumab is a blocker of IL-6R, which can effectively block IL-6 signal transduction pathway. So, tocilizumab is likely to become an effective drug for patients with severe COVID-19.

positive: Interleukin‐6 Blockade Treatment for COVID‐19 associated Cytokine Release Syndrome in a Patient with Poorly Controlled Chronic Myeloid Leukaemia In December 2019, a novel coronavirus pneumonia, coronavirus disease 2019 (COVID‐19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) was reported in Wuhan, China. A hyperinflammatory immune response, or cytokine release syndrome (CRS) is observed in critically unwell patients with SARS‐CoV‐2 globally. Severe lymphopenia, hyperactivated pro‐inflammatory T cells(1) and decreased regulatory T cells(2) are seen in these critically ill patients, suggesting dysregulated immune responses.

positive: SARS-CoV-2, which induces COVID-19, causes kawasaki-like disease in children: role of pro-inflammatory and anti-inflammatory cytokines Acute severe respiratory syndrome coronavirus-2 (SARS-CoV-2) caused a global pandemic coronavirus disease 2019 (COVID-19). In humans, SARS-CoV-2 infection leads to acute respiratory distress syndrome which presents edema, hemorrhage, intra-alveolar fibrin deposition, and vascular changes characterized by thrombus formation, micro-angiopathy and thrombosis. These clinical signs are mediated by pro-inflammatory cytokines. In recent studies it has been noted that COVID-19 pandemic can affect patients of all ages, including children (even if less severely) who were initially thought to be immune. Kawasaki disease is an autoimmune acute febrile inflammatory condition, which primarily affects young children. The disease can present immunodeficiency with the inability of the immune system to fight inflammatory pathogens and leads to fever, rash, alterations of the mucous membranes, conjunctiva infection, pharyngeal erythema, adenopathy, and inflammation. In the COVID-19 period, virus infection aggravates the condition of Kawasaki disease, but it has also been noted that children affected by SARS-V-2 may develop a disease similar to Kawasaki's illness. However, it is uncertain whether the virus alone can give Kawasaki disease-like forms. As in COVID-19, Kawasaki disease and its similar forms are mediated by pro-inflammatory cytokines produced by innate immunity cells such as macrophages and mast cells (MCs). In light of the above, it is therefore pertinent to think that by blocking pro-inflammatory cytokines with new anti-inflammatory cytokines, such as IL-37 and IL-38, it is possible to alleviate the symptoms of the disease and have a new available therapeutic tool. However, since Kawasaki and Kawasaki-like diseases present immunodeficiency, treatment with anti-inflammatory/immunosuppressant molecules must be applied very carefully.

positive: Clinical observations of low molecular weight heparin in relieving inflammation in COVID-19 patients: A retrospective cohort study Abstract: Background On March 11, 2020, the World Health Organization declared its assessment of COVID-19 as a global pandemic. Effective therapeutic drugs are urgently needed to improve the overall prognosis of patients, but currently no such drugs are available. Methods Patients in the study were divided into a heparin and a control group based on whether low molecular weight heparin (LMWH) was used. D-dimer, C-reactive protein (CRP), peripheral blood lymphocyte percentage, interleukin-6, and other indices in 42 patients with novel coronavirus pneumonia were retrospectively analyzed to compare and evaluate the progress of patients before and after LMWH treatment. Results Compared to the control group, D-dimer levels in the heparin group significantly increased before treatment, and there was no significant difference after treatment. There was no significant difference in the change of CRP levels between the two groups of patients before and after LMWH treatment, and levels for both groups were significantly lower after, compared to before, treatment. Compared to the control group, patients in the heparin group had a higher percentage of lymphocytes after treatment and lower levels of interleukin-6; these differences were statistically significant. Conclusions Under conventional antiviral treatment regimens, LMWH can improve hypercoagulability, inhibit IL-6 release, and counteract IL-6 biological activity in patients. LMWH has potential antiviral effects and can help delay or block inflammatory cytokine storms. It can also increase the lymphocytes (LYM%)of patients and has the potential for treatment of COVID-19.

positive: The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of "inflame-aging" PURPOSE: Novel Coronavirus disease 2019 (COVID-19), is an acute respiratory distress syndrome (ARDS), which is emerged in Wuhan, and recently become worldwide pandemic. Strangely, ample evidences have been shown that the severity of COVID-19 infections varies widely from children (asymptomatic), adults (mild infection), as well as elderly adults (deadly critical). It has proven that COVID-19 infection in some elderly critical adults leads to a cytokine storm, which is characterized by severe systemic elevation of several pro-inflammatory cytokines. Then, a cytokine storm can induce edematous, ARDS, pneumonia, as well as multiple organ failure in aged patients. It is far from clear till now why cytokine storm induces in only COVID-19 elderly patients, and not in young patients. However, it seems that aging is associated with mild elevated levels of local and systemic pro-inflammatory cytokines, which is characterized by "inflamm-aging". It is highly likely that "inflamm-aging" is correlated to increased risk of a cytokine storm in some critical elderly patients with COVID-19 infection. METHODS: A systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, as well as Google Scholar pre-print database using all available MeSH terms for COVID-19, Coronavirus, SARS-CoV-2, senescent cell, cytokine storm, inflame-aging, ACE2 receptor, autophagy, and Vitamin D. Electronic database searches combined and duplicates were removed. RESULTS: The aim of the present review was to summarize experimental data and clinical observations that linked the pathophysiology mechanisms of "inflamm-aging", mild-grade inflammation, and cytokine storm in some elderly adults with severe COVID-19 infection.

positive: Biologics for psoriasis in COVID‐19 era: what do we know?

positive: SARS-CoV-2 triggered neutrophil extracellular traps (NETs) mediate COVID-19 pathology Severe COVID-19 patients develop acute respiratory distress syndrome that may progress to respiratory failure. These patients also develop cytokine storm syndrome, and organ dysfunctions, which is a clinical picture that resembles sepsis. Considering that neutrophil extracellular traps (NETs) have been described as an important factors of tissue damage in sepsis, we investigated whether NETs would be produced in COVID-19 patients and participate in the lung tissue damage. A cohort of 32 hospitalized patients with a confirmed diagnosis of COVID-19 and respective healthy controls were enrolled. NETs concentration was assessed by MPO-DNA PicoGreen assay or by confocal immunofluorescence. The cytotoxic effect of SARS-CoV-2-induced NETs was analyzed in human epithelial lung cells (A549 cells). The concentration of NETs was augmented in plasma and tracheal aspirate from COVID-19 patients and their neutrophils spontaneously released higher levels of NETs. NETs were also found in the lung tissue specimens from autopsies of COVID-19 patients. Notably, viable SARS-CoV-2 can directly induce in vitro release of NETs by healthy neutrophils in a PAD-4-dependent manner. Finally, NETs released by SARS-CoV-2-activated neutrophils promote lung epithelial cell death in vitro. These results unravel a possible detrimental role of NETs in the pathophysiology of COVID-19. Therefore, the inhibition of NETs represent a potential therapeutic target for COVID-19.

positive: Potential Role of Anti-interleukin (IL)-6 Drugs in the Treatment of COVID-19: Rationale, Clinical Evidence and Risks The epidemic due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been spreading globally, raising increasing concerns. This public health emergency has triggered a race to find medications to improve the prognosis of this disease. There is currently great interest in drug repositioning to manage SARS-CoV-2 infection, that is, the evaluation of the potential benefits of a drug that has already been proven safe and effective in humans for other approved indications. As interleukin-6 (IL-6) acts as a key driver of the inflammation associated with coronavirus disease 2019 (COVID-19), IL-6 and IL-6 receptor (IL-6R) inhibition appear to be promising targets for the treatment of COVID-19 patients. It is important to critically analyze the available evidence concerning the use of the available anti-IL-6 (siltuximab) and anti-IL-6R (tocilizumab and sarilumab) agents in COVID-19 patients, in terms of both benefit and risk. In this review, the pathogenesis of the cytokine storm induced by COVID-19, the role of IL-6 in this cytokine storm, the rationale for the use of anti-IL-6 agents, and key information on potential benefits and safety monitoring of these biologicals in COVID-19 patients is discussed.

positive: Biosensors for Managing the COVID-19 Cytokine Storm: Challenges Ahead The global COVID-19 pandemic has oversaturated many intensive care units to the point of collapse, leading to enormous spikes in death counts. Before critical care becomes a necessity, identifying patients who are likely to become critically ill and providing prompt treatment is a strategy to avoid ICU oversaturation. There is a consensus that a hyperinflammatory syndrome or a "cytokine storm" is responsible for poor outcomes in COVID-19. Measuring cytokine levels at the point of care is required in order to better understand this process. In this Perspective, we summarize the main events behind the cytokine storm in COVID-19 as well as current experimental treatments. We advocate for a new biosensor-enabled paradigm to personalize the management of COVID-19 and stratify patients. Biosensor-guided dosing and timing of immunomodulatory therapies could maximize the benefits of these anti-inflammatory treatments while minimizing deleterious effects. Biosensors will also be essential in order to detect complications such as coinfections and sepsis, which are common in immunosuppressed patients. Finally, we propose the ideal features of these biosensors using some prototypes from the recent literature as examples. Multisensors, lateral flow tests, mobile biosensors, and wearable biosensors are seen as key players for precision medicine in COVID-19.

positive: The potential role of TNFα in 2019 novel coronavirus pneumonia The outbreak of 2019 novel coronavirus has spread rapidly in multiple countries. We report the first case of 2019-nCoV infection in a patient with Ankylosing Spondylitisthe (AS), who was a biological agent (anti-TNFα) user in Wenzhou, China, and describe the clinical course and management of the case.

positive: The Role of Chest Imaging in Patient Management during the COVID-19 Pandemic: A Multinational Consensus Statement from the Fleischner Society With more than 900,000 confirmed cases worldwide and nearly 50,000 deaths during the first three months of 2020, the COVID-19 pandemic has emerged as an unprecedented healthcare crisis. The spread of COVID-19 has been heterogeneous, resulting in some regions having sporadic transmission and relatively few hospitalized patients with COVID-19 and others having community transmission that has led to overwhelming numbers of severe cases. For these regions, healthcare delivery has been disrupted and compromised by critical resource constraints in diagnostic testing, hospital beds, ventilators, and healthcare workers who have fallen ill to the virus exacerbated by shortages of personal protective equipment. While mild cases mimic common upper respiratory viral infections, respiratory dysfunction becomes the principal source of morbidity and mortality as the disease advances. Thoracic imaging with chest radiography (CXR) and computed tomography (CT) are key tools for pulmonary disease diagnosis and management, but their role in the management of COVID-19 has not been considered within the multivariable context of the severity of respiratory disease, pre-test probability, risk factors for disease progression, and critical resource constraints. To address this deficit, a multidisciplinary panel comprised principally of radiologists and pulmonologists from 10 countries with experience managing COVID-19 patients across a spectrum of healthcare environments evaluated the utility of imaging within three scenarios representing varying risk factors, community conditions, and resource constraints. Fourteen key questions, corresponding to 11 decision points within the three scenarios and three additional clinical situations, were rated by the panel based upon the anticipated value of the information that thoracic imaging would be expected to provide. The results were aggregated, resulting in five main and three additional recommendations intended to guide medical practitioners in the use of CXR and CT in the management of COVID-19.

positive: Coronavirus disease 2019 (COVID-19) and anti-rheumatic drugs

positive: Nitric oxide inhalation as an interventional rescue therapy for COVID-19-induced acute respiratory distress syndrome COVID-19 is an emerging disease of public health concern. While there is no specific recommended treatment for COVID-19, nitric oxide has the potential to be of therapeutic value for managing acute respiratory distress syndrome in patients with COVID-19. However, inhaled nitric oxide has not yet been formally evaluated. Given the extent of the COVID-19 pandemic, and the large numbers of hospitalized patients requiring respiratory support, clinical use of inhaled nitric oxide may become an alternate rescue therapy before extracorporeal membrane oxygenation for the management of acute respiratory distress syndrome in patients with COVID-19.

positive: Interleukin‐18: Biological properties and role in disease pathogenesis Initially described as an interferon (IFN)γ‐inducing factor, interleukin (IL)‐18 is indeed involved in Th1 and NK cell activation, but also in Th2, IL‐17‐producing γδ T cells and macrophage activation. IL‐18, a member of the IL‐1 family, is similar to IL‐1β for being processed by caspase 1 to an 18 kDa‐biologically active mature form. IL‐18 binds to its specific receptor (IL‐18Rα, also known as IL‐1R7) forming a low affinity ligand chain. This is followed by recruitment of the IL‐18Rβ chain. IL‐18 then uses the same signaling pathway as IL‐1 to activate NF‐kB and induce inflammatory mediators such as adhesion molecules, chemokines and Fas ligand. IL‐18 also binds to the circulating high affinity IL‐18 binding protein (BP), such as only unbound free IL‐18 is active. IL‐18Rα may also bind IL‐37, another member of the IL‐1 family, but in association with the negative signaling chain termed IL‐1R8, which transduces an anti‐inflammatory signal. IL‐18BP also binds IL‐37 and this acts as a sink for the anti‐inflammatory properties of IL‐37. There is now ample evidence for a role of IL‐18 in various infectious, metabolic or inflammatory diseases such as influenza virus infection, atheroma, myocardial infarction, chronic obstructive pulmonary disease, or Crohn's disease. However, IL‐18 plays a very specific role in the pathogenesis of hemophagocytic syndromes (HS) also termed Macrophage Activation Syndrome. In children affected by NLRC4 gain‐of‐function mutations, IL‐18 circulates in the range of tens of nanograms/mL. HS is treated with the IL‐1 Receptor antagonist (anakinra) but also specifically with IL‐18BP. Systemic juvenile idiopathic arthritis or adult‐onset Still's disease are also characterized by high serum IL‐18 concentrations and are treated by IL‐18BP.

positive: Calming the Cytokine Storm in Pneumonia by Biomimetic Nanoparticles Recently, the Wang group at Soochow University and the Gu group at the University of California, Los Angeles demonstrated the targeting ability of platelet-derived extracellular vesicles to deliver anti-inflammatory drug [5-(p-fluorophenyl)-2-ureido] thiophene-3-carboxamide (TPCA-1) to pneumonia for calming the local cytokine storm in acute lung injury.

positive: COVID-19 and myocarditis: What do we know so far? COVID-19 has been declared a global pandemic by the World Health Organization and is responsible for hundreds of thousands of deaths worldwide. COVID-19 is caused by SARS-CoV-2, and common clinical symptoms include fever, cough, sore throat, headache, and fatigue. Myocardial injury is relatively common in COVID-19, accounting for 7-23% of cases, and is associated with a higher morbidity and mortality. There is a discrepancy in the literature about myocarditis as the etiology of myocardial injury in COVID-19; although many anecdotal reports of myocarditis have been noted, there are only a handful of case reports in the literature about myocarditis related to COVID-19. This review summarizes the most up-to-date literature around the association between COVID-19 and myocarditis and gives clinicians a practical framework about the clinical manifestations, diagnostic tools and treatment options currently available. Importantly, this review will heighten suspicion for myocarditis as an etiology of myocardial injury in COVID-19 patients, therefore improving clinical outcomes and encouraging shared clinical decision-making. This will also open the door for further research to build around this review. Emergent treatment options for COVID-19 are in clinical trials and may be of benefit to COVID-19 patients with myocarditis in addition to current guideline-based recommendations.

positive: Classical drug digitoxin inhibits influenza cytokine storm, with implications for COVID-19 therapy Influenza viruses, corona viruses and related pneumotropic viruses cause sickness and death partly by inducing a hyper-proinflammatory response by immune cells and cytokines in the host airway. Here we show that the cardiac glycoside digitoxin suppresses this response induced by influenza virus strain A/Wuhan/H3N2/359/95 in the cotton rat lung. The cytokines TNFα, GRO/KC, MIP2, MCP1, TGFβ, and IFNγ. are significantly and differentially reduced. Since the hyper-proinflammatory expression of cytokines is a host response, we suggest that digitoxin may have therapeutic potential for not only influenza and but also for coronavirus infections.

positive: Nrf2 Activator PB125(®) as a Potential Therapeutic Agent against COVID-19 Nrf2 is a transcription factor that regulates cellular redox balance and the expression of a wide array of genes involved in immunity and inflammation, including antiviral actions. Nrf2 activity declines with age, making the elderly more susceptible to oxidative stress-mediated diseases, which include type 2 diabetes, chronic inflammation, and viral infections. Published evidence suggests that Nrf2 activity may regulate important mechanisms affecting viral susceptibility and replication. We examined gene expression levels by GeneChip microarray and by RNA-seq assays. We found that the potent Nrf2-activating composition PB125(®) downregulates ACE2 and TMPRSS2 mRNA expression in human liver-derived HepG2 cells. ACE2 is a surface receptor and TMPRSS2 activates the spike protein for SARS-CoV-2 entry into host cells. Furthermore, in endotoxin-stimulated primary human pulmonary artery endothelial cells, we report the marked downregulation by PB125 of 36 genes encoding cytokines. These include IL-1-beta, IL-6, TNF-α, the cell adhesion molecules ICAM-1, VCAM-1, and E-selectin, and a group of IFN-γ-induced genes. Many of these cytokines have been specifically identified in the “cytokine storm” observed in fatal cases of COVID-19, suggesting that Nrf2 activation may significantly decrease the intensity of the storm.

positive: Role of thymopoiesis and inflamm-aging in COVID-19 phenotype

positive: A single-cell atlas of the peripheral immune response to severe COVID-19 There is an urgent need to better understand the pathophysiology of Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2. Here, we apply single-cell RNA sequencing (scRNA-seq) to peripheral blood mononuclear cells (PBMCs) of 7 patients hospitalized with confirmed COVID-19 and 6 healthy controls. We identify substantial reconfiguration of peripheral immune cell phenotype in COVID-19, including a heterogeneous interferon-stimulated gene (ISG) signature, HLA class II downregulation, and a novel B cell-derived granulocyte population appearing in patients with acute respiratory failure requiring mechanical ventilation. Importantly, peripheral monocytes and lymphocytes do not express substantial amounts of pro-inflammatory cytokines, suggesting that circulating leukocytes do not significantly contribute to the potential COVID-19 cytokine storm. Collectively, we provide the most thorough cell atlas to date of the peripheral immune response to severe COVID-19.

positive: IL-6: relevance for immunopathology of SARS-CoV-2 COVID-19 mortality is strongly associated with the development of severe pneumonia and acute respiratory distress syndrome with the worst outcome resulting in cytokine release syndrome and multiorgan failure. It is becoming critically important to identify at the early stage of the infection those patients who are prone to develop the most adverse effects. Elevated systemic interleukin-6 levels in patients with COVID-19 are considered as a relevant parameter in predicting most severe course of disease and the need for intensive care. This review discusses the mechanisms by which IL-6 may possibly contribute to disease exacerbation and the potential of therapeutic approaches based on anti-IL-6 biologics.

positive: Could hemophagocytic lymphohistiocytosis be the core issue of severe COVID-19 cases? BACKGROUND: COVID-19, a disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), commonly presents as fever, cough, dyspnea, and myalgia or fatigue. Although the majority of patients with COVID-19 have mild symptoms, some are more prone to serious outcomes, including pneumonia, acute respiratory distress syndrome (ARDS), and even death. Hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening inflammatory syndrome associated with intense cytokine release (also known as a “cytokine storm”). Similar to COVID-19, HLH is characterized by aggressive course leading to multi-organ failure. MAIN TEXT: The purpose of this review article is to draw attention to the possibility of the complication of HLH in patients with the severe course of COVID-19. Indeed, some of the clinical characteristics observed in the more severe cases of COVID-19 are reminiscent of secondary HLH (which can be triggered by infections, malignancies, rheumatological diseases, or autoimmune/immunodeficiency conditions). The pathogenesis of SARS-CoV-2 infection also suggests that HLH or a similar hyperinflammatory syndrome is the cause of the severe course of the infection. CONCLUSION: The pathogenesis and clinical symptoms of severe COVID-19 indicate that an increased inflammatory response corresponding to HLH is occurring. Therefore, patients with severe COVID-19 should be screened for hyperinflammation using standard laboratory tests to identify those for whom immunosuppressive therapy may improve outcomes.

positive: Therapeutic Potential of B-1a Cells in COVID-19 Coronavirus disease 2019 (COVID-19) is a life-threatening respiratory illness caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Its clinical presentation can vary from the asymptomatic state to acute respiratory distress syndrome (ARDS) and multi-organ dysfunction. Due to our insufficient understanding of its pathophysiology and lack of effective treatment, the morbidity and mortality of severe COVID-19 patients are high. Patients with COVID-19 develop ARDS fueled by exaggerated neutrophil influx into the lungs and cytokine storm. B-1a cells represent a unique subpopulation of B lymphocytes critical for circulating natural antibodies, innate immunity, and immunoregulation. These cells spontaneously produce natural IgM, interleukin (IL)-10, and granulocyte-monocyte colony stimulating factor (GM-CSF). Natural IgM neutralizes viruses and opsonizes bacteria, IL-10 attenuates the cytokine storm, and GM-CSF induces IgM production by B-1a cells in an autocrine manner. Indeed, B-1a cells have been shown to ameliorate influenza virus infection, sepsis, and pneumonia, all of which are similar to COVID-19. The recent discovery of B-1a cells in humans further reinforces their potentially critical role in the immune response against SARS-CoV-2 and their anticipated translational applications against viral and microbial infections. Given that B-1a cells protect against ARDS via immunoglobulin production and the anti-COVID-19 effects of convalescent plasma treatment, we recommend that studies be conducted to further examine the role of B-1a cells in the pathogenesis of COVID-19 and explore their therapeutic potential to treat COVID-19 patients.

positive: CLEC2 and CLEC5A: Pathogenic Host Factors in Acute Viral Infections The protective roles of endosomal toll-like receptors (TLRs) and cytosolic nucleic acid sensors are well elucidated, but the pathogenic host factors during viral infections remain unclear. Spleen tyrosine kinase (Syk)-coupled C-type lectins (CLECs) CLEC2 and CLEC5A are highly expressed on platelets and myeloid cells, respectively. CLEC2 has been shown to recognize snake venom aggretin and the endogenous ligand podoplanin and acts as a critical regulator in the development and immunothrombosis. Although CLEC2 has been reported to interact with type I immunodeficiency virus (HIV-1), its role in viral infections is still unclear. CLEC5A binds to fucose and mannose moieties of dengue virus membrane glycans, as well as to N-acetylglucosamine (GlcNAc)/N-acetylmuramic acid (MurNAc) disaccharides that form the backbone of L. monocytogenes peptidoglycans. Recently, we demonstrated that both CLEC2 and CLEC5A are critical in microbe-induced “neutrophil extracellular trap” (NET) formation and proinflammatory cytokine production. Moreover, activation of CLEC2 by dengue virus (DV) and H5N1 influenza virus (IAV) induces the release of extracellular vesicles (EVs), which further enhance NETosis and proinflammatory cytokine production via CLEC5A and Toll-like receptor 2 (TLR2). These findings not only illustrate the immunomodulatory effects of EVs during platelet-leukocyte interactions, but also demonstrate the critical roles of CLEC2 and CLEC5A in acute viral infections.

positive: The Endothelial Dysfunction and Pyroptosis Driving the SARS-CoV-2 Immune-Thrombosis Objective: Endothelial activation after viral infection could contribute to changes in the vascular glycocalyx associated with programmed inflammatory cell death called pyroptosis. Thus, our goal is to recognize endothelial activation and pyroptosis in lung and myocardial samples of Coronavirus disease (COVID-19) cases and compare to H1N1pdm09 and control cases. Approach and Results: Post-mortem lung (6 cases of COVID-19 group; 10 cases of H1N1 group and 11 cases of Control group) and myocardial samples (2 cases of COVID-19 and one control) were analyzed by conventional immunohistochemistry by using antibodies to identify molecules involving with endothelial activation (CD163, Interleukin-6 (IL-6), Tumor Necrosis Factor alpha (TNF-alpha), Intercellular Adhesion Molecule 1 (ICAM-1)) and pyroptosis (Caspase-1). As a result, IL-6, TNF-alpha, ICAM-1, and Caspase-1 show higher tissue expression in the COVID-19 group compared to H1N1 and Control groups. Conclusion: Our results indicate that the vascular endothelium has been activated and the presence of pyroptosis and endothelial dysfunction in lung and myocardial samples. These conditions could lead to a systemic immune-thrombotic process that may impair the clinical staff's efforts to prevent fatal outcomes. One aim of the health professionals is to avoid COVID-19 systemic vascular injury and immune-thrombosis by blocking the endothelial dysfunction and its consequences.

positive: Hot Topic Commentary on COVID-19 The recent pandemic outbreak of COVID-19 (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2) worldwide caught the health care systems in every country around the world by storm and without a proper defense mechanism to cope and control such a pandemic. In this special Theme issue, we would like to discuss the latest treatment modalities available around the world in tackling this dreadful disease.

positive: COVID-19 in persons with haematological cancers Infection with SARS-CoV-2, the cause of coronavirus infectious disease–19 (COVID-19), has caused a pandemic with >850,000 cases worldwide and increasing. Several studies report outcomes of COVID-19 in predominately well persons. There are also some data on COVID-19 in persons with predominately solid cancer but controversy whether these persons have the same outcomes. We conducted a cohort study at two centres in Wuhan, China, of 128 hospitalised subjects with haematological cancers, 13 (10%) of whom developed COVID-19. We also studied 226 health care providers, 16 of whom developed COVID-19 and 11 of whom were hospitalised. Co-variates were compared with the 115 subjects with haematological cancers without COVID-19 and with 11 hospitalised health care providers with COVID-19. There were no significant differences in baseline co-variates between subjects with haematological cancers developing or not developing COVID-19. Case rates for COVID-19 in hospitalised subjects with haematological cancers was 10% (95% Confidence Interval [CI], 6, 17%) compared with 7% (4, 12%; P = 0.322) in health care providers. However, the 13 subjects with haematological cancers had more severe COVID-19 and more deaths compared with hospitalised health care providers with COVID-19. Case fatality rates were 62% (32, 85%) and 0 (0, 32%; P = 0.002). Hospitalised persons with haematological cancers have a similar case rate of COVID-19 compared with normal health care providers but have more severe disease and a higher case fatality rate. Because we were unable to identify specific risk factors for COVID-19 in hospitalised persons with haematological cancers, we suggest increased surveillance and possible protective isolation.

positive: Obesity and COVID-19: immune and metabolic derangement as a possible link to adverse clinical outcomes Recent reports have shown a strong association between obesity and the severity of COVID-19 infection, even in the absence of other comorbidities. After infecting the host cells, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may cause a hyperinflammatory reaction through the excessive release of cytokines, a condition known as "cytokine storm," while inducing lymphopenia and a disrupted immune response. Obesity is associated with chronic low-grade inflammation and immune dysregulation, but the exact mechanisms through which it exacerbates COVID-19 infection are not fully clarified. The production of increased amounts of cytokines such as TNFα, IL-1, IL-6, and monocyte chemoattractant protein (MCP-1) lead to oxidative stress and defective function of innate and adaptive immunity, whereas the activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome seems to play a crucial role in the pathogenesis of the infection. Endothelial dysfunction and arterial stiffness could favor the recently discovered infection of the endothelium by SARS-CoV-2, whereas alterations in cardiac structure and function and the prothrombotic microenvironment in obesity could provide a link for the increased cardiovascular events in these patients. The successful use of anti-inflammatory agents such as IL-1 and IL-6 blockers in similar hyperinflammatory settings, like that of rheumatoid arthritis, has triggered the discussion of whether such agents could be administrated in selected patients with COVID-19 disease.

positive: Treatment of severely ill COVID-19 patients with anti-interleukin drugs (COV-AID): A structured summary of a study protocol for a randomised controlled trial OBJECTIVES: The purpose of this study is to test the safety and effectiveness of individually or simultaneously blocking IL-6, IL-6 receptor and IL-1 versus standard of care on blood oxygenation and systemic cytokine release syndrome in patients with COVID-19 coronavirus infection and acute hypoxic respiratory failure and systemic cytokine release syndrome. TRIAL DESIGN: A phase 3 prospective, multi-center, interventional, open label, 6-arm 2x2 factorial design study. PARTICIPANTS: Subjects will be recruited at the specialized COVID-19 wards and/or ICUs at 16 Belgian participating hospitals. Only adult (≥18y old) patients will be recruited with recent (≤16 days) COVID-19 infection and acute hypoxia (defined as PaO2/FiO2 below 350mmHg or PaO2/FiO2 below 280 on supplemental oxygen and immediately requiring high flow oxygen device or mechanical ventilation) and signs of systemic cytokine release syndrome characterized by high serum ferritin, or high D-dimers, or high LDH or deep lymphopenia or a combination of those, who have not been on mechanical ventilation for more than 24 hours before randomisation. Patients should have had a chest X-ray and/or CT scan showing bilateral infiltrates within the last 2 days before randomisation. Patients with active bacterial or fungal infection will be excluded. INTERVENTION AND COMPARATOR: Patients will be randomized to 1 of 5 experimental arms versus usual care. The experimental arms consist of Anakinra alone (anti-IL-1 binding the IL-1 receptor), Siltuximab alone (anti-IL-6 chimeric antibody), a combination of Siltuximab and Anakinra, Tocilizumab alone (humanised anti-IL-6 receptor antibody) or a combination of Anakinra with Tocilizumab in addition to standard care. Patients treated with Anakinra will receive a daily subcutaneous injection of 100mg for a maximum of 28 days or until hospital discharge, whichever comes first. Siltuximab (11mg/kg) or Tocilizumab (8mg/kg, with a maximum dose of 800mg) are administered as a single intravenous injection immediately after randomization. MAIN OUTCOMES: The primary end point is the time to clinical improvement defined as the time from randomization to either an improvement of two points on a six-category ordinal scale measured daily till day 28 or discharge from the hospital or death. This ordinal scale is composed of (1) Death; (2) Hospitalized, on invasive mechanical ventilation or ECMO; (3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; (4) Hospitalized, requiring supplemental oxygen; (5) Hospitalized, not requiring supplemental oxygen; (6) Not hospitalized. RANDOMISATION: Patients will be randomized using an Interactive Web Response System (REDCap). A 2x2 factorial design was selected with a 2:1 randomization regarding the IL-1 blockade (Anakinra) and a 1:2 randomization regarding the IL-6 blockade (Siltuximab and Tocilizumab). BLINDING (MASKING): In this open-label trial neither participants, caregivers, nor those assessing the outcomes are blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 342 participants will be enrolled: 76 patients will receive usual care, 76 patients will receive Siltuximab alone, 76 patients will receive Tocilizumab alone, 38 will receive Anakinra alone, 38 patients will receive Anakinra and Siltuximab and 38 patients will receive Anakinra and Tocilizumab. TRIAL STATUS: COV-AID protocol version 3.0 (15 Apr 2020). Participant recruitment is ongoing and started on April 4(th) 2020. Given the current decline of the COVID-19 pandemic in Belgium, it is difficult to anticipate the rate of participant recruitment. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on April 1st, 2020 (ClinicalTrials.gov Identifier: NCT04330638) and on EudraCT on April 3rd 2020 (Identifier: 2020-001500-41). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

positive: Translation: Management of Coronavirus Disease 2019 (COVID-19): Experience in Zhejiang Province, China The current epidemic situation of coronavirus disease 2019 (COVID-19) still remains severe. As the National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital of the Zhejiang University School of Medicine is the primary medical care center for COVID-19 in Zhejiang Province. Based on the present expert consensus carried out by the National Health Commission and National Administration of Traditional Chinese Medicine, our team summarized and established an effective treatment strategy centered on “Four-Anti and Two-Balance” for clinical practice. The “Four-Anti and Two-Balance” strategy includes antivirus, anti-shock, anti-hypoxemia, and anti-secondary infection, and maintaining of water, electrolyte and acid/base balance and microecological balance. Simultaneously, an integrated multidisciplinary personalized treatment is recommended to improve therapeutic effects. The importance of early viral detection, dynamic monitoring of inflammatory indexes, and chest radiographs has been emphasized in clinical decision-making. Sputum was observed with the highest positive rate by RT-PCR. Viral nucleic acids could be detected in 10% of the patients’ blood samples at the acute phase and 50% of patients had positive RT-PCR results in their feces. We also isolated live viral strains from feces, indicating potential infectiousness of feces. Dynamic cytokine detection was necessary to timely identify cytokine storms and for the application of the artificial liver blood purification system. The “Four-Anti and Two-Balance” strategy effectively increased cure rates and reduced mortality. Early antiviral treatment alleviated disease severity and prevented illness progression. We found that lopinavir/ritonavir combined with abidol showed antiviral effects against COVID-19. Shock and hypoxemia were usually caused by cytokine storms. The artificial liver blood purification system was able to rapidly remove inflammatory mediators and block the cytokine storm. Moreover, it also contributed to the balance of fluids, electrolytes, and acids/bases and thus improved treatment efficacy during critical illness. For cases of severe illness, early and also short periods of moderate glucocorticoid administration was supported. Patients with an oxygenation index below 200 mm Hg were transferred to the intensive care unit. Conservative oxygen therapy was preferred and noninvasive ventilation (NIV) was not recommended. Patients with mechanical ventilation were strictly supervised with cluster ventilator-associated pneumonia prevention strategies. Antimicrobial prophylaxis was prescribed rationally and was not recommended, except for patients with a long course of disease, repeated fever, and elevated procalcitonin, similarly secondary fungal infections were of concern. Some patients with COVID-19 showed intestinal microbial dysbiosis with decreased genus such as Lactobacillus and Bifidobacterium. Nutritional and gastrointestinal function should; therefore, be assessed for all patients. Nutritional support and application of prebiotics or probiotics were suggested to regulate the balance of intestinal microbiota and reduce the risk of secondary infections due to bacterial translocation. Anxiety and fear were common in patients with COVID-19. Therefore, we established a dynamic assessment and warning for psychological crises. We also integrated Chinese medicine in the treatment to promote rehabilitation. We optimized nursing processes for severe patients to promote their rehabilitation. Since viral clearance patterns after severe acute respiratory syndrome coronavirus 2 infections remained unclear, 2 weeks quarantine for discharged patients was required, and a regular following-up was also needed. These Zhejiang experiences and suggestions have been implemented in our center and achieved good results. However, since COVID-19 was a newly emerging disease, more work is warranted to further improve strategies of prevention, diagnosis, and treatment for COVID-19.

positive: Profiling COVID-19 pneumonia progressing into the cytokine storm syndrome: Results from a single Italian Centre study on tocilizumab versus standard of care OBJECTIVE: Approximately 5% of patients with coronavirus disease 2019 (COVID-19) develop a life-threatening pneumonia that often occurs in the setting of increased inflammation or "cytokine storm". Anti-cytokine treatments are being evaluated but optimal patient selection remains unclear, and the aim of our study is to address this point. METHODS: Between February 29 to April 6, 2020, 111 consecutive hospitalized patients with COVID-19 pneumonia were evaluated in a single centre retrospective study. Patients were divided in two groups: 42 severe cases (TOCI) with adverse prognostic features including raised CRP and IL-6 levels, who underwent anti-cytokine treatments, mostly tocilizumab, and 69 standard of care patients (SOC). RESULTS: In the TOCI group, all received anti-viral therapy and 40% also received glucocorticoids. In TOCI, 62% of cases were ventilated and there were three deaths (17.8 ± 10.6 days, mean follow up) with 7/26 cases remaining on ventilators, without improvement, and 17/26 developed bacterial superinfection. One fatality occurred in the 15 TOCI cases treated on noninvasive ventilation and one serious bacterial superinfection. Of the 69 cases in SOC, there was no fatalities and no bacterial complications. The TOCI group had higher baseline CRP and IL-6 elevations (p < 0.0001 for both) and higher neutrophils and lower lymphocyte levels (p = 0.04 and p = 0.001, respectively) with the TOCI ventilated patients having higher markers than non-ventilated TOCI patients. CONCLUSION: Higher inflammatory markers, more infections and worse outcomes characterized ventilated TOCI cases compared to ward based TOCI. Despite the confounding factors, this suggests that therapy time in anti-cytokine randomized trials will be key.

positive: Targeting JAK-STAT Signaling to Control Cytokine Release Syndrome in COVID-19 Recent advances in the pathophysiologic understanding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has indicated that patients with severe COVID-19 might experience cytokine release syndrome (CRS), characterized by increased interleukin (IL)-6, IL-2, IL-7, IL-10, etc. Therefore, the treatment of cytokine storm has been proposed as a critical part of rescuing severe COVID-19. Several of the cytokines involved in COVID-19 employ a distinct intracellular signaling pathway mediated by Janus kinases (JAKs). JAK inhibition, therefore, presents an attractive therapeutic strategy for CRS, which is a common cause of adverse clinical outcomes in COVID-19. Below, we review the possibilities and challenges of targeting the pathway in COVID-19.

positive: Can mesenchymal stem cell therapy be the interim management of COVID-19? COVID-19 pandemic has accounted for ~ 4.3 million confirmed cases and ~ 292,000 deaths (till 12th May, 2020) across the globe since its outbreak. Several anti-viral drugs such as RNA dependent RNA polymerase inhibitors (remdesivir, favipiravir, ribavirin), protease inhibitors (lopinavir, ritonavir) and drugs targeting endocytic pathway (hydroxychloroquine) are being evaluated for COVID-19 but standard therapeutics yet not available. Severe health deterioration in critically ill patients is characterized by pulmonary edema, severe respiratory distress, cytokine storm and septic shock. To combat cytokine storm, immune-therapy targeting IL-1, IL-2, IL-6 and TNFα are being evaluated and one of the promising immune-modulator is the mesenchymal stem cells (MSCs) that can surmount the severity of COVID-19 infections. Recent studies have shown that MSC-therapy significantly dampens the cytokine storm in critically ill COVID-19 patients. This communication endows with the insight of stem cell therapy and summarizes the recent studies on COVID-19 patients.

positive: Colchicina: una herramienta terapéutica potencial frente a COVID-19. Experiencia en 5 pacientes Resumen COVID-19 es una enfermedad de aparición reciente, que se ha convertido en un reto global de salud pública. Debido a la falta de conocimiento acerca del virus, se ha propuesto un número significativo de objetivos potenciales para utilizar un fármaco en particular. Presentamos aquí cinco casos con historia clínica de biopolímeros en la región glútea, que desarrollaron alogenosis iatrogénica (AI). A los 5 casos se les administró tratamiento de colchicina debido a crisis de AI, no teniendo síntomas específicos (cefalea, tos sin disnea, y artralgias), con resultado positivo en el test de SARS-CoV-2. Sus contactos cercanos tenían síntomas de leves a graves, y tres de ellos fallecieron. En la infección por SARS-CoV-2 se alteran diferentes rutas inflamatorias, en las que la colchicina reduce los niveles de citocinas y la activación de macrófagos, neutrófilos e inflamasoma. Revisamos también en este artículo los posibles mecanismos que puede utilizar colchicina para prevenir el síndrome de distrés respiratorio agudo (SDRA) en pacientes con COVID-19. Abstract COVID-19 is a newly emerged disease that has become a global public health challenge. Due to a lack of knowledge about the virus, a significant number of potential targets for using a particular drug have been proposed. Five cases with a clinical history of biopolymers in the gluteal region that developed iatrogenic allogenosis (IA) are presented here. The 5 cases were put under colchicine treatment for IA crisis and had non-specific symptoms (headache, cough without dyspnoea, and arthralgias) with a positive SARS-CoV-2 test. Their close contacts had mild to severe symptoms and three of them died. In the SARS-CoV-2 infection different inflammatory pathways are altered where colchicine reduces cytokine levels as well as the activation of macrophages, neutrophils, and the inflammasome. The possible mechanisms that colchicine may use to prevent acute respiratory distress syndrome (ARDS) in patients with COVID-19 infection are also reviewed in this article.

positive: Mechanistic modeling of the SARS-CoV-2 and immune system interplay unravels design principles for diverse clinicopathological outcomes The disease caused by SARS-CoV-2 is a global pandemic that threatens to bring long-term changes worldwide. Approximately 80% of infected patients are asymptomatic or have mild symptoms such as fever or cough, while rest of the patients have varying degrees of severity of symptoms, with 3-4% mortality rate. Severe symptoms such as pneumonia and Acute Respiratory Distress Syndrome can be caused by tissue damage mostly due to aggravated and unresolved innate and adaptive immune response, often resulting from a cytokine storm. However, the mechanistic underpinnings of such responses remain elusive, with an incomplete understanding of how an intricate interplay among infected cells and cells of innate and adaptive immune system can lead to such diverse clinicopathological outcomes. Here, we use a dynamical systems approach to dissect the emergent nonlinear intra-host dynamics among virally infected cells, the immune response to it and the consequent immunopathology. By mechanistic analysis of cell-cell interactions, we have identified key parameters affecting the diverse clinical phenotypes associated with COVID-19. This minimalistic yet rigorous model can explain the various phenotypes observed across the clinical spectrum of COVID-19, various co-morbidity risk factors such as age and obesity, and the effect of antiviral drugs on different phenotypes. It also reveals how a fine-tuned balance of infected cell killing and resolution of inflammation can lead to infection clearance, while disruptions can drive different severe phenotypes. These results will help further the case of rational selection of drug combinations that can effectively balance viral clearance and minimize tissue damage simultaneously. Significance Statement The SARS-CoV-2 pandemic has already infected millions of people, and thousands of lives have been lost to it. The pandemic has already tested the limits of our public healthcare systems with a wide spectrum of clinicopathological symptoms and outcomes. The mechanistic underpinnings of the resultant immunopathology caused by the viral infection still remains to be elucidated. Here we propose a minimalistic but rigorous description of the interactions of the virus infected cells and the core components of the immune system that can potentially explain such diversity in the observed clinical outcomes. Our proposed framework could enable a platform to determine the efficacy of various treatment combinations and can contributes a conceptual understanding of dynamics of disease pathogenesis in SARS-CoV-2 infections.

positive: Cytokine Storms: Understanding COVID-19 The elevated circulating levels of cytokines associated with a variety of infectious and immune-mediated conditions are frequently termed a cytokine storm. Here, we explain the protective functions of cytokines in "ideal" responses; the multi-factorial origins that can drive these responses to become pathological; and how this ultimately leads to vascular damage, immunopathology, and worsening clinical outcomes.

positive: Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients Abstract Infection caused by SARS-CoV-2 can result in severe respiratory complications and death. Patients with a compromised immune system are expected to be more susceptible to a severe disease course. In this report we suggest that patients with systemic lupus erythematous might be especially prone to severe COVID-19 independent of their immunosuppressed state from lupus treatment. Specifically, we provide evidence in lupus to suggest hypomethylation and overexpression of ACE2, which is located on the X chromosome and encodes a functional receptor for the SARS-CoV-2 spike glycoprotein. Oxidative stress induced by viral infections exacerbates the DNA methylation defect in lupus, possibly resulting in further ACE2 hypomethylation and enhanced viremia. In addition, demethylation of interferon-regulated genes, NFκB, and key cytokine genes in lupus patients might exacerbate the immune response to SARS-CoV-2 and increase the likelihood of cytokine storm. These arguments suggest that inherent epigenetic dysregulation in lupus might facilitate viral entry, viremia, and an excessive immune response to SARS-CoV-2. Further, maintaining disease remission in lupus patients is critical to prevent a vicious cycle of demethylation and increased oxidative stress, which will exacerbate susceptibility to SARS-CoV-2 infection during the current pandemic. Epigenetic control of the ACE2 gene might be a target for prevention and therapy in COVID-19.

positive: Contrasting evidence for corticosteroid treatment for coronavirus-induced cytokine storm

positive: An Open Question: Is It Rational to Inhibit the mTor-Dependent Pathway as COVID-19 Therapy?

positive: Diarrhea and altered inflammatory cytokine pattern in severe COVID-19: impact on disease course and in-hospital mortality. BACKGROUND Dynamic changes of immunocyte subsets and inflammatory profiles in coronavirus disease 2019(COVID-19) patients with gastrointestinal symptoms were undetermined. METHODS A single center retrospective analysis of 409 severe hospitalized COVID-19 patients from Jan 20 to Feb 29, 2020 was performed. The longitudinal characteristics of immune inflammatory cytokines in patients with/without diarrhea were analyzed. The relations of diarrhea and immuno-inflammatory factors with illness course and clinical outcomes were further explored. RESULTS Diarrhea was more common and more serious with longer duration (4.9 ± 1.5 days vs 4.2 ± 1.5 days, P=0.039) and higher frequency (5.5 ± 2.1 times/day vs 4.0 ± 2.0 times/day, P=0.001) in deceased patients than in the survivors. Also, diarrhea patients were more inclined to develop multi-organ damage, who had longer illness course (media 41.0 days vs 36.0 days, P=0.052) and hospital stays (media 27.0 days vs 23.0 days, P=0.041) in survivors, and higher mortality (33.0% vs 22.6%, P=0.045) and earlier death (media 20.0 days vs 25.0 days, P=0.038) in the deceased patients. Progressively neutrophilia and lymphopenia, especially the declined CD8+ T cells, were demonstrated in diarrhea patients relative to the non-diarrhea cases. The inflammatory cytokines including IL-6, IL-10 and TNF-α were intensively increased in patients with diarrhea. The multivariable logistic analysis showed longer duration of diarrhea (P=0.036), higher neutrophil counts (P=0.011) and lower lymphocyte counts (P<0.001) were independent risk factors of in-hospital death. The proportional hazards model indicated longer duration of diarrhea (P=0.002), higher frequency of diarrhea (P=0.058), higher neutrophil counts (P=0.001), lower lymphocyte counts (P=0.035) and decreased proportion of CD8+ T cells (P<0.001) were independently associated with longer illness course of the survivors. CONCLUSIONS Diarrhea patients were more likely to present with neutrophilia, lymphopenia and cytokine storm, and to develop multi-organ damage. The inflammatory patterns were independent factors associated with illness course of the survivors and in-hospital death of severe COVID-19.

positive: Mechanisms of neurological injury in COVID -19

positive: Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response PURPOSE OF REVIEW: Coronavirus disease of 2019 (COVID-19) is a cause of significant morbidity and mortality worldwide. While cardiac injury has been demonstrated in critically ill COVID-19 patients, the mechanism of injury remains unclear. Here, we review our current knowledge of the biology of SARS-CoV-2 and the potential mechanisms of myocardial injury due to viral toxicities and host immune responses. RECENT FINDINGS: A number of studies have reported an epidemiological association between history of cardiac disease and worsened outcome during COVID infection. Development of new onset myocardial injury during COVID-19 also increases mortality. While limited data exist, potential mechanisms of cardiac injury include direct viral entry through the angiotensin-converting enzyme 2 (ACE2) receptor and toxicity in host cells, hypoxia-related myocyte injury, and immune-mediated cytokine release syndrome. Potential treatments for reducing viral infection and excessive immune responses are also discussed. SUMMARY: COVID patients with cardiac disease history or acquire new cardiac injury are at an increased risk for in-hospital morbidity and mortality. More studies are needed to address the mechanism of cardiotoxicity and the treatments that can minimize permanent damage to the cardiovascular system.

positive: Melatonin: Roles in influenza, Covid‐19, and other viral infections There is a growing appreciation that the regulation of the melatonergic pathways, both pineal and systemic, may be an important aspect in how viruses drive the cellular changes that underpin their control of cellular function. We review the melatonergic pathway role in viral infections, emphasizing influenza and covid‐19 infections. Viral, or preexistent, suppression of pineal melatonin disinhibits neutrophil attraction, thereby contributing to an initial “cytokine storm”, as well as the regulation of other immune cells. Melatonin induces the circadian gene, Bmal1, which disinhibits the pyruvate dehydrogenase complex (PDC), countering viral inhibition of Bmal1/PDC. PDC drives mitochondrial conversion of pyruvate to acetyl‐coenzyme A (acetyl‐CoA), thereby increasing the tricarboxylic acid cycle, oxidative phosphorylation, and ATP production. Pineal melatonin suppression attenuates this, preventing the circadian “resetting” of mitochondrial metabolism. This is especially relevant in immune cells, where shifting metabolism from glycolytic to oxidative phosphorylation, switches cells from reactive to quiescent phenotypes. Acetyl‐CoA is a necessary cosubstrate for arylalkylamine N‐acetyltransferase, providing an acetyl group to serotonin, and thereby initiating the melatonergic pathway. Consequently, pineal melatonin regulates mitochondrial melatonin and immune cell phenotype. Virus‐ and cytokine‐storm‐driven control of the pineal and mitochondrial melatonergic pathway therefore regulates immune responses. Virus‐and cytokine storm‐driven changes also increase gut permeability and dysbiosis, thereby suppressing levels of the short‐chain fatty acid, butyrate, and increasing circulating lipopolysaccharide (LPS). The alterations in butyrate and LPS can promote viral replication and host symptom severity via impacts on the melatonergic pathway. Focussing on immune regulators has treatment implications for covid‐19 and other viral infections.

positive: Lilly to test baricitinib against COVID-19 Eli Lilly and Company and the US National Institute of Allergy and Infectious Diseases will study baricitinib, a Lilly rheumatoid arthritis drug, as a potential treatment for people with COVID-19 It’s thought that baricitinib’s anti-inflammatory effect could help reduce the cytokine storm that COVID-19 can trigger in patients Ruxolitinib, a cancer treatment from Novartis and Regeneron, is also being tested for its potential to dampen the cytokine storm

positive: COVID‐19 pneumonia treated with Sarilumab: A clinical series of eight patients The development of cytokine release syndrome and T cell abnormalities plays a key role in the progression of Coronavirus disease in 2019 (COVID-19). Under these circumstances, persistent viral stimulation leads to a significant increase in circulating cytokines such as interleukin (IL) -6, IL-10 and TNF-α. We describe a clinical series of eight patients treated with Sarilumab an IL-6R inhibitor administered early in Covid-19 pneumonia. This article is protected by copyright. All rights reserved.

positive: Is Adipose Tissue a Reservoir for Viral Spread, Immune Activation, and Cytokine Amplification in Coronavirus Disease 2019? Coronavirus disease 2019 (COVID‐19), the worst pandemic in more than a century, has claimed >125,000 lives worldwide to date. Emerging predictors for poor outcomes include advanced age, male sex, preexisting cardiovascular disease, and risk factors including hypertension, diabetes, and, more recently, obesity. This article posits new obesity‐driven predictors of poor COVID‐19 outcomes, over and above the more obvious extant risks associated with obesity, including cardiometabolic disease and hypoventilation syndrome in intensive care patients. This article also outlines a theoretical mechanistic framework whereby adipose tissue in individuals with obesity may act as a reservoir for more extensive viral spread, with increased shedding, immune activation, and cytokine amplification. This paper proposes studies to test this reservoir concept with a focus on specific cytokine pathways that might be amplified in individuals with obesity and COVID‐19. Finally, this paper underscores emerging therapeutic strategies that might benefit subsets of patients in which cytokine amplification is excessive and potentially fatal.

positive: Cytokine storm and immunomodulatory therapy in COVID-19: Role of chloroquine and anti-IL-6 monoclonal antibodies

positive: Calming Cytokine Storm in Pneumonia by Targeted Delivery of TPCA-1 Using Platelet-derived Extracellular Vesicles Summary Pneumonia can cause high morbidity and mortality due to the uncontrolled inflammation in the lung tissue. Calming the cytokine storm may be one key to save the life of patients with severe pneumonia. Here, inspired by the intrinsic affinity of platelets to the site of inflammation, we have engineered platelet-derived extracellular vesicles (PEVs) for pneumonia-targeted drug delivery. It is demonstrated that PEVs that are easily generated from the activated platelets can selectively target pneumonia in the mice model with acute lung injury (ALI). By loading with [5-(p-Fluorophenyl)-2-ureido] thiophene-3-carboxamide (TPCA-1) that can inhibit the production of inflammatory factors, the PEVs significantly improve therapeutic benefits by inhibiting the pulmonary inflammatory cells infiltration, and calming local cytokine storm compared with the free drug-treated group. Furthermore, we find that PEVs could serve as a broad platform that can selectively target various inflammatory sites, including chronic atherosclerotic plaque, rheumatoid arthritis and wound associated with skin.

positive: COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs In the Wuhan Province of China, in December 2019, the novel coronavirus 2019 (COVID-19) has caused a severe involvement of the lower respiratory tract leading to an acute respiratory syndrome. Subsequently, coronavirus 2 (SARS-CoV-2) provoked a pandemic which is considered a life-threatening disease. The SARS-CoV-2, a family member of betacoronaviruses, possesses single-stranded positive-sense RNA with typical structural proteins, involving the envelope, membrane, nucleocapsid and spike proteins that are responsible for the viral infectivity, and nonstructural proteins. The effectual host immune response including innate and adaptive immunity against SARS-Cov-2 seems crucial to control and resolve the viral infection. However, the severity and outcome of the COVID-19 might be associated with the excessive production of proinflammatory cytokines "cytokine storm" leading to an acute respiratory distress syndrome. Regretfully, the exact pathophysiology and treatment, especially for the severe COVID-19, is still uncertain. The results of preliminary studies have shown that immune-modulatory or immune-suppressive treatments such as hydroxychloroquine, interleukin (IL)-6 and IL-1 antagonists, commonly used in rheumatology, might be considered as treatment choices for COVID-19, particularly in severe disease. In this review, to gain better information about appropriate anti-inflammatory treatments, mostly used in rheumatology for COVID-19, we have focused the attention on the structural features of SARS-CoV-2, the host immune response against SARS-CoV-2 and its association with the cytokine storm.

positive: Flattening the COVID-19 Curve With Natural Killer Cell Based Immunotherapies Natural Killer (NK) cells are innate immune responders critical for viral clearance and immunomodulation. Despite their vital role in viral infection, the contribution of NK cells in fighting SARS-CoV-2 has not yet been directly investigated. Insights into pathophysiology and therapeutic opportunities can therefore be inferred from studies assessing NK cell phenotype and function during SARS, MERS, and COVID-19. These studies suggest a reduction in circulating NK cell numbers and/or an exhausted phenotype following infection and hint toward the dampening of NK cell responses by coronaviruses. Reduced circulating NK cell levels and exhaustion may be directly responsible for the progression and severity of COVID-19. Conversely, in light of data linking inflammation with coronavirus disease severity, it is necessary to examine NK cell potential in mediating immunopathology. A common feature of coronavirus infections is that significant morbidity and mortality is associated with lung injury and acute respiratory distress syndrome resulting from an exaggerated immune response, of which NK cells are an important component. In this review, we summarize the current understanding of how NK cells respond in both early and late coronavirus infections, and the implication for ongoing COVID-19 clinical trials. Using this immunological lens, we outline recommendations for therapeutic strategies against COVID-19 in clearing the virus while preventing the harm of immunopathological responses.

positive: On the Alert for Cytokine Storm: Immunopathology in COVID‐19 Poor outcomes in COVID‐19 correlate with clinical and laboratory features of cytokine storm syndrome. Broad screening for cytokine storm and early, targeted antiinflammatory therapy may prevent immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in cytokine storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID‐19.

positive: COVID-19 and ethnicity: A novel pathophysiological role for inflammation INTRODUCTION: There have been recent mounting concerns regarding multiple reports stating a significantly elevated relative-risk of COVID-19 mortality amongst the Black and Minority Ethnic (BAME) population. An urgent national enquiry investigating the possible reasons for this phenomenon has been issued in the UK. Inflammation is at the forefront of COVID-19 research as disease severity appears to correlate with pro-inflammatory cytokine dysregulation. This narrative review aims to shed light on the novel, pathophysiological role of inflammation in contributing towards the increased COVID-19 mortality risk amongst the BAME population. METHODS: Searches in PubMed, Medline, Scopus, medRxiv and Google Scholar were performed to identify articles published in English from inception to 18th June 2020. These databases were searched using keywords including: 'COVID-19' or 'Black and Minority Ethnic' or 'Inflammation'. A narrative review was synthesized using these included articles. RESULTS: We suggest a novel pathophysiological mechanism by which acute inflammation from COVID-19 may augment existing chronic inflammation, in order to potentiate a 'cytokine storm' and thus the more severe disease phenotype observed in the BAME population. Obesity, insulin resistance, cardiovascular disease, psychological stress, chronic infections and genetic predispositions are all relevant factors which may be contributing to elevated chronic systemic inflammation amongst the BAME population. CONCLUSION: Overall, this review provides early insights and directions for ongoing research regarding the pathophysiological mechanisms that may explain the severe COVID-19 disease phenotype observed amongst the BAME population. We suggest 'personalization' of chronic disease management, which can be used with other interventions, in order to tackle this.

positive: COVID-19 and immunomodulator/immunosuppressant use in dermatology

positive: Hypertension, the renin–angiotensin system, and the risk of lower respiratory tract infections and lung injury: implications for COVID-19: European Society of Hypertension COVID-19 Task Force Review of Evidence Systemic arterial hypertension (referred to as hypertension herein) is a major risk factor of mortality worldwide, and its importance is further emphasized in the context of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection referred to as COVID-19. Patients with severe COVID-19 infections commonly are older and have a history of hypertension. Almost 75% of patients who have died in the pandemic in Italy had hypertension. This raised multiple questions regarding a more severe course of COVID-19 in relation to hypertension itself as well as its treatment with renin–angiotensin system (RAS) blockers, e.g. angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). We provide a critical review on the relationship of hypertension, RAS, and risk of lung injury. We demonstrate lack of sound evidence that hypertension per se is an independent risk factor for COVID-19. Interestingly, ACEIs and ARBs may be associated with lower incidence and/or improved outcome in patients with lower respiratory tract infections. We also review in detail the molecular mechanisms linking the RAS to lung damage and the potential clinical impact of treatment with RAS blockers in patients with COVID-19 and a high cardiovascular and renal risk. This is related to the role of angiotensin-converting enzyme 2 (ACE2) for SARS-CoV-2 entry into cells, and expression of ACE2 in the lung, cardiovascular system, kidney, and other tissues. In summary, a critical review of available evidence does not support a deleterious effect of RAS blockers in COVID-19 infections. Therefore, there is currently no reason to discontinue RAS blockers in stable patients facing the COVID-19 pandemic.

positive: COVID-19: Pathogenesis, cytokine storm and therapeutic potential of interferons The outbreak of the novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) responsible for coronavirus disease 2019 (COVID-19) has developed into an unprecedented global pandemic. Clinical investigations in patients with COVID-19 has shown a strong upregulation of cytokine and interferon production in SARS-CoV2- induced pneumonia, with an associated cytokine storm syndrome. Thus, the identification of existing approved therapies with proven safety profiles to treat hyperinflammation is a critical unmet need in order to reduce COVI-19 associated mortality. To date, no specific therapeutic drugs or vaccines are available to treat COVID-19 patients. This review evaluates several options that have been proposed to control SARS-CoV2 hyperinflammation and cytokine storm, eincluding antiviral drugs, vaccines, small-molecules, monoclonal antibodies, oligonucleotides, peptides, and interferons (IFNs).

positive: Reduced inflammatory responses to SARS-CoV-2 infection in children presenting to hospital with COVID19 in China Background Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children is associated with better outcomes than in adults. The inflammatory response to COVID-19 infection in children remains poorly characterised. Methods We retrospectively analysed the medical records of 127 laboratory-confirmed COVID-19 patients aged 1 month to 16 years from Wuhan and Jingzhou of Hubei Province. Patients presented between January 25th and March 24th 2020. Information on clinical features, laboratory results, plasma cytokines/chemokines and lymphocyte subsets were analysed. Findings Children admitted to hospital with COVID-19 were more likely to be male (67.7%) and the median age was 7.3 [IQR 4.9] years. All but one patient with severe disease was aged under 2 and the majority (5/7) had significant co-morbidities. Despite 53% having viral pneumonia on CT scanning only 2 patients had low lymphocyte counts and no differences were observed in the levels of plasma proinflammatory cytokines, including interleukin (IL)-2, IL-4, IL-6, tumour necrosis factor (TNF)-alpha; and interferon (IFN)-gamma; between patients with mild, moderate or severe disease. Interpretations We demonstrated that the immune responses of children to COVID-19 infection is significantly different from that seen in adults. Our evidence suggests that SARS-CoV-2 does not trigger a robust inflammatory response or "cytokine storm" in children with COVID-19, and this may underlie the generally better outcomes seen in children with this disease. These data also imply anti-cytokine therapies may not be effective in children with moderate COVID-19.

positive: Rapid systematic review on clinical evidence of chloroquine and hydroxychloroquine in COVID-19: critical assessment and recommendation for future clinical trials Purpose: This study aims to critically assess the published studies of Chloroquine (CQ) and hydroxychloroquine (HCQ) for the treatment of COVID-19 and provide recommendations for future clinical trials for the COVID-19 pandemic. Method: A rapid systematic review was conducted by searching the PubMed, Embase, and China National Knowledge Infrastructure databases on April 13, 2020. Three clinical trial registry platforms, including ClinicalTrials.gov, the EU Clinical Trials Register, and the Chinese Clinical Trial Register were also complementarily searched. Results: A total of 10 clinical studies were identified, including 3 randomized controlled trials (RCTs), 1 comparative nonrandomized trial, 5 single-arm trials, and 1 interim analysis. The heterogeneity among studies of the baseline disease severity and reported endpoints made a pooled analysis impossible. CQ and HCQ (with or without azithromycin) showed significant therapeutic benefit in terms of virologic clearance rate, improvement in symptoms and imaging findings, time to clinical recovery, and length of hospital stay in 1 RCT, 4 single-arm trials, and the interim analysis, whereas no treatment benefit of CQ or HCQ was observed in the remaining 4 studies. Limitations of the included studies ranged from small sample size, to insufficient information concerning baseline patient characteristics, to potential for selection bias without detailing the rationale for exclusion, and presence of confounding factors. Conclusion: Based on the studies evaluated, there still lacked solid evidence supporting the efficacy and safety of HCQ and CQ as a treatment for COVID-19 with or without azithromycin. This emphasized the importance of robust RCTs investing HCQ/CQ to address the evidence uncertainties. Keywords: COVID-19, Systematic review, Clinical trial, Chloroquine, Hydroxychloroquine

positive: JAK1 inhibition blocks lethal sterile immune responses: implications for COVID-19 therapy Cytokine storms are drivers of pathology and mortality in myriad viral infections affecting the human population. In SARS-CoV-2-infected patients, the strength of the cytokine storm has been associated with increased risk of acute respiratory distress syndrome, myocardial damage, and death. However, the therapeutic value of attenuating the cytokine storm in COVID-19 remains to be defined. Here, we report results obtained using a novel mouse model of lethal sterile anti-viral immune responses. Using a mouse model of Down syndrome (DS) with a segmental duplication of a genomic region encoding four of the six interferon receptor genes (Ifnrs), we demonstrate that these animals overexpress Ifnrs and are hypersensitive to IFN stimulation. When challenged with viral mimetics that activate Toll-like receptor signaling and IFN anti-viral responses, these animals overproduce key cytokines, show exacerbated liver pathology, rapidly lose weight, and die. Importantly, the lethal immune hypersensitivity, accompanying cytokine storm, and liver hyperinflammation are blocked by treatment with a JAK1-specific inhibitor. Therefore, these results point to JAK1 inhibition as a potential strategy for attenuating the cytokine storm and consequent organ failure during overdrive immune responses. Additionally, these results indicate that people with DS, who carry an extra copy of the IFNR gene cluster encoded on chromosome 21, should be considered at high risk during the COVID-19 pandemic. One Sentence Summary Inhibition of the JAK1 kinase prevents pathology and mortality caused by a rampant innate immune response in mice.

positive: Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions The coronavirus disease-19 pandemic (COVID-19), which appeared in China in December 2019 and rapidly spread throughout the world, has forced clinicians and scientists to take up extraordinary challenges. This unprecedented situation led to the inception of numerous fundamental research protocols and many clinical trials. It quickly became apparent that although COVID-19, in the vast majority of cases, was a benign disease, it could also develop a severe form with sometimes fatal outcomes. Cytokines are central to the pathophysiology of COVID-19; while some of them are beneficial (type-I interferon, interleukin-7), others appear detrimental (interleukin-1ß, -6, and TNF-α) particularly in the context of the so-called cytokine storm. Yet another characteristic of the disease has emerged: concomitant immunodeficiency, notably involving impaired type-I interferon response, and lymphopenia. This review provides an overview of current knowledge on COVID-19 immunopathology. We discuss the defective type-I IFN response, the theoretical role of IL-7 to restore lymphocyte repertoire, as well as we mention the two patterns observed in severe COVID-19 (i.e. interleukin-1ß-driven macrophage activation syndrome vs. interleukin-6-driven immune dysregulation). Next, reviewing current evidence drawn from clinical trials, we examine a number of cytokine and anti-cytokine therapies, including interleukin-1, -6, and TNF inhibitors, as well as less targeted therapies, such as corticosteroids, chloroquine, or JAK inhibitors.

positive: Changing dynamics of psychoneuroimmunology during COVID-19 pandemic The Coronavirus Disease-2019 (COVID-19) pandemic has led to a global health care crisis in recent times. Emerging research suggest an unanticipated impact of COVID-19 on mental and/or psychological health of both the general community and affected individuals. The fear of the COVID-19 epidemic and the consequent lockdown and economic crisis has led to globally increased psychological distress. The biological bases of immediate and new onset of psychiatric symptoms in individuals with COVID-19 are not yet known. COVID-19 infection may lead to activated immune-inflammatory pathways and cytokine storm. Activated immune-inflammatory pathways, especially chronic low-grade inflammation, are associated with major psychiatric disorders in at least a subset of individuals. We propose that both the (sub)chronic inflammatory response and cytokine storm might crucially be involved in the immediate manifestation of neuropsychiatric symptoms in individuals with COVID-19 infection as well as heightened expression of psychiatric symptoms in COVID-19 infected individuals with prior psychiatric conditions. These events might expand concepts in psychoneuroimmunology, with the importance of chronic-low grade inflammation augmented by the cytokine storm hypothesis. Additionally, this might augment and refine diagnosis and prognostic management as well as treatment.

positive: Cytokine Storm in COVID19: A Neural Hypothesis Cytokine storm in COVID-19 is characterized by an excessive inflammatory response to SARS-CoV-2 that is caused by a dysregulated immune system of the host. We are proposing a new hypothesis that SARS-CoV-2 mediated inflammation of nucleus tractus solitarius (NTS) may be responsible for the cytokine storm in COVID 19. The inflamed NTS may result in a dysregulated cholinergic anti-inflammatory pathway and hypothalamic-pituitary-adrenal axis.

positive: Efficacy of therapeutic plasma exchange in severe COVID‐19 patients Coronavirus disease 2019 (COVID‐19) could lead to a sharp increase in the levels of inflammatory cytokines. We report the efficacy of therapeutic plasma exchange in severe COVID‐19 patients with acute respiratory distress syndrome. The results suggested TPE could be used as a strategy to attenuate circulating cytokines and inflammatory mediators.

positive: Integrative Network Biology Framework Elucidates Molecular Mechanisms of SARS-CoV-2 Pathogenesis COVID-19 (Coronavirus disease 2019) is a respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the pathophysiology of this deadly virus is complex and largely unknown, we employ a network biology-fueled approach and integrated multiomics data pertaining to lung epithelial cells-specific coexpression network and human interactome to generate Calu-3-specific human-SARS-CoV-2 Interactome (CSI). Topological clustering and pathway enrichment analysis show that SARS-CoV-2 target central nodes of host-viral network that participate in core functional pathways. Network centrality analyses discover 28 high-value SARS-CoV-2 targets, which are possibly involved in viral entry, proliferation and survival to establish infection and facilitate disease progression. Our probabilistic modeling framework elucidates critical regulatory circuitry and molecular events pertinent to COVID-19, particularly the host modifying responses and cytokine storm. Overall, our network centric analyses reveal novel molecular components, uncover structural and functional modules, and provide molecular insights into SARS-CoV-2 pathogenicity.

positive: Mechanism of thrombocytopenia in COVID-19 patients Since December 2019, a novel coronavirus has spread throughout China and across the world, causing a continuous increase in confirmed cases within a short period of time. Some studies reported cases of thrombocytopenia, but hardly any studies mentioned how the virus causes thrombocytopenia. We propose several mechanisms by which coronavirus disease 2019 causes thrombocytopenia to better understand this disease and provide more clinical treatment options.

positive: Surviving the storm: Dealing with COVID-19

positive: COVID-19: immunopathology and its implications for therapy Severe coronavirus disease 2019 (COVID-19) is characterized by pneumonia, lymphopenia, exhausted lymphocytes and a cytokine storm. Significant antibody production is observed; however, whether this is protective or pathogenic remains to be determined. Defining the immunopathological changes in patients with COVID-19 provides potential targets for drug discovery and is important for clinical management.

positive: High IL‐6/IFN‐γ ratio could be associated with severe disease in COVID‐19 patients Cytokines are important mediators of the inflammatory response, and during infection with SARS‐CoV‐2 it has been suggested that there is a cytokine storm syndrome. In this study, a meta‐analysis was performed to investigate whether the IL‐6/IFN‐γ ratio can help predict clinical severity in patients with COVID‐19. This article is protected by copyright. All rights reserved.

positive: Transcriptomic Similarities and Differences in Host Response between SARS-CoV-2 and Other Viral Infections COVID-19 is a pandemic that shares certain clinical characteristics with other acute viral infections. Here, we studied the whole-blood transcriptomic host response to SARS-CoV-2 and compared it with other viral infections to understand similarities and differences in host response. Using RNAseq we profiled peripheral blood from 24 healthy controls and 62 prospectively enrolled patients with community-acquired lower respiratory tract infection by SARS-Cov-2 within the first 24 hours of hospital admission. We also compiled and curated 23 independent studies that profiled 1,855 blood samples from patients with one of six viruses (influenza, RSV, HRV, ebola, Dengue, and SARS-CoV-1). We show gene expression changes in peripheral blood in patients with COVID-19 versus healthy controls are highly correlated with changes in response to other viral infections (r=0.74, p<0.001). However, two genes, ACO1 and ATL3, show significantly opposite changes between conditions. Pathway analysis in patients with COVID-19 or other viral infections versus healthy controls identified similar pathways including neutrophil activation, innate immune response, immune response to viral infection, and cytokine production for over-expressed genes. Conversely, for under-expressed genes, pathways indicated repression of lymphocyte differentiation and T cell activation. When comparing transcriptome profiles of patients with COVID-19 directly with those with other viral infections, we found 114 and 302 genes were over- or under-expressed, respectively, during COVID-19. Pathways analysis did not identify any significant pathways in these genes, suggesting novel responses to further study. Statistical deconvolution using immunoStates found that M1 macrophages, plasmacytoid dendritic cells, CD14+ monocytes, CD4+ T cells, and total B cells showed change consistently in the same direction across all viral infections including COVID-19. Those that increased in COVID-19 but decreased in non-COVID-19 viral infections were CD56bright NK cells, M2 macrophages, and total NK cells. The concordant and discordant responses mapped out here provide a window to explore the pathophysiology of COVID-19 versus other viral infections and show clear differences in signaling pathways and cellularity as part of the host response to SARS-CoV-2.

positive: Elucidating the Pivotal Role of Immune Players in the Management of COVID-19: Focus on Mesenchymal Stem Cells and Inflammation. The world is currently engulfed with a viral disease with no cure. So, far, millions of people are infected with the virus across the length and breadth of world with thousand losing their lives each passing day. The WHO is February 2020 classified the virus as a coronavirus and the name Coronavirus-19 (CoV-19) was offered to the virus. The disease caused by the virus was termed coronavirus disease-19 (COVID-19). The pathogenesis of COVID-19 is associated with elevation of several immune plays as well as inflammatory factors which contributes to cytokine storms. Currently, the detection of CoV-19 RNA is through reverse transcriptase polymerase chain reaction (RT-PCR). Mesenchymal stem cells (MSCs) are capable of suppressing several kinds of cytokines via the paracrine secretion system. Therefore, MSCs therapy could be game charges in the treatment of the current COVID-19 pandemic. Also, intravenous IG may be capable of suppressing the high expression of IL-6 by the CoV-19 resulting in lessen disease burden. Anti-inflammatory medications like, corticosteroids, tocilizumab, glycyrrhetinic acid, as well as etoposide may be very advantageous in decreasing the COVID-19 burden because, their mode of action targets the cytokine storms initiated by the CoV-19. It is important to indicate that, these medication does not target the virus itself. Therefore, potent CoV-19 anti-viral medications are needed to completely cure patients with COVID-19. Also, a vaccine is urgently needed to stop the spread of the virus. This review therefore elucidates the immune players in the management of COVID-19; focusing principally on MSCs and inflammatory mediators.

positive: Immunoregulation with mTOR inhibitors to prevent COVID‐19 severity: A novel intervention strategy beyond vaccines and specific antiviral medicines Coronavirus disease 2019 (COVID‐19) has become a major global public health concern. The mortality rate for critically ill patients is up to 60%, and, thus, reducing the disease severity and case mortality is a top priority. Currently, cytokine storms are considered as the major cause of critical illness and death due to COVID‐19. After a systematical review of the literature, we propose that cross‐reactive antibodies associated with antibody‐dependent enhancement (ADE) may actually be the cause of cytokine storms. It would be more difficult to develop vaccines for highly pathogenic human coronaviruses (CoVs) if ADE characteristics are taken into consideration. Therefore, it is urgent to find an effective way to prevent the occurrence of severe illness as severe acute respiratory syndrome CoV‐2 specific drugs or vaccines are still in development. If the activation of memory B cells can be selectively inhibited in high‐risk patients at an early stage of COVID‐19 to reduce the production of cross‐reactive antibodies against the virus, we speculate that ADE can be circumvented and severe symptoms can be prevented. The mammalian target of rapamycin (mTOR) inhibitors satisfy such needs and it is recommended to conduct clinical trials for mTOR inhibitors in preventing the severity of COVID‐19.

positive: Interleukin-6 blockade treatment for COVID-19 associated cytokine release syndrome in a patient with poorly controlled chronic myeloid leukaemia

positive: Targeted Immunosuppression Distinguishes COVID-19 from Influenza in Moderate and Severe Disease Coronavirus disease 2019 (COVID-19) is characterized by a high incidence of acute respiratory failure. The underlying immunopathology of that failure and how it compares to other causes of severe respiratory distress, such as influenza virus infection, are not fully understood. Here we addressed this by developing a prospective observational cohort of COVID-19 and influenza subjects with varying degrees of disease severity and assessing the quality and magnitude of their immune responses at the cellular and protein level. Additionally, we performed single-cell RNA transcriptional profiling of peripheral blood mononuclear cells from select subjects. The cohort consists of 79 COVID-19 subjects, 26 influenza subjects, and 15 control subjects, including 35 COVID-19 and 7 influenza subjects with acute respiratory failure. While COVID-19 subjects exhibited largely equivalent or greater activated lymphocyte counts compared to influenza subjects, they had fewer monocytes and lower surface HLA-class II expression on monocytes compared to influenza subjects and controls. At least two distinct immune profiles were observed by cytokine levels in severe COVID-19 patients: 3 of 71 patients were characterized by extreme inflammation, with greater than or equal to ~50% of the 35 cytokines measured greater than 2 standard deviations from the mean level of other severe patients (both influenza and COVID-19); the other immune profile, which characterized 68 of 71 subjects, had a mixed inflammatory signature, where 28 of 35 cytokines in COVID-19 patients had lower mean cytokine levels, though not all were statistically significant. Only 2 cytokines were higher in COVID-19 subjects compared to influenza subjects (IL-6 and IL-8). Influenza and COVID-19 patients could be distinguished statistically based on cytokine module expression, particularly after controlling for the significant effects of age on cytokine expression, but again with lower levels of most cytokines in COVID-19 subjects. Further, high circulating levels of IL-1RA and IL-6 were associated with increased odds of intubation in the combined influenza and COVID-19 cohort [OR = 3.93 and 4.30, respectively] as well as among only COVID-19 patients. Single cell transcriptional profiling of COVID-19 and influenza subjects with respiratory failure identified profound suppression in type I and type II interferon signaling in COVID-19 patients across multiple clusters. In contrast, COVID-19 cell clusters were enriched for alterations in metabolic, stress, and apoptotic pathways. These alterations were consistent with an increased glucocorticoid response in COVID-19 patients compared to influenza. When considered across the spectrum of innate and adaptive immune profiles, the immune pathologies underlying severe influenza and COVID-19 are substantially distinct. The majority of COVID-19 patients with acute respiratory failure do not have a cytokine storm phenotype but instead exhibit profound type I and type II IFN immunosuppression when compared to patients with acute influenza. Upregulation of a small number of inflammatory mediators, including IL-6, predicts acute respiratory failure in both COVID-19 and influenza patients.

positive: Associations between immune-suppressive and stimulating drugs and novel COVID-19—a systematic review of current evidence BACKGROUND: Cancer and transplant patients with COVID-19 have a higher risk of developing severe and even fatal respiratory diseases, especially as they may be treated with immune-suppressive or immune-stimulating drugs. This review focuses on the effects of these drugs on host immunity against COVID-19. METHODS: Using Ovid MEDLINE, we reviewed current evidence for immune-suppressing or -stimulating drugs: cytotoxic chemotherapy, low-dose steroids, tumour necrosis factorα (TNFα) blockers, interlukin-6 (IL-6) blockade, Janus kinase (JAK) inhibitors, IL-1 blockade, mycophenolate, tacrolimus, anti-CD20 and CTLA4-Ig. RESULTS: 89 studies were included. Cytotoxic chemotherapy has been shown to be a specific inhibitor for severe acute respiratory syndrome coronavirus in in vitro studies, but no specific studies exist as of yet for COVID-19. No conclusive evidence for or against the use of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of COVID-19 patients is available, nor is there evidence indicating that TNFα blockade is harmful to patients in the context of COVID-19. COVID-19 has been observed to induce a pro-inflammatory cytokine generation and secretion of cytokines, such as IL-6, but there is no evidence of the beneficial impact of IL-6 inhibitors on the modulation of COVID-19. Although there are potential targets in the JAK-STAT pathway that can be manipulated in treatment for coronaviruses and it is evident that IL-1 is elevated in patients with a coronavirus, there is currently no evidence for a role of these drugs in treatment of COVID-19. CONCLUSION: The COVID-19 pandemic has led to challenging decision-making about treatment of critically unwell patients. Low-dose prednisolone and tacrolimus may have beneficial impacts on COVID-19. The mycophenolate mofetil picture is less clear, with conflicting data from pre-clinical studies. There is no definitive evidence that specific cytotoxic drugs, low-dose methotrexate for auto-immune disease, NSAIDs, JAK kinase inhibitors or anti-TNFα agents are contraindicated. There is clear evidence that IL-6 peak levels are associated with severity of pulmonary complications.

positive: Unraveling the mystery of Covid-19 cytokine storm: From skin to organ systems COVID-19 is a global pandemic that emerged from Wuhan, China. Besides pneumonia and acute respiratory distress syndrome, the disease leads to multisystem involvement in the form of myocarditis, arrhythmias, cardiac arrest, gastrointestinal symptoms, hypoxemic brain injury, acute liver, and renal function impairment. There are also reports of cutaneous lesions in form of urticarial and maculopapular rashes, chilblain like fingers and toes (covid feet), livedoid vasculopathy, and chicken-pox like or varicelliform vesicles. Clinically, many of these skin lesions are likely secondary to occlusion of small to medium blood vessels due to microthrombi formation or due to viral laden antigen-antibody immune complexes; and same explanation may hold true for possible hypoxemic injury simultaneously occurring in other vital organs like lungs, heart, brain, and kidneys. The histopathology, immunoflorescence and RT-PCR analysis of skin biopsies can provide useful insights for ascertaining the pathogenesis of this complex viral syndrome. Apparently, it is interplay of disarmed cellular immunity and over-activated humoral immunity that culminates in end-organ changes. The morbidity and mortality can be significantly reduced by upgrading the cellular immunity and downgrading the humoral response; along with prevention of hypoxemic and reperfusion injuries by using antivirals, immunomodulators, antioxidants, anti-platelets, and anticoagulants in judicious and phased manner.

positive: Immunological determinants of clinical outcomes in COVID-19: A quantitative perspective Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a variable clinical presentation that ranges from asymptomatic, to severe disease with cytokine storm. The mortality rates also differ across the globe, ranging from 0.5-13%. This variation is likely due to both pathogen and host factors. Host factors may include genetic differences in the immune response genes as well as variation in HLA and KIR allotypes. To better understand what impact these genetic variants in immune response genes may have in the differences observed in the immune response to SARS-CoV-2, a quantitative analysis of a dynamical systems model that considers both, the magnitude of viral growth, and the subsequent innate and adaptive response required to achieve control of infection is considered. Based on this broad quantitative framework it may be posited that the spectrum of symptomatic to severely symptomatic presentations of COVID19 represents the balance between innate and adaptive immune responses. In asymptomatic patients, prompt and adequate adaptive immune response quells infection, whereas in those with severe symptoms a slower inadequate adaptive response leads to a runaway cytokine cascade fueled by ongoing viral replication. Polymorphisms in the various components of the innate and adaptive immune response may cause altered immune response kinetics that would result in variable severity of illness. Understanding how this genetic variation may alter the response to SARS-CoV-2 infection is critical to develop successful treatment strategies.

positive: Severe COVID-19, Another Piece in the Puzzle of the Hyperferritinemic Syndrome. An Immunomodulatory Perspective to Alleviate the Storm The coronavirus disease 2019 (COVID-19), an acute respiratory disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has been declared as a worldwide public health emergency. Interestingly, severe COVID-19 is characterized by fever, hyperferritinemia, and a hyper-inflammatory process with a massive release of pro-inflammatory cytokines, which may be responsible for the high rate of mortality. These findings may advocate for a similarity between severe COVID-19 and some challenging rheumatic diseases, such as adult onset Still's disease, secondary hemophagocytic lymphohistiocytosis, and catastrophic anti-phospholipid syndrome, which have been included in the "hyperferritinemic syndrome" category. Furthermore, as performed in these hyper-inflammatory states, severe COVID-19 may benefit from immunomodulatory therapies.

positive: [Advanced organ support and life-sustaining therapies in critically ill COVID-19 infected patients]. In critically ill patients with COVID-19 infection, the cardiorespiratory system may collapse by the following mechanisms: (1) cytokine storm, haemophagocytosis - septic shock, (2) uncontrollable hypoxaemia, (3) specific organ failure or multiple organ failure. In this summary, we review the currently available therapeutic options for the treatment and prevention of the above conditions. Removal of cytokines by CytoSorb haemoperfusion has been used more and more frequently and with encouraging success in recent years to treat septic shock. In the case of hypoxaemia, which can no longer be treated with conventional mechanical ventilation, inhaled nitric oxide (iNO), inhaled epoprostenol and venovenous extracorporeal membrane oxygenation (VV-ECMO) are considered. A common component of mostly late-stage organ failure is acute renal failure, which requires the initiation of one of the available continuous renal replacement therapies. Orv Hetil. 2020; 161 (17): 704-709.

positive: Targeting the NO‐cGMP‐PDE5 pathway in COVID‐19 infection A pandemic outbreak of COVID‐19 has been sweeping the world since December. It begins as a respiratory infection that, mainly in men with diabetes or renal impairment, evolves into a systemic disease, with SARDS, progressive endothelial cell damage, abnormal clotting and impaired cardiovascular and liver function. Some clinical trials are testing biological drugs to limit the immune system dysregulation, “cytokines storm”, that causes the systemic complications of COVID‐19. The contraindications of these drugs and their cost raise concerns over the implications of their widespread availability. Numerous clinical and experimental studies have revealed a role for the nitric oxide (NO)‐cyclic GMP‐phosphodiesterase type 5 (PDE5) pathway in modulating low‐grade inflammation in patients with metabolic diseases, offering cardiovascular protection. PDE5 inhibition favors an anti‐inflammatory response by modulating activated T cells, reducing cytokine release, lowering fibrosis, increasing oxygen diffusion, stimulating vascular repair. PDE5 is highly expressed in the lungs, where its inhibition improves pulmonary fibrosis, a complication of severe COVID‐19 disease. We performed a systematic review of all evidence documenting any involvement of the NO‐cGMP‐PDE5 axis in the pathophysiology of COVID‐19, presenting the ongoing clinical trials aimed at modulating this axis, including our own “silDEnafil administration in DiAbetic and dysmetaboLic patients with COVID‐19 (DEDALO trial)”. The reviewed evidence suggests that PDE5 inhibitors could offer a new strategy in managing COVID‐19 by (i) counteracting the Ang‐II‐mediated downregulation of AT‐1 receptor; (ii) acting on monocyte switching, thus reducing pro‐inflammatory cytokines, interstitial infiltration and the vessel damage responsible for alveolar hemorrhage‐necrosis; (iii) inhibiting the transition of endothelial and smooth muscle cells to mesenchymal cells in the pulmonary artery, preventing clotting and thrombotic complications. If the ongoing trials presented herein should provide positive findings, the low cost, wide availability and temperature stability of PDE5 inhibitors could make them a major resource to combat COVID‐19 in developing countries.

positive: COVID-19 Pulmonary and Olfactory Dysfunctions: Is the Chemokine CXCL10 the Common Denominator? COVID-19 is an ongoing viral pandemic that emerged from East Asia and quickly spread to the rest of the world SARS-CoV-2 is the virus causing COVID-19 Acute respiratory distress syndrome (ARDS) is definitely one of the main clinically relevant consequences in patients with COVID-19 Starting from the earliest reports of the COVID-19 pandemic, two peculiar neurological manifestations (namely, hyposmia/anosmia and dysgeusia) were reported in a relevant proportion of patients infected by SARS-CoV-2 At present, the physiopathologic mechanisms accounting for the onset of these symptoms are not yet clarified CXCL10 is a pro-inflammatory chemokine with a well-established role in the COVID-19-related cytokine storm and in subsequent development of ARDS CXCL10 is also known to be involved in coronavirus-induced demyelination On these bases, a role for CXCL10 as the common denominator between pulmonary and olfactory dysfunctions could be envisaged The aim of the present report will be to hypothesize a role for CXCL10 in COVID-19 olfactory dysfunctions Previous evidences supporting our hypothesis, with special emphasis to the role of CXCL10 in coronavirus-induced demyelination, the anatomical and physiological peculiarity of the olfactory system, and the available data supporting their link during COVID-19 infections, will be overviewed

positive: Baricitinib restrains the immune dysregulation in COVID-19 patients Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing pandemic coronavirus disease 2019 (COVID-19). The majority of patients with COVID-19 have a good prognosis, but variable percentages in different countries develop pneumonia associated with lymphocytopenia and severe inflammatory response due to uncontrolled release of cytokines. These immune mediators are transcriptionally regulated by JAK-STAT molecular pathways, which can be disabled by small molecules. Here, we provide evidences on the efficacy of baricitinib, a JAK1/JAK2 inhibitor, in correcting the immune abnormalities observed in patients hospitalized with COVID-19. Indeed, we demonstrate a significant reduction in serum levels of interleukin (IL)-6, IL-1{beta} and tumor necrosis factor (TNF), a rapid recovery in circulating T and B cell frequencies and an increased antibody production against SARS-CoV-2 spike protein in baricitinib-treated patients. Moreover, treated patients underwent a rapid reduction in oxygen flow need and progressive increase in the P/F. Our work provides the basis on developing effective treatments against COVID-19 pathogenesis using on-target therapy.

positive: Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Since the outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China, it has rapidly spread across many other countries. While the majority of patients were considered mild, critically ill patients involving respiratory failure and multiple organ dysfunction syndrome are not uncommon, which could result death. We hypothesized that cytokine storm is associated with severe outcome. We enrolled 102 COVID-19 patients who were admitted to Renmin Hospital (Wuhan, China). All patients were classified into moderate, severe and critical groups according to their symptoms. 45 control samples of healthy volunteers were also included. Inflammatory cytokines and C-Reactive Protein (CRP) profiles of serum samples were analyzed by specific immunoassays. Results showed that COVID-19 patients have higher serum level of cytokines (TNF-α, IFN-γ, IL-2, IL-4, IL-6 and IL-10) and CRP than control individuals. Within COVID-19 patients, serum IL-6 and IL-10 levels are significantly higher in critical group (n = 17) than in moderate (n = 42) and severe (n = 43) group. The levels of IL-10 is positively correlated with CRP amount (r = 0.41, P < 0.01). Using univariate logistic regression analysis, IL-6 and IL-10 are found to be predictive of disease severity and receiver operating curve analysis could further confirm this result (AUC = 0.841, 0.822 respectively). Our result indicated higher levels of cytokine storm is associated with more severe disease development. Among them, IL-6 and IL-10 can be used as predictors for fast diagnosis of patients with higher risk of disease deterioration. Given the high levels of cytokines induced by SARS-CoV-2, treatment to reduce inflammation-related lung damage is critical.

positive: [Advances in the research of mechanism and related immunotherapy on the cytokine storm induced by coronavirus disease 2019] Coronavirus disease 2019 (COVID-19) has seriously affected the safety of patients and social stability. Some COVID-19 patients in the later stage of disease may develop into acute respiratory distress syndrome or even multiple organ failure. However, one of the most important mechanisms underlying the deterioration of disease is cytokine storm. At present, some therapies such as interleukin-6 antibody blocker, stem cell therapy, and transfusion of convalescent plasma have been applied to counteract the cytokine storm with some progresses being achieved. This article reviews the influences of cytokine storm syndrome on the COVID-19 and the corresponding immunotherapies to resist cytokine storm.

positive: Are the cutaneous manifestations during or due to SARS-CoV-2 infection/COVID-19 frequent or not? Revision of possible pathophysiologic mechanisms BACKGROUND: SARS-Cov-2 is a single-stranded RNA virus, a Betacoronavirus, composed of 16 non-structural proteins, with specific roles in replication of coronaviruses. The pathogenesis of COVID-19 is not yet fully understood. The virus and host factors interplay among distinct outcomes of infected patients. METHODS: Using MeSH (Medical Subject Headings) in PubMed, authors searched for articles cotaining information on COVID-19 and the skin. RESULTS: The pathophysiology of the disease is multifactorial: association with innate immune response, hypercoagulability state, lung tissue damage, neurological and/or gastrointestinal tract involvement, monocytic/macrophage activation syndrome, culminating in exaggerated cytokine secretion, called "cytokine storm", which leads to worsening and death. These systemic conditions may be associated with cutaneous lesions, that have polymorphic aspects, where at histopathological level show involvement in different skin changes. These lesions may be associated with multisystemic manifestations that could occur due to angiotensin-converting enzyme 2 receptor and transmembrane serine protease action, allowing the pulmonary infection and possibly skin manifestation. Several reports in literature show cutaneous lesions similar to chilblain, urticarial eruptions, diffuse or disseminated erythema, livedo racemosa, blue toe syndrome, retiform purpura, vesicle trunk, purpuric exanthema or exanthema with clinical aspects of symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) and others. CONCLUSIONS: This review describes the complexity of Covid-19, pathophysiological and clinical aspects, dermatological finding and other dermatological conditions associated with SARS-CoV-2 infection or COVID-19.

positive: Current Insight into the Novel Coronavirus Disease 2019 (COVID-19) SARS-CoV-2 is a novel strain of coronavirus that has not been previously identified in humans. It has been declared a pandemic and has infected at least 1,844,683 individuals and caused 117,021 deaths as of 14th April 2020. Transmission among humans occurs via close contact with an infected individual that produces respiratory droplets. Patients have been shown to undergo acute respiratory distress syndrome, which is defined as cytokine storm. The diagnosis relies on detection of nucleic acid, IgG/IgM antibodies, and a chest radiograph of the suspected individuals. The genome of SARS-CoV-2 is similar to other coronaviruses that comprise of ten open reading frames (ORFs). SARS-CoV-2 spike protein exhibits higher affinity to ACE2 receptor as compared with SARS-CoV. Repurposing drugs like favipiravir, remdesivir, chloroquine, and TMPRSS2 protease inhibitors have been shown to be effective for the treatment of COVID-19. Personal protective measures should be followed to prevent SARS-CoV-2 infection. In addition, a clinical trial of SARS-CoV-2 vaccine, mRNA-1273, has been started. This chapter provides a glimpse of advancements made in the area of SARS-CoV-2 infection by proving recent clinical and research trials in the field.

positive: Cytokine release syndrome in severe COVID-19. Lessons from arthritis and cell therapy in cancer patients point to therapy for severe disease.

positive: Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients

positive: Tocilizumab treatment in COVID‐19: A single center experience Tocilizumab (TCZ), a monoclonal antibody against interleukin‐6 (IL‐6), emerged as an alternative treatment for COVID‐19 patients with a risk of cytokine storms recently. In the present study, we aimed to discuss the treatment response of TCZ therapy in COVID‐19 infected patients. The demographic, treatment, laboratory parameters of C‐reactive protein (CRP) and IL‐6 before and after TCZ therapy and clinical outcome in the 15 COVID‐19 patients were retrospectively assessed. Totally 15 patients with COVID‐19 were included in this study. Two of them were moderately ill, six were seriously ill and seven were critically ill. The TCZ was used in combination with methylprednisolone in eight patients. Five patients received the TCZ administration twice or more. Although TCZ treatment ameliorated the increased CRP in all patients rapidly, for the four critically ill patients who received an only single dose of TCZ, three of them (No. 1, 2, and 3) still dead and the CRP level in the rest one patient (No. 7) failed to return to normal range with a clinical outcome of disease aggravation. Serum IL‐6 level tended to further spiked firstly and then decreased after TCZ therapy in 10 patients. A persistent and dramatic increase of IL‐6 was observed in these four patients who failed treatment. TCZ appears to be an effective treatment option in COVID‐19 patients with a risk of cytokine storms. And for these critically ill patients with elevated IL‐6, the repeated dose of the TCZ is recommended.

positive: Inflammation, Immunity and Immunogenetics in COVID-19: A Narrative Review The novel Coronavirus Disease 2019 (COVID-19), that began in Wuhan Province, China was labelled as an International Public Health Emergency on January 30, 2020 and later was declared a pandemic by the World Health Organisation (WHO) on March 11, 2020. The causative agent, SARS-CoV-2 was the third coronavirus responsible for causing major disease outbreaks in human population after Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) caused by SARS-CoV and MERS-CoV respectively. The patients of COVID-19 present with a clinical feature resembling mild form of viral pneumonia which in certain cases progress to a severe form characterised by adult respiratory distress syndrome (ARDS) and/or multiorgan failure leading to death. The transition from mild to severe form of COVID-19 is affected by a lot of factors like age, co-morbidities etc. In the absence of an absolute cure, it is essential to explore the molecular pathogenesis of the disease to identify people at risk of developing severity so that alternative treatment modalities may be planned. The aim of this review is to provide an update on the general characteristics of SARS-CoV-2 and highlight the inflammatory changes and immune dysregulation that may help in identification of molecular predictors of disease severity.

negative: Glycyrrhizin inhibits the manifestations of anti-inflammatory responses that appear in association with systemic inflammatory response syndrome (SIRS)-like reactions Abstract In association with the systemic inflammatory response syndrome (SIRS), anti-inflammatory response syndrome is commonly manifested in patients with trauma, burn injury, and after major surgery. These patients are increasingly susceptible to infection with various pathogens due to the excessive release of anti-inflammatory cytokines from anti-inflammatory effector cells. Recently, CC-chemokine ligand 2 (CCL2) found in the sera of mice with pancreatitis was identified as an active molecule for SIRS-associated anti-inflammatory response manifestation. Also, the inhibitory activity of glycyrrhizin (GL) on CCL2 production was reported. Therefore, the effect of GL on SIRS-associated anti-inflammatory response manifestation was investigated in a murine SIRS model. Without any stimulation, splenic T cells from mice 5 days after SIRS induction produced cytokines associated with anti-inflammatory response manifestation. However, these cytokines were not produced by splenic T cells from SIRS mice previously treated with GL. In dual-chamber transwells, IL-4-producing cells were generated from normal T cells cultured with peripheral blood polymorphonuclear neutrophils (PMN) from SIRS mice. However, IL-4-producing cells were not generated from normal T cells in transwell cultures performed with PMN from GL-treated SIRS mice. CCL2 was produced by PMN from SIRS mice, while this chemokine was not demonstrated in cultures of PMN from SIRS mice treated with GL. These results indicate that GL has the capacity to suppress SIRS-associated anti-inflammatory response manifestation through the inhibition of CCL2 production by PMN.

negative: Simple Economical Solution for Personal Protection Equipment (Face Mask/Shield) for Health Care Staff During COVID 19 Coronavirus disease 2019 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2. It has taken a toll of lots of lives since its outbreak. Infection prevention at present is an appropriate control measure in addition to other measure like hand hygiene and personal protective equipment (PPE). In our country with a large population, supplying PPE to all the health care workers of all hospitals definitely is an economic burden. Hence we have come up with an economic and simple solution for face mask. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12070-020-01863-4) contains supplementary material, which is available to authorized users.

negative: Acalculous Acute Pancreatitis in a COVID-19 Patient Coronavirus disease 2019 (COVID-19) is a multisystemic condition caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with manifestations ranging from mild upper respiratory symptoms to cytokine storm causing acute respiratory distress syndrome. Pancreatic exocrine tissue and endocrine islets both express angiotensin-converting enzyme 2 (ACE2), the proven receptor for SARS-CoV-2 cell internalization. An increase in pancreatic enzymes has been increasingly recognized in patients with COVID-19, but little is known about the real prevalence of acute pancreatitis in this population. We report a case of acute acalculous pancreatitis in a COVID-19 patient. LEARNING POINTS: Acute pancreatitis may be a manifestation of SARS-CoV-2 infection. Future studies must address the real impact of pancreatic involvement in COVID-19 patients.

negative: Power of Artificial Intelligence to Diagnose and Prevent Further COVID-19 Outbreak: A Short Communication Novel coronavirus-19 (2019-nCoV or COVID-19) is by far the most dangerous coronavirus ever identified for the third time in the three decades capable of infecting not only the animals but also the humans across the globe. Nearly 6000 deaths have been recorded due mainly to COVID-19 outbreak worldwide and more than 50% of these deaths appeared to have evolved from China where the virus was thought to originate. The endemicity of COVID-19 dramatically surpassed severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) that were so far discovered in 2003 and 2012 respectively. Thus, the World Health Organization (WHO) has declared the 2019-nCoV outbreak not only a public health emergency but also pandemic in nature. Currently, over 120 countries including Nigeria were reported to have more than 157,844 confirmed cases and 5,846 deaths due mainly to COVID-19 outbreak as of March 15, 2020, 10:55 GMT. Artificial Intelligence (AI) is widely used to aid in the prediction, detection, response, recovery of disease and making clinical diagnosis. In this study, we highlighted the power of AI in the containment and mitigation of the spread of COVID-19 outbreak in African countries such as Nigeria where human to human contact is apparently inevitable.

negative: Association of national Bacille Calmette-Guerin vaccination policy with COVID-19 epidemiology: an ecological study in 78 countries A possible association between national Bacille Calmette-Guerin (BCG) vaccination policy and lower COVID-19 incidence has been suggested in some preprint papers. Using publicly accessible databases, I explored associations of national BCG vaccination policy with COVID-19 epidemiology in 78 countries. Data collection was conducted from April 25 to May 5, 2020. I compared countries that have a current universal BCG vaccination policy (BCG countries), with countries that currently lack such a policy (non-BCG countries). The mixed effect model revealed national BCG policy decreases in the country-specific risk of death by COVID-19, correspond to odds ratio of 0.446 (95% confidence intervals 0.323 - 0.614, P =1x10-5). In BCG countries, the case increase rate was attenuated marginally by 25.4% (95% CI 3.0 to 42.7, P=0.029) as compared with those of the non-BCG countries. Although the protective mechanism of BCG vaccination against COVID-19 remains unknown, further laboratory and clinical research should be warranted.

negative: An oncologist perspective on COVID 19: A mysterious cryptic virus

negative: Predicting COVID-19 Incidence Using Anosmia and Other COVID-19 Symptomatology: Preliminary Analysis Using Google and Twitter OBJECTIVE: To determine the relative correlations of Twitter and Google Search user trends concerning smell loss with daily coronavirus disease 2019 (COVID-19) incidence in the United States, compared to other severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) symptoms. To describe the effect of mass media communications on Twitter and Google Search user trends. STUDY DESIGN: Retrospective observational study. SETTING: United States. SUBJECTS AND METHODS: Google Search and “tweet” frequency concerning COVID-19, smell, and nonsmell symptoms of COVID-19 generated between January 1 and April 8, 2020, were collected using Google Trends and Crimson Hexagon, respectively. Spearman coefficients linking each of these user trends to COVID-19 incidence were compared. Correlations obtained after excluding a short timeframe (March 22 to March 24) corresponding to the publication of a widely read lay media publication reporting anosmia as a symptom of infection was performed for comparative analysis. RESULTS: Google searches and tweets concerning all nonsmell symptoms (0.744 and 0.761, respectively) and COVID-19 (0.899 and 0.848) are more strongly correlated with disease incidence than smell loss (0.564 and 0.539). Twitter users tweeting about smell loss during the study period were more likely to be female (52%) than users tweeting about COVID-19 more generally (47%). Tweet and Google Search frequency pertaining to smell loss increased significantly (>2.5 standard deviations) following a widely read media publication linking smell loss and SARS-CoV-2 infection. CONCLUSIONS: Google Search and tweet frequency regarding fever and shortness of breath are more robust indicators of COVID-19 incidence than anosmia. Mass media communications represent important confounders that should be considered in future analyses.

negative: Still puzzling questions in immunology (infection and immunity)

negative: Metronomic oral vinorelbine and lung cancer therapy during the COVID 19 pandemic: a single-center experience • Intravenous vinorelbine is a standard treatment for advanced NSCLC; • Oral vinorelbine is equally effective as compared to intravenous vinorelbine; • Metronomic oral formulation of vinorelbine is a safe and active treatment for advanced NSCLC; • No established treatment is a “gold standard” during COVID19 era; • Metronomic oral vinorelbine permitted to carry on active treatment during COVID Emergency; • Metronomic oral vinorelbine reduce side effects and hospital visits to lung cancer patients; • Management of lung cancer patients may be improved by metronomic oral vinorelbine.

negative: Health anxiety and behavioural changes of pregnant women during the COVID-19 pandemic

negative: Irradiation pulmonaire à faible dose pour l'orage de cytokines du COVID-19 : pourquoi pas ?/ [Low dose lung radiotherapy for COVID-19-related cytokine storm syndrome: Why not?]

negative: [Comparison of clinical and pathological features between severe acute respiratory syndrome and coronavirus disease 2019] Severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19) shared similar pathogenetic, clinical and pathological features. Fever and cough were the most common symptoms of both diseases, while myalgia and diarrhea were less common in patients with COVID-19. Acute respiratory distress syndrome (ARDS) was the most severe pulmonary complication that caused high mortality rate. Histologically, diffuse alveolar damage (DAD) was the most characteristic finding in non-survivors with either SARS or COVID-19. Cases of patients died less than 10-14 days of disease duration demonstrated acute-phase DAD, while cases beyond 10-14 days of disease duration exhibited organizing-phase DAD in SARS. Meanwhile, organization and fibrosis were usually accompanied by exudation. Coronavirus was mostly detected in pneumocytes, but less in macrophages and bronchiolar epithelial cells. Hemorrhagic necrosis and lymphocyte depletion were found in lymph nodes and spleen in both SARS and COVID-19, indicating a pathological basis of lymphocytopenia. Thrombosis was commonly observed in small vessels and microvasculaturr in lungs accompanying DAD. Microthrombosis was also found in extrapulmonary organs in COVID-19, that was less reported in SARS. Damages in multiple extrapulmonary organs were observed, but coronavirus was not detected in some of those organs, indicating an alternative mechanism beyond viral infection, such as hypoxemia, ischemia and cytokine storm induced immunological injury. DAD due to viral infection and immunological injury, as well as multi-organ dysfunction and extensive microthrombus formation, brought huge challenge to the management of patients with severe SARS or COVID-19.

negative: Potential Role of Platelets in COVID‐19: Implications for Thrombosis For the past 150 years, platelets have been recognized as the major blood component that mediates hemostasis and thrombosis. In more recent years, however, we have come to appreciate that platelets also perform profound immune functions during infection with various pathogens. We now recognize that platelets can also mediate a response to various RNA viruses such as influenza and that many viral infections, including the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), can affect platelet count. Thrombocytopenia and increased coagulation have been independently associated with increased mortality. This article provides a perspective on the potential roles of platelets during COVID‐19.

negative: Comparison of Hospitalized Patients With ARDS Caused by COVID-19 and H1N1 Background Since the outbreak of coronavirus disease 2019 (COVID-19) in China in December 2019, considerable attention has been focused on its elucidation. However, it is also important for clinicians and epidemiologists to differentiate COVID-19 from other respiratory infectious diseases such as influenza viruses. Research question The aim of this study was to explore the different clinical presentations between COVID-19 and influenza A (H1N1) pneumonia in patients with ARDS. Study Design and Methods This analysis was a retrospective case-control study. Two independent cohorts of patients with ARDS infected with either COVID-19 (n = 73) or H1N1 (n = 75) were compared. Their clinical manifestations, imaging characteristics, treatments, and prognosis were analyzed and compared. Results The median age of patients with COVID-19 was higher than that of patients with H1N1, and there was a higher proportion of male subjects among the COVID-19 cohort (P < .05). Patients with COVID-19 exhibited higher proportions of nonproductive coughs, fatigue, and GI symptoms than those of patients with H1N1 (P < .05). Patients with H1N1 had higher Sequential Organ Failure Assessment (SOFA) scores than patients with COVID-19 (P < .05). The Pao 2/Fio 2 of 198.2 mm Hg in the COVID-19 cohort was significantly higher than the Pao 2/Fio 2 of 107.0 mm Hg in the H1N1 cohort (P < .001). Ground-glass opacities was more common in patients with COVID-19 than in patients with H1N1 (P < .001). There was a greater variety of antiviral therapies administered to COVID-19 patients than to H1N1 patients. The in-hospital mortality of patients with COVID-19 was 28.8%, whereas that of patients with H1N1 was 34.7% (P = .483). SOFA score-adjusted mortality of H1N1 patients was significantly higher than that of COVID-19 patients, with a rate ratio of 2.009 (95% CI, 1.563-2.583; P < .001). Interpretation There were many differences in clinical presentations between patients with ARDS infected with either COVID-19 or H1N1. Compared with H1N1 patients, patients with COVID-19-induced ARDS had lower severity of illness scores at presentation and lower SOFA score-adjusted mortality.

negative: Ifitm3 Limits the Severity of Acute Influenza in Mice Interferon-induced transmembrane (IFITM) proteins are a family of viral restriction factors that inhibit the entry processes of several pathogenic viruses, including influenza A virus (IAV), in vitro. Here we report that IAV-infected knockout mice lacking the Ifitm locus on chromosome 7 exhibited accelerated disease progression, greater mortality, and higher pulmonary and systemic viral burdens as compared to wild type controls. We further observed that the phenotype of Ifitm3-specific knockout mice was indistinguishable from that of mice lacking the entire Ifitm locus. Ifitm3 was expressed by IAV target cells including alveolar type II pneumocytes and tracheal/bronchial respiratory epithelial cells. Robust Ifitm3 expression was also observed in several tissues in the absence of infection. Among murine Ifitm promoters, only that of Ifitm3 could be induced by type I and II interferons. Ifitm3 could also be upregulated by the gp130 cytokines IL-6 and oncostatin M on cells expressing appropriate receptors, suggesting that multiple cytokine signals could contribute to Ifitm3 expression in a cell or tissue-specific manner. Collectively, these findings establish a central role for Ifitm3 in limiting acute influenza in vivo, and provide further insight into Ifitm3 expression and regulation.

negative: COVID-19 in patients with rheumatic disease in Hubei province, China: a multicentre retrospective observational study BACKGROUND: In the ongoing COVID-19 pandemic, the susceptibility of patients with rheumatic diseases to COVID-19 remains unclear. We aimed to investigate susceptibility to COVID-19 in patients with autoimmune rheumatic diseases during the ongoing COVID-19 pandemic. METHODS: We did a multicentre retrospective study of patients with autoimmune rheumatic diseases in Hubei province, the epicentre of the COVID-19 outbreak in China. Patients with rheumatic diseases were contacted through an automated telephone-based survey to investigate their susceptibility to COVID-19. Data about COVID-19 exposure or diagnosis were collected. Families with a documented history of COVID-19 exposure, as defined by having at least one family member diagnosed with COVID-19, were followed up by medical professionals to obtain detailed information, including sex, age, smoking history, past medical history, use of medications, and information related to COVID-19. FINDINGS: Between March 20 and March 30, 2020, 6228 patients with autoimmune rheumatic diseases were included in the study. The overall rate of COVID-19 in patients with an autoimmune rheumatic disease in our study population was 0·43% (27 of 6228 patients). We identified 42 families in which COVID-19 was diagnosed between Dec 20, 2019, and March 20, 2020, in either patients with a rheumatic disease or in a family member residing at the same physical address during the outbreak. Within these 42 families, COVID-19 was diagnosed in 27 (63%) of 43 patients with a rheumatic disease and in 28 (34%) of 83 of their family members with no rheumatic disease (adjusted odds ratio [OR] 2·68 [95% CI 1·14–6·27]; p=0·023). Patients with rheumatic disease who were taking hydroxychloroquine had a lower risk of COVID-19 infection than patients taking other disease-modifying anti-rheumatic drugs (OR 0·09 [95% CI 0·01–0·94]; p=0·044). Additionally, the risk of COVID-19 was increased with age (adjusted OR 1·04 [95%CI 1·01–1·06]; p=0·0081). INTERPRETATION: Patients with autoimmune rheumatic disease might be more susceptible to COVID-19 infection than the general population. FUNDING: National Natural Science Foundation of China and the Tongji Hospital Clinical Research Flagship Program.

negative: Etoposid-based therapy for severe forms of COVID-19 Abstract The new coronavirus infection COVID-19 has quickly become a global health emergency. Mortality is principally due to severe Acute Respiratory Distress Syndrome (ARDS) which relays only on supportive treatment. Numerous pathological, clinical and laboratory findings rise the similarity between moderate to severe COVID-19 and haemophagocytic lymphohistiocytosis (HLH). Etoposide-based protocol including dexametasone is the standard of care for secondary HLH. The protocol has been successfully used in HLHs that are secondary to EBV and H1N1 infections by inducing complete response and pronged survival. These observations prompt to consider this cytotoxic therapy in HLH associated to moderately severe to severe forms of COVID-19.

negative: The involvement of the central nervous system in patients with COVID-19 Coronaviruses disease (COVID-19) has caused major outbreaks. A novel variant, SARS-CoV-2, is responsible for COVID-19 pandemic. Clinical presentations and pathological mechanisms of COVID-19 are broad. The respiratory aspect of the disease has been extensively researched. Emerging studies point out the possibility of the central nervous system (CNS) involvement by COVID-19. Here, we discuss the current evidence for CNS involvement in COVID-19 and highlight that the high pathogenicity of SARS-CoV-2 might be due to its neuroinvasive potential.

negative: Posterior Reversible Encephalopathy Syndrome: A Manifestation of COVID-19 Cytokine Storm Neuroimaging manifestations of COVID-19 are being reported with increasing frequency with recent reports of associated atypical leukoencephalopathies. We add to this literature by describing a COVID-19 + patient who demonstrated imaging findings typical for posterior reversible encephalopathy syndrome (PRES). The inflammatory syndrome associated with novel corona virus infection has shown markedly increased levels of cytokines and inflammatory markers. This has also been described in a proposed mechanism for PRES, where elevated inflammatory markers result in endothelial injury causing interstitial fluid extravasation typical of PRES. We expect that other cases of PRES will be observed in this population given the scope of the Covid-19 pandemic.

negative: The THRIVE score strongly predicts outcomes in patients treated with the Solitaire device in the SWIFT and STAR trials. BACKGROUND The Totaled Health Risks in Vascular Events (THRIVE) score strongly predicts clinical outcome, mortality, and risk of thrombolytic haemorrhage in ischemic stroke patients, and performs similarly well in patients receiving intravenous tissue plasminogen activator, endovascular stroke treatment, or no acute treatment. It is not known if the THRIVE score predicts outcomes with the Solitaire endovascular stroke treatment device. AIMS To validate the relationship between the THRIVE score and outcomes after treatment with the Solitaire endovascular stroke treatment device. METHODS The study conducted a retrospective analysis of the prospective SWIFT and STAR trials to examine the relationship between THRIVE and outcomes after treatment with the Solitaire device. We examined the relationship between THRIVE and clinical outcomes (good outcome or death at 90 days) among patients in SWIFT and STAR. Receiver-operator characteristics curve analysis was used to compare THRIVE score performance with other stroke prediction scores. Multivariable modeling was used to confirm the independence of the THRIVE score from procedure-specific predictors (successful recanalization or device used) and other predictors of functional outcome. RESULTS The THRIVE score strongly predicts good outcome and death among patients treated with the Solitaire device in SWIFT and STAR (Mantel-Haenszel chi-square test for trend P < 0·001 for good outcome, P = 0·01 for death). In receiver-operator characteristics (ROC) curve comparisons, totaled health risks in vascular events score is superior to Stroke Prognostication using Age and NIH Stroke Scale score-100 (P < 0·001) and performed similarly to Houston Intra-Arterial Therapy score (HIAT) (P = 0·98) and HIAT-2 (P = 0·54). In multivariable models, THRIVE's prediction of good outcome is not altered after controlling for recanalization or after controlling for device used. The THRIVE score remains a strong independent predictor after controlling for the above predictors together with time to procedure, rate of symptomatic haemorrhage, and use of general anesthesia. Of note, use of general anesthesia was not an independent predictor of outcome in SWIFT + STAR after controlling for totaled health risks in vascular events and other factors. CONCLUSIONS The THRIVE score strongly predicts clinical outcome and mortality in patients treated with the Solitaire device in the SWIFT and STAR trials. The lack of interaction between THRIVE and procedure-specific elements such as vessel recanalization or device choice makes the THRIVE score a reasonable candidate for use as a patient selection criterion in stroke clinical trials.

negative: Cutaneous sıde‐effects of the potential COVID‐19 drugs COVID‐19 disease is a highly contagious and particularly popular problem in all countries. A variety of repurposed drugs and investigational drugs such as remdesivir, chloroquine, hydroxychloroquine, ritonavir, lopinavir, interferon‐beta, and other potential drugs have been studied for COVID19 treatment. We reviewed the potential dermatological side‐effects of these drugs.

negative: Focus on the Crosstalk Between COVID-19 and Urogenital Systems

negative: Video-assisted thoracoscopic surgery extended thymectomy for myasthenia gravis using manual manipulators: the radius surgical system. A 32-year-old woman with ocular-typed myasthenia gravis (MG) without thymoma was admitted to the hospital to undergo surgical treatment. Video-assisted thoracoscopic surgery (VATS) extended thymectomy was successfully performed with three small ports using manual manipulators, the Radius Surgical System (RSS). The device may facilitate many degrees of freedom to general thoracic surgery.

negative: Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with Coronavirus Disease 2019 — United States, February 12–March 28, 2020 On March 11, 2020, the World Health Organization declared Coronavirus Disease 2019 (COVID-19) a pandemic (1). As of March 28, 2020, a total of 571,678 confirmed COVID-19 cases and 26,494 deaths have been reported worldwide (2). Reports from China and Italy suggest that risk factors for severe disease include older age and the presence of at least one of several underlying health conditions (3,4). U.S. older adults, including those aged ≥65 years and particularly those aged ≥85 years, also appear to be at higher risk for severe COVID-19-associated outcomes; however, data describing underlying health conditions among U.S. COVID-19 patients have not yet been reported (5). As of March 28, 2020, U.S. states and territories have reported 122,653 U.S. COVID-19 cases to CDC, including 7,162 (5.8%) for whom data on underlying health conditions and other known risk factors for severe outcomes from respiratory infections were reported. Among these 7,162 cases, 2,692 (37.6%) patients had one or more underlying health condition or risk factor, and 4,470 (62.4%) had none of these conditions reported. The percentage of COVID-19 patients with at least one underlying health condition or risk factor was higher among those requiring intensive care unit (ICU) admission (358 of 457, 78%) and those requiring hospitalization without ICU admission (732 of 1,037, 71%) than that among those who were not hospitalized (1,388 of 5,143, 27%). The most commonly reported conditions were diabetes mellitus, chronic lung disease, and cardiovascular disease. These preliminary findings suggest that in the United States, persons with underlying health conditions or other recognized risk factors for severe outcomes from respiratory infections appear to be at a higher risk for severe disease from COVID-19 than are persons without these conditions.

negative: Genetically modified mesenchymal stem cell therapy for acute respiratory distress syndrome Acute respiratory distress syndrome (ARDS) is a devastating hypoxemic respiratory failure, characterized by disruption of the alveolar-capillary membrane barrier. Current management for ARDS remains supportive, including lung-protective ventilation and a conservative fluid strategy. Mesenchymal stem cells (MSCs) have emerged as a potentially attractive candidate for the management of ARDS through facilitating lung tissue regeneration and repair by releasing paracrine soluble factors. Over the last decade, a variety of strategies have emerged to optimize MSC-based therapy. Among these, the strategy using genetically modified MSCs has received increased attention recently due to its distinct advantage, in conferring incremental migratory capacity and, enhancing the anti-inflammatory, immunomodulatory, angiogenic, and antifibrotic effects of these cells in numerous preclinical ARDS models, which may in turn provide additional benefits in the management of ARDS. Here, we provide an overview of recent studies testing the efficacy of genetically modified MSCs using preclinical models of ARDS.

negative: Novel Alphacoronaviruses and Paramyxoviruses Cocirculate with Type 1 and Severe Acute Respiratory System (SARS)-Related Betacoronaviruses in Synanthropic Bats of Luxembourg. Several infectious disease outbreaks with high mortality in humans have been attributed to viruses that are thought to have evolved from bat viruses. In this study from Luxembourg, the genetic diversity and epidemiology of paramyxoviruses and coronaviruses shed by the bat species Rhinolophus ferrumequinum and Myotis emarginatus were evaluated. Feces collection (n = 624) was performed longitudinally in a mixed-species colony in 2015 and 2016. In addition, feces (n = 254) were collected cross-sectionally from six Myotis emarginatus colonies in 2016. By use of degenerate primers in a nested format, overall prevalences of 1.1% (10/878) and 4.9% (43/878) were determined for paramyxoviruses and coronaviruses. Sequences of the partial RNA-dependent RNA polymerase and spike glycoprotein genes of coronaviruses, as well as sequences of the partial L gene of paramyxoviruses, were obtained. Novel paramyxovirus and Alphacoronavirus strains were identified in different Myotis emarginatus colonies, and severe acute respiratory syndrome (SARS)-related Betacoronavirus strains were shed by Rhinolophus ferrumequinum Logistic regression revealed that the level of Alphacoronavirus shedding was highest in July (odds ratio, 2.8; P < 0.01), probably due to periparturient stress. Phylogenetic analyses point to close virus-host coevolution, and the high genetic similarity of the study strains suggests that the Myotis emarginatus colonies in Luxembourg are socially connected. Most interestingly, we show that bats also host Betacoronavirus1 strains. The high similarity of the spike gene sequences of these viruses with mammalian Betacoronavirus 1 strains may be of concern. Both the SARS-related and Betacoronavirus 1 strains detected in bats in Luxembourg may cross the species barrier after a host adaptation process.IMPORTANCE Bats are a natural reservoir of a number of zoonotic pathogens. Several severe outbreaks in humans (e.g., a Nipah virus outbreak in Malaysia in 1998, and the almost global spread of severe acute respiratory syndrome in 2003) have been caused by bat-borne viruses that were transmitted to humans mostly after virus adaptation (e.g., in intermediate animal hosts). Despite the indigenousness of bat species that host viruses with suspected zoonotic potential and despite the zoonotic transmission of European bat 1 lyssavirus in Luxembourg, knowledge about the diversity and epidemiology of bat viruses remains limited in this country. Moreover, in contrast to other European countries, bat viruses are currently not included in the national surveillance activities of this land-locked country. We suggest that this gap in disease surveillance should be addressed, since we show here that synanthropic bats host viruses that may be able to cross the species barrier.

negative: Informational needs assessment of non‐Hodgkin lymphoma survivors and their physicians

negative: Prior diagnoses and medications as risk factors for COVID-19 in a Los Angeles Health System With the continuing coronavirus disease 2019 (COVID-19) pandemic coupled with phased reopening, it is critical to identify risk factors associated with susceptibility and severity of disease in a diverse population to help shape government policies, guide clinical decision making, and prioritize future COVID-19 research. In this retrospective case-control study, we used de-identified electronic health records (EHR) from the University of California Los Angeles (UCLA) Health System between March 9(th), 2020 and June 14(th), 2020 to identify risk factors for COVID-19 susceptibility (severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) PCR test positive), inpatient admission, and severe outcomes (treatment in an intensive care unit or intubation). Of the 26,602 individuals tested by PCR for SARS-CoV-2, 992 were COVID-19 positive (3.7% of Tested), 220 were admitted in the hospital (22% of COVID-19 positive), and 77 had a severe outcome (35% of Inpatient). Consistent with previous studies, males and individuals older than 65 years old had increased risk of inpatient admission. Notably, individuals self-identifying as Hispanic or Latino constituted an increasing percentage of COVID-19 patients as disease severity escalated, comprising 24% of those testing positive, but 40% of those with a severe outcome, a disparity that remained after correcting for medical comorbidities. Cardiovascular disease, hypertension, and renal disease were premorbid risk factors present before SARS-CoV-2 PCR testing associated with COVID-19 susceptibility. Less well-established risk factors for COVID-19 susceptibility included pre-existing dementia (odds ratio (OR) 5.2 [3.2–8.3], p=2.6 × 10(−10)), mental health conditions (depression OR 2.1 [1.6–2.8], p=1.1 × 10(−6)) and vitamin D deficiency (OR 1.8 [1.4–2.2], p=5.7 × 10(−6)). Renal diseases including end-stage renal disease and anemia due to chronic renal disease were the predominant premorbid risk factors for COVID-19 inpatient admission. Other less established risk factors for COVID-19 inpatient admission included previous renal transplant (OR 9.7 [2.8–39], p=3.2×10(−4)) and disorders of the immune system (OR 6.0 [2.3, 16], p=2.7×10(−4)). Prior use of oral steroid medications was associated with decreased COVID-19 positive testing risk (OR 0.61 [0.45, 0.81], p=4.3×10(−4)), but increased inpatient admission risk (OR 4.5 [2.3, 8.9], p=1.8×10(−5)). We did not observe that prior use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers increased the risk of testing positive for SARS-CoV-2, being admitted to the hospital, or having a severe outcome. This study involving direct EHR extraction identified known and less well-established demographics, and prior diagnoses and medications as risk factors for COVID-19 susceptibility and inpatient admission. Knowledge of these risk factors including marked ethnic disparities observed in disease severity should guide government policies, identify at-risk populations, inform clinical decision making, and prioritize future COVID-19 research.

negative: Demystifying the myths about COVID-19 infection and its societal importance

negative: Development of a rapid test kit for SARS-CoV-2: an example of product design We present an example of applying ‘need-driven’ product design principle to the development of a rapid test kit to detect SARS-COV-2 (COVID-19). The tests are intended for use in the field and, longer term, for home use. They detect whether a subject is currently infected with the virus and is infectious. The urgent need for large numbers of tests in field setting imposes constraints such as short test time and lack of access to specialist equipment, laboratories and skilled technicians to perform the test and interpret results. To meet these needs, an antigen test based on RT-LAMP with colorimetric readout was chosen. Direct use of swab sample with no RNA extraction was explored. After extensive experimental study (reported elsewhere), a rapid test kit has been fabricated to satisfy all design criteria.

negative: Considerations for the Development of Nasal Dosage Forms The anatomy and physiology of the nasal cavity provide unique advantages for accessing targets for local, systemic, and potentially central nervous system drug delivery. This chapter discusses these advantages and the challenges that must be overcome to reach these targets. The chapter then comprehensively reviews nasal dosage forms, analytical testing, and regulatory requirements in the context of existing nasal spray products. Since nasal sprays are moving towards being preservative-free, the chapter covers specialized methods of achieving a sterile product, namely, formulation strategies, manufacturing strategies, and the device landscape that support this upcoming platform. Finally, the chapter reviews various pathways for regulatory approval around the world, for brand and generic, with particular emphasis on the growing acceptance of in vitro data for locally acting nasal spray products.

negative: Cardiovascular manifestations and treatment considerations in covid-19 Since its recognition in December 2019, covid-19 has rapidly spread globally causing a pandemic. Pre-existing comorbidities such as hypertension, diabetes, and cardiovascular disease are associated with a greater severity and higher fatality rate of covid-19. Furthermore, covid-19 contributes to cardiovascular complications, including acute myocardial injury as a result of acute coronary syndrome, myocarditis, stress-cardiomyopathy, arrhythmias, cardiogenic shock, and cardiac arrest. The cardiovascular interactions of covid-19 have similarities to that of severe acute respiratory syndrome, Middle East respiratory syndrome and influenza. Specific cardiovascular considerations are also necessary in supportive treatment with anticoagulation, the continued use of renin-angiotensin-aldosterone system inhibitors, arrhythmia monitoring, immunosuppression or modulation, and mechanical circulatory support.

negative: SARS-CoV-2 Infection with Different Radiological Insights Severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) is a novel viral infection characterized by several symptoms range from mild to severe clinical conditions that could lead to death. We report two different radiological findings on computed tomography (CT) in two patients affected by SARS-CoV-2: a lung acute embolism (APE) in the first case and a radiological picture of acute respiratory distress syndrome (ARDS) in the second case. This is an important issue to be identified in order to provide more specific therapy earlier, including both antiviral and anti-inflammatory drugs associated with anti anticoagulant therapy.

negative: Relative antioxidant activities of quercetin and its structurally related substances and their effects on NF-κB/CRE/AP-1 signaling in murine macrophages Reactive oxygen species (ROS) and reactive nitrogen species (RNS) produced by the oxidative burst in activated macrophages and neutrophils cause oxidative stressimplicated diseases. Quercetin is flavonoid that occurs naturally in plants and is widely used as a nutritional supplement due to its antioxidant and anti-inflammatory properties. In this study, we investigated antioxidant activities and mechanisms of action in zymosan-induced macrophages of quercetin and quercetin-related flavonoids such as quercitrin, isoquercitrin, quercetin 3-O-β-(2″-galloyl)-rhamnopyranoside (QGR) and quercetin 3-O-β-(2″-galloyl)-glucopyranoside (QGG) as well as gallic acid, a building moiety of QGR and QGG. QGR and QGG exhibited stronger antioxidant activities compared with quercetin, whereas quercitrin, isoquercitrin and gallic acid exhibited weak-tono antioxidant activities, assessed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, superoxide production, superoxide scavenging, nitric oxide (NO) production, peroxynitrite (ONOO(−)) scavenging and myeloperoxidase (MPO) activity. Regarding mechanisms, the quercetincontaining flavonoids QGR and QGG differentially targeted compared with quercetin in the NF-κB signaling pathway that inhibited the DNA binding activity of the NF-κB complex without affecting the degradation and phosphorylation of IκBα and NF-κB phosphorylation. In addition, QGR and QGG inhibited CRE and activator protein (AP-1) transcriptional activity and JNK phosphorylation by inhibiting the cAMP/protein kinase A (PKA) and protein kinase C (PKC) signaling in a different manner than quercetin. Our results showed that although QGR and QGG exhibited stronger antioxidant activities than querce-tin in macrophages, their mechanisms of action in terms of the NF-κB, PKA and PKC signaling pathways were different.

negative: Extracorporeal Membrane Oxygenation in the Treatment of Severe Pulmonary and Cardiac Compromise in Coronavirus Disease 2019: Experience with 32 Patients As coronavirus disease 2019 (COVID-19) cases surge worldwide, an urgent need exists to enhance our understanding of the role of extracorporeal membrane oxygenation (ECMO) in the management of severely ill patients with COVID-19 who develop acute respiratory and cardiac compromise refractory to conventional therapy. The purpose of this manuscript is to review our initial clinical experience in 32 patients with confirmed COVID-19 treated with ECMO. A multi-institutional registry and database was created and utilized to assess all patients who were supported with ECMO provided by SpecialtyCare. Data captured included patient characteristics, pre-COVID-19 risk factors and comorbidities, confirmation of COVID-19 diagnosis, features of ECMO support, specific medications utilized to treat COVID-19, and short-term outcomes through hospital discharge. This analysis includes all of our patients with COVID-19 supported with ECMO, with an analytic window starting March 17, 2020, when our first COVID-19 patient was placed on ECMO, and ending April 9, 2020. During the 24 days of this study, 32 consecutive patients with COVID-19 were placed on ECMO at nine different hospitals. As of the time of analysis, 17 remain on ECMO, 10 died before or shortly after decannulation, and five are alive and extubated after removal from ECMO, with one of these five discharged from the hospital. Adjunctive medication in the surviving patients while on ECMO was as follows: four of five survivors received intravenous steroids, three of five survivors received antiviral medications (Remdesivir), two of five survivors were treated with anti-interleukin-6-receptor monoclonal antibodies (Tocilizumab or Sarilumab), and one of five survivors received hydroxychloroquine. An analysis of 32 COVID-19 patients with severe pulmonary compromise supported with ECMO suggests that ECMO may play a useful role in salvaging select critically ill patients with COVID-19. Additional patient experience and associated clinical and laboratory data must be obtained to further define the optimal role of ECMO in patients with COVID-19 and acute respiratory distress syndrome (ARDS). These initial data may provide useful information to help define the best strategies to care for these challenging patients and may also provide a framework for much-needed future research about the use of ECMO to treat patients with COVID-19.

negative: Ontology-based systematic classification and analysis of coronaviruses, hosts, and host-coronavirus interactions towards deep understanding of COVID-19 Given the existing COVID-19 pandemic worldwide, it is critical to systematically study the interactions between hosts and coronaviruses including SARS-Cov, MERS-Cov, and SARS-CoV-2 (cause of COVID-19). We first created four host-pathogen interaction (HPI)-Outcome postulates, and generated a HPI-Outcome model as the basis for understanding host-coronavirus interactions (HCI) and their relations with the disease outcomes. We hypothesized that ontology can be used as an integrative platform to classify and analyze HCI and disease outcomes. Accordingly, we annotated and categorized different coronaviruses, hosts, and phenotypes using ontologies and identified their relations. Various COVID-19 phenotypes are hypothesized to be caused by the backend HCI mechanisms. To further identify the causal HCI-outcome relations, we collected 35 experimentally-verified HCI protein-protein interactions (PPIs), and applied literature mining to identify additional host PPIs in response to coronavirus infections. The results were formulated in a logical ontology representation for integrative HCI-outcome understanding. Using known PPIs as baits, we also developed and applied a domain-inferred prediction method to predict new PPIs and identified their pathological targets on multiple organs. Overall, our proposed ontology-based integrative framework combined with computational predictions can be used to support fundamental understanding of the intricate interactions between human patients and coronaviruses (including SARS-CoV-2) and their association with various disease outcomes.

negative: Anti-radiation damage effect of polyethylenimine as a toll-like receptor 5 targeted agonist A number of agents are now available for use in protecting against ionizing radiation. These radiation-protective agents, however, have many adverse effects. Efforts have been made to develop new radiation-protective agents for medical application. Here, we investigated whether a compound, polyethylenimine (PEI), which activates Toll-like receptor 5 (TLR5)-mediated NF-kB signaling pathways, could have an anti-radiation effect on a mouse model. First, a cell-based screening model for an agonist of TLR5-mediated NF-kB pathway was established and then validated by activation of TLR5-mediated NF-kB luciferase reporter activity with a known TLR5 agonist, flagellin. We found that PEI induced dose-dependent activation of the TLR5-mediated NF-kB pathway, indicating that PEI is indeed a TLR5 agonist. Furthermore, the anti-radiation effect of polyethylenimine was assessed using a γ-ray total body irradiation (TBI) mouse model. Compared with the irradiation control, both survival time and survival rate were significantly improved in mice that received either a low dose of polyethylenimine (P= 0.019) or a high dose of polyethylenimine (P< 0.001). We also observed a positive correlation between animal body weight and survival time in mice that received a low dose of polyethylenimine, a high dose of polyethylenimine and amifostine, over a period of 30 days, r= 0.42 (P< 0.02), 0.72 (P< 0.0001) and 0.95 (P< 0.0001), respectively, while a negative correlation between animal body weight and survival time was observed in the irradiation control (r= –0.89; P< 0.0001). These results indicate that polyethylenimine is a new TLR5 agonist with potential application in offering protection for patients receiving radiotherapy or in radiation-related accidents.

negative: Prise en charge des cancers du sein pendant la pandémie de COVID 19 : le CNGOF se mobilise

negative: SARS-CoV-2 Infection Associated Hemophagocytic Lymphohistiocytosis: An autopsy series with clinical and laboratory correlation. Background: A subset of COVID-19 patients exhibit clinical features of cytokine storm. However, clinicopathologic features diagnostic of hemophagocytic lymphohistiocytosis (HLH) have not been reported. Pathologic studies to date have largely focused on the pulmonary finding of diffuse alveolar damage (DAD). To this aim, we study the reticuloendothelial organs of four consecutive patients dying of COVID-19 and correlate with clinical and laboratory parameters to detect HLH. Methods: Autopsies restricted to chest and abdomen were performed on four patients who succumbed to COVID-19. Spleen, liver, and multiple pulmonary hilar/mediastinal lymph nodes were sampled in all cases. Bone marrow was obtained by rib squeeze in a subset of cases. Routine H&E staining as well as immunohistochemical staining for CD163 was performed to detect hemophagocytosis. Clinical and laboratory results from pre-mortem blood samples were used to calculate H-scores. Findings: All four cases demonstrated DAD within the lungs. Three of the four cases had histologic evidence of hemophagocytosis within pulmonary hilar/mediastinal lymph nodes. One case showed hemophagocytosis in the spleen but none showed hemophagocytosis in liver or bone marrow. Lymphophagocytosis was the predominant form of hemophagocytosis observed. One patient showed diagnostic features of HLH with an H-score of 217 while a second patient was likely HLH with a partial H-score of 145 due to missing triglyceride level. Both patients exhibited high fever and early onset rise in serum ferritin; however, neither bicytopenia, pancytopenia, nor hypofibrinogenemia were observed in either. The remaining two patients had H-scores of 131 and 96. Interpretation: This is the first report of SARS-CoV-2 associated HLH. Identification of HLH in a subset of patients with severe COVID-19 will inform clinical trials of therapeutic strategies.

negative: Acute Kidney Injury in COVID-19 Pandemic

negative: Radiotherapy imaging: an unexpected ally in fighting COVID 19 pandemic

negative: Risk factors related to hepatic injury in patients with corona virus disease 2019 Aims: Corona virus disease 2019 (COVID-19) has rapidly become the most severe public health issue all over the world. Despite respiratory symptoms, hepatic injury has also been observed in clinical settings. This study aimed to investigate the risk factors involved with hepatic injury in the patients with COVID-19. Methods: A total of 85 hospitalized patients who were diagnosed with COVID-19 in Beijing Youan Hospital were retrospectively analyzed. According to liver function, they were divided into ALT normal group (n=52) and ALT elevation group (n=33). Clinical features and laboratory data were compared between the two groups. The independent risk factors for liver injury were analyzed. Results: There were 33 patients with hepatic injury in our study, accounting for 38.8% (33/85). The patients in ALT elevation group were older than those in ALT normal group. The levels of lactic acid, CRP, myoglobin, and neutrophils were significantly higher in ALT elevation group. The lymphocytes and albumin were significantly lower in ALT elevation group. The proportion of severe and critical patients in ALT elevation group was significantly higher. Multivariate logistic regression analysis showed CRP ≥20 mg/L and lymphocyte count< 1.1*10^9/L were independently related to hepatic injury. Conclusions: Lymphopenia and CRP may serve as the risk factors related to hepatic injury in patients with COVID-19, which might be related to inflammatory cytokine storm in liver injury. Early detection and timely treatment of hepatic injury in patients with COVID-19 are necessary.

negative: Program and Abstracts for the 2007 Meeting of the Society for Glycobiology

negative: International Expert Consensus Statement on Chest Imaging in Pediatric COVID-19 Patient Management: Imaging Findings, Imaging Study Reporting and Imaging Study Recommendations The coronavirus disease 2019 (COVID-19) has quickly spread since it was first detected in December of 2019 to a global pandemic with over 1.7 million confirmed cases in over 200 countries around the world at the time this document is being prepared. Due to the novel nature of the virus and the rapidly evolving understanding of the disease, there is a great deal of uncertainty surrounding the diagnosis and management of COVID-19 pneumonia in pediatric patients. Chest imaging plays an important role in evaluation of pediatric patients with COVID-19, however there is currently little information available describing imaging manifestations of pediatric COVID-19 and even less discussing utilization of imaging studies in pediatric patients. To specifically address these concerns, a group of international experts in pediatric thoracic imaging from 5 continents convened to create a consensus statement describing the imaging manifestations of COVID-19 in the pediatric population, discussing the potential utility of structured reporting during the coronavirus 2019 pandemic, and generating consensus recommendations for utilization of chest radiographs (CXR) and computed tomography (CT) in the evaluation of pediatric patients with COVID-19. The results were compiled into 2 structured reporting algorithms (one for CXR and one for chest CT) and 8 consensus recommendations for utilization of chest imaging in pediatric COVID-19 infection.

negative: Seven recommendations to rescue the patients and reduce the mortality from COVID-19 infection: An immunological point of view Now COVID-19 is causing a severe public health emergency and the mortality is rapidly increasing all over the world. In the current pandemic era, although there have been many efforts to diagnose a number of patients with symptoms or close contacts, there is no definite guideline for the initial therapeutic approach for them and therefore, many patients have been dying due to a hyperinflammatory immunological reaction labeled as "cytokine storm". Severe patients are hospitalized and the treatment is done, though they have not been established yet. Currently, however, no treatment is provided for those who are isolated at home or shelter until they get severe symptoms, which will increase the harms to the patients. In this review, we discuss some important points dedicated to the management of patients with COVID-19, which should help reducing morbidity and mortality. In this era, we suggest 7 recommendations to rescue the patients and to reduce the morbidity and mortality due to COVID-19 based on the immunological point of view.

negative: COVID-19 and homelessness in England: a modelling study of theCOVID-19 pandemic among people experiencing homelessness, and theimpact of a residential intervention to isolate vulnerable people andcare for people with symptoms Background: There is an ongoing pandemic of the viral respiratory disease COVID-19. People experiencing homelessness are vulnerable to infection and severe disease. Health and housing authorities in England have developed a residential intervention that aims to isolate those vulnerable to severe disease (COVID-PROTECT) and care for people with symptoms (COVID CARE). Methods: We used a discrete-time Markov chain model to forecast COVID-19 infections among people experiencing homelessness, given strong containment measures in the general population and some transmission among 35,817 people living in 1,065 hostels, and 11,748 people sleeping rough (the 'do nothing' scenario). We then estimated demand for beds if those eligible are offered COVID-PROTECT and COVID-CARE. We estimated the reduction in the number of COVID-19 cases, deaths, and hospital admissions that could be achieved by these interventions. We also conducted sensitivity and scenario analyses to identify programme success factors. Results: In a 'do nothing' scenario, we estimate that 34% of the homeless population could get COVID-19 between March and August 2020, with 364 deaths, 4,074 hospital admissions and 572 critical care admissions. In our 'base intervention' scenario, demand for COVID-PROTECT peaks at 9,934 beds, and demand for COVID-CARE peaks at 1,366 beds. The intervention could reduce transmission by removing symptomatic individuals from the community, and preventing vulnerable individuals from being infected. This could lead to a reduction of 164 deaths, 2,624 hospital admissions, and 248 critical care admissions over this period. Sensitivity analyses showed that the number of deaths is sensitive to transmission of COVID-19 in COVID-PROTECT. If COVID-PROTECT capacity is limited, scenario analyses show the benefit of prioritising people who are vulnerable to severe disease. Conclusion: Supportive accommodation can mitigate the impact of the COVID-19 pandemic on the homeless population of England, and reduce the burden on acute hospitals.

negative: Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2 ACE2 (angiotensin-converting enzyme 2) has a multiplicity of physiological roles that revolve around its trivalent function: a negative regulator of the renin-angiotensin system, facilitator of amino acid transport, and the severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2 receptor. ACE2 is widely expressed, including, in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 has recently been identified as the SARS-CoV-2 receptor, the infective agent responsible for coronavirus disease 2019, providing a critical link between immunity, inflammation, ACE2, and cardiovascular disease. Although sharing a close evolutionary relationship with SARS-CoV, the receptor-binding domain of SARS-CoV-2 differs in several key amino acid residues, allowing for stronger binding affinity with the human ACE2 receptor, which may account for the greater pathogenicity of SARS-CoV-2. The loss of ACE2 function following binding by SARS-CoV-2 is driven by endocytosis and activation of proteolytic cleavage and processing. The ACE2 system is a critical protective pathway against heart failure with reduced and preserved ejection fraction including, myocardial infarction and hypertension, and against lung disease and diabetes mellitus. The control of gut dysbiosis and vascular permeability by ACE2 has emerged as an essential mechanism of pulmonary hypertension and diabetic cardiovascular complications. Recombinant ACE2, gene-delivery of Ace2, Ang 1-7 analogs, and Mas receptor agonists enhance ACE2 action and serve as potential therapies for disease conditions associated with an activated renin-angiotensin system. rhACE2 (recombinant human ACE2) has completed clinical trials and efficiently lowered or increased plasma angiotensin II and angiotensin 1-7 levels, respectively. Our review summarizes the progress over the past 20 years, highlighting the critical role of ACE2 as the novel SARS-CoV-2 receptor and as the negative regulator of the renin-angiotensin system, together with implications for the coronavirus disease 2019 pandemic and associated cardiovascular diseases.

negative: AI4COVID-19: AI enabled preliminary diagnosis for COVID-19 from cough samples via an app BACKGROUND: The inability to test at scale has become humanity's Achille's heel in the ongoing war against the COVID-19 pandemic. A scalable screening tool would be a game changer. Building on the prior work on cough-based diagnosis of respiratory diseases, we propose, develop and test an Artificial Intelligence (AI)-powered screening solution for COVID-19 infection that is deployable via a smartphone app. The app, named AI4COVID-19 records and sends three 3-s cough sounds to an AI engine running in the cloud, and returns a result within 2 min. METHODS: Cough is a symptom of over thirty non-COVID-19 related medical conditions. This makes the diagnosis of a COVID-19 infection by cough alone an extremely challenging multidisciplinary problem. We address this problem by investigating the distinctness of pathomorphological alterations in the respiratory system induced by COVID-19 infection when compared to other respiratory infections. To overcome the COVID-19 cough training data shortage we exploit transfer learning. To reduce the misdiagnosis risk stemming from the complex dimensionality of the problem, we leverage a multi-pronged mediator centered risk-averse AI architecture. RESULTS: Results show AI4COVID-19 can distinguish among COVID-19 coughs and several types of non-COVID-19 coughs. The accuracy is promising enough to encourage a large-scale collection of labeled cough data to gauge the generalization capability of AI4COVID-19. AI4COVID-19 is not a clinical grade testing tool. Instead, it offers a screening tool deployable anytime, anywhere, by anyone. It can also be a clinical decision assistance tool used to channel clinical-testing and treatment to those who need it the most, thereby saving more lives.

negative: Smoking prevalence and COVID-19 in Europe INTRODUCTION: This ecological study investigates the association between smoking prevalence and COVID-19 occurrence and mortality in 38 European nations as of 30(th) May 2020. METHODS: Data were collected from Our World in Data. Regression analysis was conducted to adjust for potential confounding factors such as economic activity (GDP), the rate of COVID-19 testing, and the stringency of COVID-19 control policies. RESULTS: There was a statistically significant negative association between smoking prevalence and the prevalence of COVID-19 across the 38 European nations after controlling for confounding factors (p = 0.001). A strong association was found between the prevalence of COVID-19 per million people and economic activity (p = 0.002) and the rate of COVID-19 testing (p = 0.0006). Nations with stricter policy enactment showed fewer COVID-19 cases per million people, but the association was not significant (p = 0.122). Delaying policy enactment was associated with a greater prevalence of COVID-19 (p = 0.0535). Evidence of a direct association between smoking prevalence and COVID-19 mortality was not found (p = 0.626). There was a strong positive association between COVID-19 mortality rate and the prevalence of COVID-19 cases (p < 0.0001) as well as the proportion of the population over 65 years of age (p = 0.0034) and a negative association with the rate of COVID-19 testing (p = 0.0023). CONCLUSIONS: We found a negative association between smoking prevalence and COVID-19 occurrence at the population level in 38 European countries. This association may not imply a true or causal relationship, and smoking is not advocated as a prevention or treatment of COVID-19.

negative: Novel coronavirus (COVID-19) infection: What a doctor on the frontline needs to know Coronavirus disease 2019 (COVID-19) is a zoonotic respiratory infection originating from Wuhan, China. Rapidly spreading from Wuhan to all inhabited continents of the world, the World Health Organisation declared COVID-19 a pandemic on March 11, 2019. Infected patients present with fever and cough; radiological features include bilateral infiltrates on chest x-ray and computed tomography scanning. Management is supportive with oxygen supplementation, broad-spectrum antibiotics as well as careful fluid balancing. A number of drugs, both new and old, are currently in clinical trials and being used on an experimental basis in clinical practice. The COVID-19 pandemic is the greatest worldwide public health crisis of a generation, and has led to seismic political, economic and social changes. This review provides an overview of COVID-19 for junior doctors who find themselves on a new frontline of healthcare.

negative: Prise en charge des cancers du sein pendant la pandémie de COVID 19: le CNGOF se mobilise

negative: Knowledge of Avian Influenza (H5N1) among Poultry Workers, Hong Kong, China In 2009, a cross-sectional survey of 360 poultry workers in Hong Kong, China, showed that workers had inadequate levels of avian influenza (H5N1) risk knowledge, preventive behavior, and outbreak preparedness. The main barriers to preventive practices were low perceived benefits and interference with work. Poultry workers require occupation-specific health promotion.

negative: Putative conformations of the receptor-binding domain in S protein of hCoV-EMC in complex with its receptor dipeptidyl peptidase-4

negative: Cytokine Storm: is it the only major death factor in COVID-19 patients? Coagulation role

negative: COVID-19, SARS and MERS: A neurological perspective Abstract Central to COVID-19 pathophysiology is an acute respiratory infection primarily manifesting as pneumonia. Two months into the COVID-19 outbreak, however, a retrospective study in China involving more than 200 participants revealed a neurological component to COVID-19 in a subset of patients. The observed symptoms, the cause of which remains unclear, included impaired consciousness, skeletal muscle injury and acute cerebrovascular disease, and appeared more frequently in severe disease. Since then, findings from several studies have hinted at various possible neurological outcomes in COVID-19 patients. Here, we review the historical association between neurological complications and highly pathological coronaviruses including SARS, MERS and COVID-19. We draw from evidence derived from past coronavirus outbreaks, noting the similarities and differences between SARS and MERS and the current COVID-19 pandemic. We end by briefly discussing possible mechanisms by which the coronavirus impacts on the human nervous system, as well as neurology-specific considerations that arise from the repercussions of COVID-19.

negative: Electrical Storm in COVID-19 Abstract COVID-19 is a global pandemic caused by SARS-CoV-2. Infection is associated with significant morbidity and mortality. Individuals with pre-existing cardiovascular disease or evidence of myocardial injury are at risk for severe disease and death. Little is understood about the mechanisms of myocardial injury or life-threatening cardiovascular sequelae.

negative: Any unique image biomarkers associated with COVID-19? OBJECTIVE: To define the uniqueness of chest CT infiltrative features associated with COVID-19 image characteristics as potential diagnostic biomarkers. METHODS: We retrospectively collected chest CT exams including n = 498 on 151 unique patients RT-PCR positive for COVID-19 and n = 497 unique patients with community-acquired pneumonia (CAP). Both COVID-19 and CAP image sets were partitioned into three groups for training, validation, and testing respectively. In an attempt to discriminate COVID-19 from CAP, we developed several classifiers based on three-dimensional (3D) convolutional neural networks (CNNs). We also asked two experienced radiologists to visually interpret the testing set and discriminate COVID-19 from CAP. The classification performance of the computer algorithms and the radiologists was assessed using the receiver operating characteristic (ROC) analysis, and the nonparametric approaches with multiplicity adjustments when necessary. RESULTS: One of the considered models showed non-trivial, but moderate diagnostic ability overall (AUC of 0.70 with 99% CI 0.56–0.85). This model allowed for the identification of 8–50% of CAP patients with only 2% of COVID-19 patients. CONCLUSIONS: Professional or automated interpretation of CT exams has a moderately low ability to distinguish between COVID-19 and CAP cases. However, the automated image analysis is promising for targeted decision-making due to being able to accurately identify a sizable subsect of non-COVID-19 cases. KEY POINTS: • Both human experts and artificial intelligent models were used to classify the CT scans. • ROC analysis and the nonparametric approaches were used to analyze the performance of the radiologists and computer algorithms. • Unique image features or patterns may not exist for reliably distinguishing all COVID-19 from CAP; however, there may be imaging markers that can identify a sizable subset of non-COVID-19 cases.

negative: Blood transfusion utilization in hospitalized COVID‐19 patients BACKGROUND: The acute respiratory illness designated coronavirus disease 2019 (COVID‐19) was first reported in Wuhan, China, in December 2019 and caused a worldwide pandemic. Concerns arose about the impact of the COVID‐19 pandemic on blood donations and potential significant blood transfusion needs in severely ill COVID‐19 patients. Data on blood usage in hospitalized COVID‐19 patients are scarce. STUDY DESIGN AND METHODS: We performed a retrospective observational study of blood component transfusions in the first 4 weeks of COVID‐19 ward admissions. The study period began 14 days before the first COVID‐19 cohort wards opened in our hospital in March 2020 and ended 28 days afterward. The number of patients and blood components transfused in the COVID‐19 wards was tabulated. Transfusion rates of each blood component were compared in COVID‐19 wards versus all other inpatient wards. RESULTS: COVID‐19 wards opened with seven suspected patients and after 4 weeks had 305 cumulative COVID‐19 admissions. Forty‐one of 305 hospitalized COVID‐19 patients (13.4%) received transfusions with 11.1% receiving red blood cells (RBCs), 1.6% platelets (PLTs), 1.0% plasma, and 1.0% cryoprecipitate (cryo). COVID‐19 wards had significantly lower transfusion rates compared to non‐COVID wards for RBCs (0.03 vs 0.08 units/patient‐day), PLTs (0.003 vs 0.033), and plasma (0.002 vs 0.018; all p < 0.0001). Cryo rates were similar (0.008 vs 0.009, p = 0.6). CONCLUSIONS: Hospitalized COVID‐19 patients required many fewer blood transfusions than other hospitalized patients. COVID‐19 transfusion data will inform planning and preparation of blood resource utilization during the pandemic.

negative: Safety Guidelines for Sterility of Face Shields During COVID 19 Pandemic Face shields are personal protective equipment devices that are to be used by many health care workers during COVID 19 pandemic for protection of the facial area and associated mucous membranes (eyes, nose, mouth) from droplet spread of infection. Face shields are generally not used alone, but in conjunction with other protective equipment like cap, mask, goggle, and are therefore classified as adjunctive personal protective equipment. In the wake of scarcity of face shields during the COVID 19 Pandemic, consideration of innovating newer methods of manufacturing must be considered to overcome the present day scarcity without jeopardising the safety of front line Heath care workers. All initial fast innovations comes with advantages and disadvantages, hence we thought of putting down simple guidelines for new emerged face shield use.

negative: Description and Proposed Management of the Acute COVID-19 Cardiovascular Syndrome Coronavirus disease 2019 (COVID-19) is a rapidly expanding global pandemic caused by severe acute respiratory syndrome coronavirus 2, resulting in significant morbidity and mortality. A substantial minority of patients hospitalized develop an acute COVID-19 cardiovascular syndrome, which can manifest with a variety of clinical presentations but often presents as an acute cardiac injury with cardiomyopathy, ventricular arrhythmias, and hemodynamic instability in the absence of obstructive coronary artery disease. The cause of this injury is uncertain but is suspected to be related to myocarditis, microvascular injury, systemic cytokine-mediated injury, or stress-related cardiomyopathy. Although histologically unproven, severe acute respiratory syndrome coronavirus 2 has the potential to directly replicate within cardiomyocytes and pericytes, leading to viral myocarditis. Systemically elevated cytokines are also known to be cardiotoxic and have the potential to result in profound myocardial injury. Prior experience with severe acute respiratory syndrome coronavirus 1 has helped expedite the evaluation of several promising therapies, including antiviral agents, interleukin-6 inhibitors, and convalescent serum. Management of acute COVID-19 cardiovascular syndrome should involve a multidisciplinary team including intensive care specialists, infectious disease specialists, and cardiologists. Priorities for managing acute COVID-19 cardiovascular syndrome include balancing the goals of minimizing healthcare staff exposure for testing that will not change clinical management with early recognition of the syndrome at a time point at which intervention may be most effective. This article aims to review the best available data on acute COVID-19 cardiovascular syndrome epidemiology, pathogenesis, diagnosis, and treatment. From these data, we propose a surveillance, diagnostic, and management strategy that balances potential patient risks and healthcare staff exposure with improvement in meaningful clinical outcomes.

negative: Inflammatory Bowel Diseases and Biological Treatment in SARS-CoV-2 Era. Why Not?

negative: COVID-19 Comes 40 Years After AIDS - Any Lesson? The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has hit health-care systems and societies in an unprecedented manner. In 1981, the first cases of AIDS were reported and wide diagnostic testing helped to characterize high-risk groups and the global burden of the epidemic. With Coronavirus Disease (COVID)-19, everything has happened too fast and both cases and fatalities are huge but still uncertain in most places. Diagnostic testing of active and past SARS-CoV-2 infections needs to expand rapidly, ideally using rapid tests. COVID-19 deaths are highly concentrated in the elderly population, with a large proportion of fatalities being "with" rather than "by" SARS-CoV-2 infection. They are often the result of inadequate health care due to overwhelming demands. To date, there is no specific therapy for SARS-CoV-2 infection. Several antivirals are being tested clinically, including remdesivir, at this time the most promising. For others such as lopinavir/ritonavir, neither significant virological nor clinical benefit has been shown. Given the characteristic pulmonary cytokine storm underlying the pathogenic mechanism of severe COVID-19 pneumonia and acute respiratory distress, antiinflammatory agents are being investigated. The benefit of orticosteroids, hydroxychloroquine, etc., is limited. Monoclonal antibodies targeting different pro-inflammatory cytokines, such as tocilizumab, an anti-interleukin 6 agent, are being tried with encouraging results. Ultimately a protective vaccine will be the best response for controlling the COVID-19 pandemic.

negative: Equity360: Gender, Race, and Ethnicity-COVID-19 and Preparing for the Next Pandemic

negative: Hazardous Postoperative Outcomes of Unexpected COVID-19 Infected Patients: A Call for Global Consideration of Sampling all Asymptomatic Patients Before Surgical Treatment BACKGROUND: In December 2019, a novel coronavirus was identified as the cause of many pneumonia cases in China and eventually declared as a pandemic as the virus spread globally. Few reports were published on the outcome of surgical procedures in diagnosed COVID-19 patients and even fewer on the surgical outcomes of asymptomatic undiagnosed COVID-19 surgical patients. We aimed to review all published data regarding surgical outcomes of preoperatively asymptomatic untested coronavirus disease 2019 (COVID-19) patients. METHODS: This report is a review on the perioperative period in COVID-19 patients who were preoperatively asymptomatic and not tested for COVID-19. Searches were conducted in PubMed April 4th, 2020. All publications, of any design, were considered for inclusion. RESULTS: Four reports were identified through our literature search, comprising 64 COVID-19 carriers, of them 51 were diagnosed only in the postoperative period. Synthesis of these reports, concerning the postoperative outcomes of patients diagnosed with COVID-19 during the perioperative period, suggested a 14/51 (27.5%) postoperative mortality rate and severe mostly pulmonic complications, as well as medical staff exposure and transmission. CONCLUSIONS: COVID-19 may have potential hazardous implications on the perioperative course. Our review presents results of unacceptable mortality rate and a high rate of severe complications. These observations warrant further well-designed studies, yet we believe it is time for a global consideration of sampling all asymptomatic patients before surgical treatment.

negative: Cytokines Cytokines, currently known to be more than 130 in number, are small MW (<30 kDa) key signaling proteins that modulate cellular activities in immunity, infection, inflammation, and malignancy. Key to understanding their function is recognition of their pleiotropism and often overlapping and functional redundancies. Classified here into 9 main families, most of the 23 approved cytokine preparations (19 different cytokines and 4 pegylated), all in recombinant human (rh) form, are grouped in the hematopoietic growth factor, interferon (IFN), platelet-derived growth factor (PDGF), and transforming growth factor β (TGFβ) families. In the hematopoietin family, approved cytokines are aldesleukin (rhIL-2), oprelvekin (rhIL-11), filgrastim and tbo-filgrastim (rhG-CSF), sargramostim (rhGM-CSF), metreleptin (rh-leptin), ancestim (rh-SCF), and the rh-erythropoietins, epoetin and darbepoetin alfa. Anakinra, a recombinant receptor antagonist for IL-1, is in the IL-1 family; recombinant interferons alfa-1, alfa-2, beta-1, and gamma-1 make up the interferon family; palifermin (rhKGF) and becaplermin (rhPDGF) are in the PDGF family; and rhBMP-2 and rhBMP-7 represent the TGFβ family. The main physicochemical features, FDA-approved indications, modes of action and side effects of these approved cytokines are presented. Underlying each adverse events profile is their pleiotropism, potency and capacity to release other cytokines producing cytokine “cocktails.” Side effects, some serious, occur despite cytokines being endogenous proteins, and this therefore demands caution in attempts to introduce individual members into the clinic. This caution is reflected in the relatively small number of cytokines currently approved by regulatory agencies and by the fact that 15 of the FDA-approved preparations carry warnings, with 10 being black box warnings.

negative: Reply: The Optimal Management of Electrodiagnostic Studies during COVID-19 Outbreak

negative: Keeping the Country Positive during the COVID 19 Pandemic: Evidence from India

negative: Cystic Fibrosis Gene Therapy: Looking Back, Looking Forward Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes a cAMP-regulated anion channel. Although CF is a multi-organ system disease, most people with CF die of progressive lung disease that begins early in childhood and is characterized by chronic bacterial infection and inflammation. Nearly 90% of people with CF have at least one copy of the ΔF508 mutation, but there are hundreds of CFTR mutations that result in a range of disease severities. A CFTR gene replacement approach would be efficacious regardless of the disease-causing mutation. After the discovery of the CFTR gene in 1989, the in vitro proof-of-concept for gene therapy for CF was quickly established in 1990. In 1993, the first of many gene therapy clinical trials attempted to rescue the CF defect in airway epithelia. Despite the initial enthusiasm, there is still no FDA-approved gene therapy for CF. Here we discuss the history of CF gene therapy, from the discovery of the CFTR gene to current state-of-the-art gene delivery vector designs. While implementation of CF gene therapy has proven more challenging than initially envisioned; thanks to continued innovation, it may yet become a reality.

negative: The effects of injection of bovine vaccine into a human digit: a case report BACKGROUND: The incidence of needlestick injuries in farmers and veterinary surgeons is significant and the consequences of such an injection can be serious. CASE PRESENTATION: We report accidental injection of bovine vaccine into the base of the little finger. This resulted in increased pressure in the flexor sheath causing signs and symptoms of ischemia. Amputation of the digit was required despite repeated surgical debridement and decompression. CONCLUSION: There have been previous reports of injection of oil-based vaccines into the human hand resulting in granulomatous inflammation or sterile abscess and causing morbidity and tissue loss. Self-injection with veterinary vaccines is an occupational hazard for farmers and veterinary surgeons. Injection of vaccine into a closed compartment such as the human finger can have serious sequelae including loss of the injected digit. These injuries are not to be underestimated. Early debridement and irrigation of the injected area with decompression is likely to give the best outcome. Frequent review is necessary after the first procedure because repeat operations may be required.

negative: Comparisons of substitution, insertion and deletion probes for resequencing and mutational analysis using oligonucleotide microarrays Although oligonucleotide probes complementary to single nucleotide substitutions are commonly used in microarray-based screens for genetic variation, little is known about the hybridization properties of probes complementary to small insertions and deletions. It is necessary to define the hybridization properties of these latter probes in order to improve the specificity and sensitivity of oligonucleotide microarray-based mutational analysis of disease-related genes. Here, we compare and contrast the hybridization properties of oligonucleotide microarrays consisting of 25mer probes complementary to all possible single nucleotide substitutions and insertions, and one and two base deletions in the 9168 bp coding region of the ATM (ataxia telangiectasia mutated) gene. Over 68 different dye-labeled single-stranded nucleic acid targets representing all ATM coding exons were applied to these microarrays. We assess hybridization specificity by comparing the relative hybridization signals from probes perfectly matched to ATM sequences to those containing mismatches. Probes complementary to two base substitutions displayed the highest average specificity followed by those complementary to single base substitutions, single base deletions and single base insertions. In all the cases, hybridization specificity was strongly influenced by sequence context and possible intra- and intermolecular probe and/or target structure. Furthermore, single nucleotide substitution probes displayed the most consistent hybridization specificity data followed by single base deletions, two base deletions and single nucleotide insertions. Overall, these studies provide valuable empirical data that can be used to more accurately model the hybridization properties of insertion and deletion probes and improve the design and interpretation of oligonucleotide microarray-based resequencing and mutational analysis.

negative: Low-dose radiation therapy for COVID-19 pneumopathy: what is the evidence? In the current dismal situation of the COVID-19 pandemic, effective management of patients with pneumonia and acute respiratory distress syndrome is of vital importance. Due to the current lack of effective pharmacological concepts, this situation has caused interest in (re)considering historical reports on the treatment of patients with low-dose radiation therapy for pneumonia. Although these historical reports are of low-level evidence per se, hampering recommendations for decision-making in the clinical setting, they indicate effectiveness in the dose range between 0.3 and 1 Gy, similar to more recent dose concepts in the treatment of acute and chronic inflammatory/degenerative benign diseases with, e.g., a single dose per fraction of 0.5 Gy. This concise review aims to critically review the evidence for low-dose radiation treatment of COVID-19 pneumopathy and discuss whether it is worth investigating in the present clinical situation.

negative: Psychometric Testing of Three COVID-19-Related Scales Among People with Mental Illness Fear of novel coronavirus 2019 (COVID-19) may result in psychological health problems among different populations. Moreover, believing COVID-19 information and preventive COVID-19 infection behaviors are relevant constructs associated with fear of COVID-19. Therefore, the present study validated three instruments assessing fear, beliefs, and preventive behaviors related to COVID-19 among individuals with mental illness. Moreover, relationships between the three constructs were examined. Individuals with mental illness (N = 400; 178 females; mean age = 46.91 years) completed the Fear of COVID-19 Scale (FCV-19S), Believing COVID-19 Information Scale (BCIS), Preventive COVID-19 Infection Behaviors Scale (PCIBS), and Depression Anxiety Stress Scale-21 (DASS-21). The FCV-19S, BCIS, and PCIBS demonstrated a single-factor structure with satisfactory fit indices. Moreover, believing COVID-19 information positively and significantly associated with fear of COVID-19, and fear of COVID-19 negatively and significantly associated with preventive behaviors and positively and significantly associated with psychological distress. The FCV-19S, BCIS, and PCIBS may assist healthcare providers in assessing COVID-19-related information among individuals with mental illness. Consequently, relevant programs may be designed to help individuals with mental illness going through the period of crisis.

negative: Acute upper limb ischemia in a patient with COVID-19 Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection mainly present with upper and lower respiratory tract symptoms, with complications related to cytokine storm syndrome and acute respiratory distress syndrome. It has also been described to predispose to venous and arterial thromboembolism; however, limited published data is available regarding thrombosis in coronavirus disease 2019 (COVID-19). Here we are presenting a case of arterial thrombosis in a patient with COVID-19 and a systematic review on coagulopathy associated with COVID-19.

negative: Comparison of risk factors for viral and nonviral asthma exacerbations

negative: Change in practice in gynecologic oncology during the COVID-19 pandemic: a social media survey OBJECTIVE: COVID-19 has affected gynecologic cancer management. The goal of this survey was to evaluate changes that occurred in gynecologic oncology practice during the COVID-19 pandemic. METHODS: A anonymous survey consisting of 33 questions (https://sites.google.com/view/gyncacovidfmartinelli) regarding interaction between gynecologic cancers and COVID-19 was distributed online via social media from April 9 to April 30, 2020. Basic descriptive statistics were applied. Analytics of survey-diffusion and generated-interest (visualizations, engagement rates, response rate) were analyzed. RESULTS: The survey received 20 836 visualizations, generating an average engagement rates by reach of 4.7%. The response rate was 30%. A total of 86% of respondents completed the survey, for a total of 187 physicians surveyed across 49 countries. The majority (143/187; 76%) were gynecologic oncologists, and most were ≤50 years old (146/187; 78%). A total of 49.7% (93/187) were facing the early phase of the COVID-19 pandemic, while 26.7% (50/187) and 23.5% (44/187) were in the peak and plateau phases, respectively. For 97.3% (182/187) of respondents COVID-19 affected or changed their respective clinical practice. Between 16% (27/165) (before surgery) and 25% (26/102) (before medical treatment) did not perform any tests to rule out COVID-19 infection among patients. The majority of respondents did not alter indications of treatment if patients were COVID-19-negative, while treatments were generally postponed in COVID-19-positive patients. Treatments were considered priority for: early stage high-risk uterine cancers (85/187; 45%), newly diagnosed epithelial ovarian cancer (76/187; 41%), and locally advanced cervical cancer (76/187; 41%). Treatment of early stage low-grade endometrioid endometrial cancer was deferred according to 49% (91/187) of respondents, with hormonal treatment as the option of therapy (31%; 56/178). A total of 77% (136/177) of respondents reported no changes in (surgical) treatment for early stage cervical cancer in COVID-19-negative patients, while treatment was postponed by 54% (96/177) of respondent, if the patient tested COVID-19-positive. Neoadjuvant chemotherapy for advanced ovarian cancers was considered by over one-third of respondents as well as hypofractionation of radiation treatment for locally advanced cervical cancers. CONCLUSION: COVID-19 affected the treatment of gynecologic cancers patients, both in terms of prioritization and identification of strategies to reduce hospital access and length of stay. Social media is a reliable tool to perform fast-tracking, worldwide surveys.

negative: Deep-COVID: Predicting COVID-19 From Chest X-Ray Images Using Deep Transfer Learning The COVID-19 pandemic is causing a major outbreak in more than 150 countries around the world, having a severe impact on the health and life of many people globally. One of the crucial step in fighting COVID-19 is the ability to detect the infected patients early enough, and put them under special care. Detecting this disease from radiography and radiology images is perhaps one of the fastest way to diagnose the patients. Some of the early studies showed specific abnormalities in the chest radiograms of patients infected with COVID-19. Inspired by earlier works, we study the application of deep learning models to detect COVID-19 patients from their chest radiography images. We first prepare a dataset of 5,000 Chest X-rays from the publicly available datasets. Images exhibiting COVID-19 disease presence were identified by board-certified radiologist. Transfer learning on a subset of 2,000 radiograms was used to train four popular convolutional neural networks, including ResNet18, ResNet50, SqueezeNet, and DenseNet-121, to identify COVID-19 disease in the analyzed chest X-ray images. We evaluated these models on the remaining 3,000 images, and most of these networks achieved a sensitivity rate of 97\%($\pm$ 5\%), while having a specificity rate of around 90\%. While the achieved performance is very encouraging, further analysis is required on a larger set of COVID-19 images, to have a more reliable estimation of accuracy rates. Besides sensitivity and specificity rates, we also present the receiver operating characteristic (ROC), area under the curve (AUC), and confusion matrix of each model. The dataset, model implementations (in PyTorch), and evaluations, are all made publicly available for research community, here: https://github.com/shervinmin/DeepCovid.git

negative: Response by Gheblawi et al to Letter Regarding Article, "Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2"

negative: The mechanism and treatment of gastrointestinal symptoms in patients with COVID-19. In addition to the typical respiratory response, new coronavirus pneumonia (COVID-19) is also associated with very common gastrointestinal symptoms. Cases with gastrointestinal symptoms are more likely to be complicated by liver injury and acute respiratory distress syndrome (ARDS), and diarrhea can also lead to electrolyte disturbances, causing nausea and vomiting, headache, fatigue, etc. If not treated in time, coma and circulatory failure may ensue. As SARS-CoV-2 infects the human body through the combination of ACE2 in the gastrointestinal tract, the mechanism underlying the gastrointestinal symptoms may involve damage to the intestinal mucosal barrier and promotion of the production of inflammatory factors, causing cytokine storms. Indeed, after cells in the lungs become infected by SARS-CoV-2, effector CD4+ T cells reach the small intestine through the gut-lung axis, causing intestinal immune damage and diarrhea; early extensive use of antibacterial and antiviral drugs can also lead to diarrhea in patients. Thus, treatment options for COVID-19 patients should be promptly adjusted when they have gastrointestinal symptoms. Additionally, when drug-induced diarrhea occurs, drugs should be withdrawn or reduced, and microecological regulators should be applied to maintain the intestinal microecological balance and prevent secondary bacterial infections. To guarantee effective treatment, attention should be paid to the patient's enteral nutrition and digestive tract function. As SARS-CoV-2 has been detected in the feces of COVID-19 patients, future prevention and control efforts must consider the possibility of fecal-oral transmission of the virus.

negative: Atrial fibrillation: a risk factor for unfavourable outcome in COVID-19? A case report BACKGROUND: Fulminant cardiac involvement in COVID-19 patients has been reported; the underlying suspected mechanisms include myocarditis, arrhythmia, and cardiac tamponade. In parallel, atrial fibrillation is common in the elderly population which is at particularly high risk for COVID-19 morbidity and mortality. CASE SUMMARY: A 72-year-old male SARS-CoV2-positive patient was admitted to the intensive care unit due to delirium and acute respiratory failure. Atrial fibrillation known from history was exacerbated, and made complex rate and rhythm control necessary. Progressive heart failure with haemodynamic deterioration and acute kidney injury with the need for continuous renal replacement therapy were further aggravated by pericardial tamponade. DISCUSSION: Treatment of acute heart failure in COVID-19 patients with a cytokine storm complicated by tachycardic atrial fibrillation should include adequate rate or rhythm control, and potentially immunomodulation.

negative: Novel coronavirus pneumonia related liver injury: etiological analysis and treatment strategy/ 中华肝脏病杂志 The outbreak of novel coronavirus pneumonia(NCP) caused by 2019 novel coronavirus has become a global public health challenge. Some patients accompany with liver function damage in addition to the main typical respiratory symptom. Here we analyzed the clinical features, susceptible population, potential causes and therapeutic strategies of NCP related liver injury.

negative: Instrumental Role of Helicobacter pylori γ-Glutamyl Transpeptidase in VacA-Dependent Vacuolation in Gastric Epithelial Cells Helicobacter pylori causes cellular vacuolation in host cells, a cytotoxic event attributed to vacuolating cytotoxin (VacA) and the presence of permeant weak bases such as ammonia. We report here the role of γ-glutamyl transpeptidase (GGT), a constitutively expressed secretory enzyme of H. pylori, in potentiating VacA-dependent vacuolation formation in H. pylori-infected AGS and primary gastric cells. The enhancement is brought about by GGT hydrolysing glutamine present in the extracellular medium, thereby releasing ammonia which accentuates the VacA-induced vacuolation. The events of vacuolation in H. pylori wild type (WT)- and Δggt-infected AGS cells were first captured and visualized by real-time phase-contrast microscopy where WT was observed to induce more vacuoles than Δggt. By using semi-quantitative neutral red uptake assay, we next showed that Δggt induced significantly less vacuolation in AGS and primary gastric epithelial cells as compared to the parental strain (P<0.05) indicating that GGT potentiates the vacuolating effect of VacA. Notably, vacuolation induced by WT was significantly reduced in the absence of GGT substrate, glutamine (P<0.05) or in the presence of a competitive GGT inhibitor, serine-borate complex. Furthermore, the vacuolating ability of Δggt was markedly restored when co-incubated with purified recombinant GGT (rGGT), although rGGT itself did not induce vacuolation independently. Similarly, the addition of exogenous ammonium chloride as a source of ammonia also rescued the ability of Δggt to induce vacuolation. Additionally, we also show that monoclonal antibodies against GGT effectively inhibited GGT activity and successfully suppressed H. pylori-induced vacuolation. Collectively, our results clearly demonstrate that generation of ammonia by GGT through glutamine hydrolysis is responsible for enhancing VacA-dependent vacuolation. Our findings provide a new perspective on GGT as an important virulence factor and a promising target in the management of H. pylori-associated gastric diseases.

negative: The Chronic Kidney Disease and Acute Kidney Injury Involvement in COVID-19 Pandemic: A Systematic Review and Meta-analysis Aim: The aim of this study was to uncover whether kidney diseases were involved in COVID-19 pandemic from a systematic review. Methods: The studies reported the kidney outcomes in different severity of COVID-19 were included in this study. Standardized mean differences or odds ratios were calculated by employing Review Manager meta-analysis software. Results: Thirty-six trials were included in this systematic review with a total of 6395 COVID-19 patients. The overall effects indicated that the comorbidity of chronic kidney disease (CKD) (OR = 3.28), complication of acute kidney injury (AKI) (OR = 11.02), serum creatinine (SMD = 0.68), abnormal serum creatinine (OR = 4.86), blood urea nitrogen (SMD = 1.95), abnormal blood urea nitrogen (OR = 6.53), received continuous renal replacement therapy (CRRT) (OR = 23.63) was significantly increased in severe group than that in nonsevere group. Additionally, the complication of AKI (OR = 13.92) and blood urea nitrogen (SMD = 1.18) were remarkably elevated in critical group than that in severe group. Conclusion: CKD and AKI are susceptible to occur in patients with severe COVID-19. CRRT is applied frequently in severe COVID-19 patients than that in nonsevere COVID-19 patients. The risk of AKI is higher in critical group than that in severe group.

negative: Demographic, etiological, and histological pulmonary analysis of patients with acute respiratory failure: a study of 19 years of autopsies INTRODUCTION: Acute respiratory failure has been one of the most important causes of death in intensive care units, and certain aspects of its pulmonary pathology are currently unknown. OBJECTIVES: The objective was to describe the demographic data, etiology, and pulmonary histopathological findings of different diseases in the autopsies of patients with acute respiratory failure. METHOD: Autopsies of 4,710 patients with acute respiratory failure from 1990 to 2008 were reviewed, and the following data were obtained: age, sex, and major associated diseases. The pulmonary histopathology was categorized as diffuse alveolar damage, pulmonary edema, alveolar hemorrhage, and lymphoplasmacytic interstitial pneumonia. The odds ratio of the concordance between the major associated diseases and specific autopsy findings was calculated using logistic regression. RESULTS: Bacterial bronchopneumonia was present in 33.9% of the cases and cancer in 28.1%. The pulmonary histopathology showed diffuse alveolar damage in 40.7% (1,917) of the cases. A multivariate analysis showed a significant and powerful association between diffuse alveolar damage and bronchopneumonia, HIV/AIDS, sepsis, and septic shock, between liver cirrhosis and pulmonary embolism, between pulmonary edema and acute myocardial infarction, between dilated cardiomyopathy and cancer, between alveolar hemorrhage and bronchopneumonia and pulmonary embolism, and between lymphoplasmacytic interstitial pneumonia and HIV/AIDS and liver cirrhosis. CONCLUSIONS: Bronchopneumonia was the most common diagnosis in these cases. The most prevalent pulmonary histopathological pattern was diffuse alveolar damage, which was associated with different inflammatory conditions. Further studies are necessary to elucidate the complete pathophysiological mechanisms involved with each disease and the development of acute respiratory failure.

negative: TWIRLS, an automated topic-wise inference method based on massive literature, suggests a possible mechanism via ACE2 for the pathological changes in the human host after coronavirus infection Faced with the current large-scale public health emergency, collecting, sorting, and analyzing biomedical information related to the “coronavirus” should be done as quickly as possible to gain a global perspective, which is a basic requirement for strengthening epidemic control capacity. However, for human researchers studying the viruses and the hosts, the vast amount of information available cannot be processed effectively and in a timely manner, particularly when the scientific understanding may be limited, which can further lower the information processing efficiency. We present TWIRLS, a method that can automatically acquire, organize, and classify information. Additionally, independent functional data sources can be added to build an inference system using a machine-based approach, which can provide relevant knowledge to help human researchers quickly establish subject cognition and to make more effective decisions. TWIRLS can automatically analyze more than three million words in more than 14,000 literature articles in only 4 hours. Combining with generalized gene interaction databases creates a data interface that can help researchers to further analyze the information. Using the TWIRLS system, we found that an important regulatory factor angiotensin-converting enzyme 2 (ACE2) may be involved in the host pathological changes on binding to the coronavirus after infection. After triggering functional changes in ACE2/AT2R, an imbalance in the steady-state cytokine regulatory axis involving the Renin-Angiotensin System and IP-10 leads to a cytokine storm.

negative: Phosphatidylserine’s role in Ebola’s inflammatory cytokine storm and hemorrhagic consumptive coagulopathy and the therapeutic potential of annexin V Abstract The phosphatidylserine (PS) molecule is present in cell membranes where it is actively kept on their inner leaflets but when cells are damaged it moves to the surface and become a signal for their removal, the platform upon which the coagulation cascade takes place and a ligand that activates a feedback cycle of inflammatory cytokine secretion and initiates the wakeup call for the innate immune response. These are physiologic responses to PS but the Ebola virus displays PS molecules on its membrane’s surface and the huge numbers of viruses cause a pathologic inflammatory cytokine storm and a hemorrhagic consumptive coagulopathy. Annexin V is an innate molecule that can cloak membrane displayed PS and prevents its Th1 cell’s inflammatory cytokine generation and cascade thrombin generation. The hypothesis presented is that its administration will cloak PS and prevent Ebola’s consumptive coagulopathy and its cytokine storm.

negative: Is the anti-psychotic, 10-(3-(dimethylamino)propyl)phenothiazine (promazine), a potential drug with which to treat SARS infections? Lack of efficacy of promazine on SARS-CoV replication in a mouse model Phenothiazine and derivatives were tested for inhibition of SARS-CoV replication. Phenothiazine slightly inhibited SARS-CoV replication in a neutral red (NR) uptake assay. Adding a propylamino group to give promazine reduced virus yields (VYR assay) with an EC(90) = 8.3 ± 2.8 µM, but without selectivity. Various substitutions in the basic phenothiazine structure did not promote efficacy. Phenazine ethosulfate was the most potent compound by VYR assay (EC(90) = 6.1 ± 4.3 µM). All compounds were toxic (IC(50) = 6.6–74.5 µM) except for phenoxathiin (IC(50) = 858 ± 208 µM) and 10-(alpha-diethylamino-propionyl) phenothiazine·HCl (IC(50) = 195 ± 71.2 µM). Consequently, none were selective inhibitors of SARS-CoV replication (SI values <1–3.3 µM). These data portended the poor efficacy of promazine in a SARS-CoV mouse lung replication model. Intraperitoneal treatment with promazine using a prophylactic (−4 h)/therapeutic regimen of 1, 10, or 50 mg/(kg day) did not reduce virus lung titers at day 3, yet prolonged virus replication to 14 days. Similar therapeutic promazine doses were not efficacious. Thus, promazine did not affect SARS-CoV replication in vitro or in vivo, nor were any other phenothiazines efficacious in reducing virus replication. Therefore, treating SARS infections with compounds like promazine is not warranted.

negative: Cognitive, Affective, and Behavioral Constructs of COVID-19 Health Beliefs: A Comparison Between Sexual Minority and Heterosexual Individuals in Taiwan This online survey study aimed to compare the cognitive, affective, and behavioral constructs of health beliefs related to coronavirus disease 2019 (COVID-19) between sexual minority and heterosexual individuals in Taiwan. In total, 533 sexual minority and 1421 heterosexual participants were recruited through a Facebook advertisement. The constructs pertaining to cognition (perceived relative susceptibility to COVID-19, perceived COVID-19 severity, having sufficient knowledge and information on COVID-19, and confidence in coping with COVID-19), affect (worry toward COVID-19), and behavior (adoption of health-protective behaviors) in relation to health beliefs about COVID-19 were compared between sexual minority and heterosexual participants. The results indicated that sexual minority participants had lower perceived susceptibility to COVID-19, greater self-confidence in coping with COVID-19, and lower worry about COVID-19 and were less likely to maintain good indoor ventilation and disinfect their household than heterosexual individuals. Sexual orientation is the modifying factor for the Health Belief Model in the COVID-19 pandemic and should be taken into consideration when medical professionals establish prevention programs for COVID-19.

negative: COVID-19 and ischemic stroke: should we systematically look for lupus anticoagulant and antiphospholipid antibodies?

negative: International expert consensus statement regarding radiotherapy treatment options for rectal cancer during the COVID 19 pandemic

negative: A Cured COVID-19 case of 86-year-old with 13 chronic diseases: A Case Report

negative: Impact of COVID-19 on Children and Pediatricians

negative: Cloning of IRAK1 and its upregulation in symptomatic mandarin fish infected with ISKNV Abstract Interleukin-1 receptor activated kinases (IRAKs) play crucial roles in the Toll-like receptor (TLR) mediated signal transduction pathways that control host innate immune responses. Here we report the cloning of an IRAK1 cDNA (named ScIRAK1) from the mandarin fish. The predicted ScIRAK1 peptide contains a death domain and a serine/threonine-specific kinase domain. Quantitative RT-PCR showed that ScIRAK1 mRNA was primarily expressed in blood cells and posterior kidney. Seven days following infection with infectious spleen and kidney necrosis virus (ISKNV), the ScIRAK1 mRNA level was significantly higher in the blood cells of clinically symptomatic fish than in the blood cells of asymptomatic fish or control fish injected with phosphate-buffered saline. Additional experiments showed that overexpression of ScIRAK1 in the 293T cells could induce NF-κB activation. These results suggest that ScIRAK1 may play a role in the pathology of ISKNV infection in the mandarin fish.

negative: COVID-19 Datasets: A Survey and Future Challenges In December 2019, a novel virus named as COVID-19 emerged in the city of Wuhan, China. In early 2020, the COVID-19 virus spread in all continents of the world except Antarctica causing widespread infections and deaths due to its contagious characteristics and no medically proven treatment. The COVID-19 pandemic has been termed as most consequential global crisis after the World Wars. The first line of defense against the COVID-19 spread are the non-pharmaceutical measures like social distancing and personal hygiene. On the other hand, the medical service providers are the first responders for infected persons with severe symptoms of COVID-19. The great pandemic affecting billions of lives economically and socially has motivated the scientific community to come up with solutions based on computer-aided digital technologies for diagnosis, prevention, and estimation of COVID-19. Some of these efforts focus on statistical and Artificial Intelligence-based analysis of the available data concerning COVID-19. All of these scientific efforts necessitate that the data brought to service for the analysis should be open-source to promote the extension, validation, and collaboration of the work in the fight against the global pandemic. Our survey is motivated by the open-source efforts that can be mainly categorized as: (a) COVID-19 diagnosis from CT scans and X-ray images, (b) COVID-19 case reporting, transmission estimation, and prognosis from epidemiological, demographic, and mobility data, (c) COVID-19 emotional and sentiment analysis from social media, and (d) knowledge-based discovery and semantic analysis from the collection of scholarly articles covering COVID-19. We review and critically analyze works in these directions that are accompanied by open-source data and code. We hope that the article will provide the scientific community with an initiative to start open-source extensible and transparent research in the collective fight against COVID-19.

negative: Knowledge and understanding among medical imaging professionals in India during the rapid rise of the covid-19 pandemic During the first week of March,2020 the surge of coronavirus disease (COVID-19) cases reached all over the globe with more than 100,000 cases. Healthcare national and international authorities have already initiated awareness and lockdown activities. A poor understanding of the disease among medical imaging professionals (MIPs) may result in rapid spread of infection. This study aimed to investigate the knowledge and understanding of MIPs about COVID-19. A cross-sectional, web-based study was conducted among MIPs about COVID- 19 during the fourth week of March 2020. An online sample of MIPs was successfully recruited via the authors’ networks in India using data collection tool – write google forms. A self-developed online KAP questionnaire was completed by the participants. The knowledge and understanding questionnaire consisted questions regarding the clinical characteristics and transmission routes of COVID-19. Assessment on practices towards COVID-19 included questions on techniques while imaging against COVID-19 suspected patients. Of 700 participants, a total of 550 MIPs completed the survey (response rate: 78.57%); 56.7% were males, 85.4.1% were aged 17–26 years, and most were undergraduates (77.6%) and postgraduates (17.1%). Regarding COVID-19, most of the participants answered correctly (95.5%) on symptoms, (84.4%) time interval for visible symptoms, (98.0%) transmission and (44%) airborne transmission respectively. A significant proportion of MIPs (36.4%) had poor knowledge about wearing multiple masks as an effective measure against coronavirus infection. Most of the respondents (48.5%) incorrectly considered X-ray as the reliable method of diagnosis for suspected COVID-19 patients. 44.6% of the respondents lacked knowledge about the steps involved in hand washing technique which is one of the most important safety practice methods in medical imaging to prevent spread of infection. Factors such as age and occupation were associated with inadequate knowledge and poor perception of COVID-19. As the current global threat of COVID-19 continues to emerge, it is crucial and critical to improve the knowledge and understanding of MIPs. Educational videos and live webinars are urgently needed to reach MIPs and further detailed studies are the need of the hour. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12553-020-00437-2) contains supplementary material, which is available to authorized users.

negative: Risk Factors Prediction, Clinical Outcomes, and Mortality of COVID-19 Patients Background: Preventing communicable diseases requires understanding the spread, epidemiology, clinical features, progression, and prognosis of the disease. Early identification of risk factors and clinical outcomes might help to identify critically ill patients, provide proper treatment and prevent mortality. Methods: We conducted a prospective study in patients with flu-like symptoms referred to the imaging department of a tertiary hospital in IRAN between 3 March 2020 and 8 April 2020. Patients with COVID-19 were followed up to check their health condition after two months. The categorical data between groups were analyzed by Fisher exact test and continuous data by Wilcoxon Rank-Sum Test. Findings: 319 patients (mean age 45.48 years, 177 women) were enrolled. Fever, dyspnea, weakness, shivering, C-reactive protein (CRP), fatigue, dry cough, anorexia, anosmia, ageusia, dizziness, sweating and age were the most important symptoms of COVID-19 infection. Traveling in past three months, asthma, taking corticosteroids, liver disease, rheumatological disease, cough with sputum, eczema, conjunctivitis, tobacco use, and chest pain did not have any relationship with COVID-19. Interpretation: Finding clinical symptoms for early diagnosis of COVID-19 is a critical part of prevention. These symptoms can help in the assessment of disease progression. To the best of our knowledge, some of the effective features on the mortality due to COVID-19 are investigated for the first time in this research. Funding: None

negative: Knowledge-based repositioning of the anti-HCV direct antiviral agent Sofosbuvir as SARS-CoV-2 treatment The new human coronavirus named SARS-CoV-2 is a positive-sense RNA virus for which no specific drugs are currently available. A knowledge-based analysis strongly suggests a possible repositioning of the anti-HCV direct antiviral agent (DAA) Sofosbuvir as treatment for SARS-CoV-2. Indeed, the RNA-dependent RNA-polymerases (RdRp) of the two viruses show high sequence and structural homology, supporting the likelihood of binding the Sofosbuvir molecule with similar efficiency. Such a repositioning would allow the containment of the SARS-CoV-2 pandemic and limit the progression of disease to potentially deadly COVID19.

negative: AI4COVID-19: AI Enabled Preliminary Diagnosis for COVID-19 from Cough Samples via an App Inability to test at scale has become Achille's heel in humanity's ongoing war against COVID-19 pandemic. An agile, scalable and cost-effective testing, deployable at a global scale, can act as a game changer in this war. To address this challenge, building on the promising results of our prior work on cough-based diagnosis of a motley of respiratory diseases, we develop an Artificial Intelligence (AI)-based test for COVID-19 preliminary diagnosis. The test is deployable at scale through a mobile app named AI4COVID-19. The AI4COVID-19 app requires 2-second cough recordings of the subject. By analyzing the cough samples through an AI engine running in the cloud, the app returns a preliminary diagnosis within a minute. Unfortunately, cough is common symptom of over two dozen non-COVID-19 related medical conditions. This makes the COVID-19 diagnosis from cough alone an extremely challenging problem. We solve this problem by developing a novel multi-pronged mediator centered risk-averse AI architecture that minimizes misdiagnosis. At the time of writing, our AI engine can distinguish between COVID-19 patient coughs and several types of non-COVID-19 coughs with over 90% accuracy. AI4COVID-19's performance is likely to improve as more and better data becomes available. This paper presents a proof of concept to encourage controlled clinical trials and serves as a call for labeled cough data. AI4COVID-19 is not designed to compete with clinical testing. Instead, it offers a complementing tele-testing tool deployable anytime, anywhere, by anyone, so clinical-testing and treatment can be channeled to those who need it the most, thereby saving more lives.

negative: [Intervention mechanism of Qingwen Baidu Yin on cytokine storm based on network pharmacology] The aim of this paper was to explore the intervention mechanism of Qingwen Baidu Yin in cytokine storm based on network pharmacology. TCMSP and TCMIP V2.0 server were used to predict all chemical components and action targets of Qingwen Baidu Yin. Diseases that could be treated by Qingwen Baidu Yin were predicted through Enrichr database. A compound target interaction(PPI) network diagram was constructed using STRING 11.0. OmicShare was used to analyzed the gene ontology(GO) enrichment and enrichment of the Kyoto encyclopedia of genes and genomes(KEGG) pathway of core targets. Component-target-path network diagram was constructed with Cytoscape 3.6.0 software. After analysis of the database, 267 compounds were screened for Qingwen Baidu Yin, involving 1 450 targets, and a protein interaction network was constructed. Total 219 core target proteins were predicted, such as NFKB1, STAT1, RAF1, IL2, JAK1, IL6, TNF, BCL2 and other important targets, and 221 core target pathways were enriched, including cancer pathway, Kaposi's sarcoma-associated herpes virus infection, chemokine signal pathway, PI3 K-AKT signal pathway, EB virus infection, virus carcinogenesis and T cell receptor signaling pathways, a collection of which were highly related to cytokine storms. GO annotation analysis suggested that Qingwen Baidu Yin Decoction may exert therapeutic effects by regulating protein phosphorylation, cell response to cytokine stimulation, cell proliferation, inflammatory response, transmembrane receptor protein tyrosine kinase signaling pathway, and cytokine-mediated signaling pathways. This study revealed potential active components of Qingwen Baidu Yin in defending against cytokine storm and its possible mechanism of action, and provided theoretical basis and technical support for further clinical application of this prescription.

negative: The role of afferent pulmonary innervation in poor prognosis of acute respiratory distress syndrome in COVID-19 patients and proposed use of resiniferatoxin (RTX) to improve patient outcomes in advanced disease state: A review Abstract Acute respiratory distress is one of the major causes of mortality associated with COVID-19 disease. Many patients will require intensive care with ventilatory support. Despite progress and best efforts, the mortality rates projected remain high. Historical data outlook points towards 80% expected fatality for patients progressing to advanced pulmonary disease, even when hospitalized in the intensive care unit. This is particularly true among the patient population over 65. Novel life-saving strategies are desperately needed to mitigate the high mortality that will be associated with the late stage SARS-CoV-2 viral infection associated with the fatal respiratory distress. We hypothesize that the morbidity, severity of the disease, and underlying physiological events leading to mortality are closely linked to the TRPV1 expressing neuronal system (afferent/efferent neurons) in the lungs. TRPV1 expressing cells are responsible for pain transmission, inflammation and immunomodulation throughout the entire pulmonary system and are modulating the processes associated with localized cytokine release (storm) and overall rapid disease progression. We suggest that therapeutic approaches targeting TRPV1 containing nerve fibers in the lungs will modulate the inflammatory and immune signal activity, leading to reduced mortality and better overall outcomes. We also propose to further explore the use of resiniferatoxin (RTX), an ultra-potent TRPV1 agonist currently in clinical trials for cancer and osteoarthritis pain, as a possible ablating agent of TRPV1 positive pulmonary pathways in patients with advanced COVID-19 disease.

negative: Reshaping neonatal intensive care units (NICUs) to avoid the spread of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) to high-risk infants

negative: Water scarcity and COVID-19 in sub-Saharan Africa

negative: Role of Regulatory T Cells in Pathogenesis and Biological Therapy of Multiple Sclerosis Multiple sclerosis (MS) is an inflammatory disease in which the myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms. It is caused by an autoimmune response to self-antigens in a genetically susceptible individual induced by unknown environmental factors. Principal cells of the immune system that drive the immunopathological processes are T cells, especially of T(H)1 and T(H)17 subsets. However, in recent years, it was disclosed that regulatory T cells took part in, too. Subsequently, there was endeavour to develop ways how to re-establish their physiological functions. In this review, we describe known mechanisms of action, efficacy, and side-effects of contemporary and emerging MS immunotherapeutical agents on Treg cells and other cells of the immune system involved in the immunopathogenesis of the disease. Furthermore, we discuss how laboratory immunology can offer physicians its help in the diagnosis process and decisions what kind of biological therapy should be used.

negative: COVID-19 during pregnancy: Potential risk for neurodevelopmental disorders in neonates?

negative: EEG findings in acutely ill patients investigated for SARS‐CoV‐2/COVID‐19: A small case series preliminary report OBJECTIVE: Acute encephalopathy may occur in COVID‐19‐infected patients. We investigated whether medically indicated EEGs performed in acutely ill patients under investigation (PUIs) for COVID‐19 report epileptiform abnormalities and whether these are more prevalent in COVID‐19 positive than negative patients. METHODS: In this retrospective case series, adult COVID‐19 inpatient PUIs underwent EEGs for acute encephalopathy and/or seizure‐like events. PUIs had 8‐channel headband EEGs (Ceribell; 20 COVID‐19 positive, 6 COVID‐19 negative); 2 more COVID‐19 patients had routine EEGs. Overall, 26 Ceribell EEGs, 4 routine and 7 continuous EEG studies were reviewed. EEGs were interpreted by board‐certified clinical neurophysiologists (n = 16). EEG findings were correlated with demographic data, clinical presentation and history, and medication usage. Fisher's exact test was used. RESULTS: We included 28 COVID‐19 PUIs (30‐83 years old), of whom 22 tested positive (63.6% males) and 6 tested negative (33.3% male). The most common indications for EEG, among COVID‐19‐positive vs COVID‐19‐negative patients, respectively, were new onset encephalopathy (68.2% vs 33.3%) and seizure‐like events (14/22, 63.6%; 2/6, 33.3%), even among patients without prior history of seizures (11/17, 64.7%; 2/6, 33.3%). Sporadic epileptiform discharges (EDs) were present in 40.9% of COVID‐19‐positive and 16.7% of COVID‐19‐negative patients; frontal sharp waves were reported in 8/9 (88.9%) of COVID‐19‐positive patients with EDs and in 1/1 of COVID‐19‐negative patient with EDs. No electrographic seizures were captured, but 19/22 COVID‐19‐positive and 6/6 COVID‐19‐negative patients were given antiseizure medications and/or sedatives before the EEG. SIGNIFICANCE: This is the first preliminary report of EDs in the EEG of acutely ill COVID‐19‐positive patients with encephalopathy or suspected clinical seizures. EDs are relatively common in this cohort and typically appear as frontal sharp waves. Further studies are needed to confirm these findings and evaluate the potential direct or indirect effects of COVID‐19 on activating epileptic activity.

negative: A Conformation-Sensitive Monoclonal Antibody against the A2 Domain of von Willebrand Factor Reduces Its Proteolysis by ADAMTS13 The size of von Willebrand factor (VWF), controlled by ADAMTS13-dependent proteolysis, is associated with its hemostatic activity. Many factors regulate ADAMTS13-dependent VWF proteolysis through their interaction with VWF. These include coagulation factor VIII, platelet glycoprotein 1bα, and heparin sulfate, which accelerate the cleavage of VWF. Conversely, thrombospondin-1 decreases the rate of VWF proteolysis by ADAMTS13 by competing with ADAMTS13 for the A3 domain of VWF. To investigate whether murine monoclonal antibodies (mAbs) against human VWF affect the susceptibility of VWF to proteolysis by ADAMTS13 in vitro, eight mAbs to different domains of human VWF were used to evaluate the effects on VWF cleavage by ADAMTS13 under fluid shear stress and static/denaturing conditions. Additionally, the epitope of anti-VWF mAb (SZ34) was mapped using recombinant proteins in combination with enzyme-linked immunosorbent assay and Western blot analysis. The results indicate that mAb SZ34 inhibited proteolytic cleavage of VWF by ADAMTS13 in a concentration-dependent manner under fluid shear stress, but not under static/denaturing conditions. The binding epitope of SZ34 mAb is located between A1555 and G1595 in the central A2 domain of VWF. These data show that an anti-VWF mAb against the VWF-A2 domain (A1555-G1595) reduces the proteolytic cleavage of VWF by ADAMTS13 under shear stress, suggesting the role of this region in interaction with ADAMTS13.

negative: Mechanisms of Myocardial Injury in Coronavirus Disease 2019 Coronavirus disease 2019 (COVID-19) predominantly presents with symptoms of fever, fatigue, cough and respiratory failure. However, it appears to have a unique interplay with cardiovascular disease (CVD); patients with pre-existing CVD are at highest risk for mortality from COVID-19, along with the elderly. COVID-19 contributes to cardiovascular complications including arrhythmias, myocardial dysfunction and myocardial inflammation. Although the exact mechanism of myocardial inflammation in patients with COVID-19 is not known, several plausible mechanisms have been proposed based on early observational reports. In this article, the authors summarise the available literature on mechanisms of myocardial injury in COVID-19.

negative: Hyperacute multi-organ thromboembolic storm in COVID-19: a case report Acute viral pneumonia, hypoxemic respiratory failure and severe inflammatory response are hallmarks of severe coronavirus disease 2019 (COVID-19). The COVID-19-associated inflammatory state may further lead to symptomatic thromboembolic complications despite prophylaxis. We report a 66-year-old female patient with post-mortem diagnosis of COVID-19 who presented progressive livedo racemosa, acute renal failure and myocardial injury, as well as an absence of respiratory symptoms. Transthoracic echocardiography showed severe spontaneous echo contrast in the right cardiac chambers and right-sided cardiac overload presumed to result from pulmonary microvascular thrombosis or embolism. d-dimer levels were increased. The patient developed an acute ischemic stroke and died 2 days following presentation despite therapeutic anticoagulation. Her predominantly thromboembolic presentation supports the concept of coronavirus infection of endothelial cells and hypercoagulability, or COVID-19 endotheliitis. The case we report highlights that COVID-19-associated hyperacute multi-organ thromboembolic storm may precede or present disproportionately to respiratory involvement. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11239-020-02173-w) contains supplementary material, which is available to authorized users.

negative: A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19 PURPOSE: COVID-19 (coronavirus disease 2019) is a public health emergency of international concern. As of this time, there is no known effective pharmaceutical treatment, although it is much needed for patient contracting the severe form of the disease. The aim of this systematic review was to summarize the evidence regarding chloroquine for the treatment of COVID-19. METHODS: PubMed, EMBASE, and three trial Registries were searched for studies on the use of chloroquine in patients with COVID-19. RESULTS: We included six articles (one narrative letter, one in-vitro study, one editorial, expert consensus paper, two national guideline documents) and 23 ongoing clinical trials in China. Chloroquine seems to be effective in limiting the replication of SARS-CoV-2 (virus causing COVID-19) in vitro. CONCLUSIONS: There is rationale, pre-clinical evidence of effectiveness and evidence of safety from long-time clinical use for other indications to justify clinical research on chloroquine in patients with COVID-19. However, clinical use should either adhere to the Monitored Emergency Use of Unregistered Interventions (MEURI) framework or be ethically approved as a trial as stated by the World Health Organization. Safety data and data from high-quality clinical trials are urgently needed.

negative: Patient-Reported Outcome Questionnaires for the evaluation of olfactory and gustatory dysfunctions in COVID-19

negative: Chemical composition and pharmacological mechanism of Qingfei Paidu Decoction and Ma Xing Shi Gan Decoction against Coronavirus Disease 2019 (COVID-19): in silico and experimental study Abstract The Coronavirus Disease 2019 (COVID-19) pandemic has become a huge threaten to global health, which raise urgent demand of developing efficient therapeutic strategy. The aim of the present study is to dissect the chemical composition and the pharmacological mechanism of Qingfei Paidu Decoction (QFPD), a clinically used Chinese medicine for treating COVID-19 patients in China. Through comprehensive analysis by liquid chromatography coupled with high resolution mass spectrometry (MS), a total of 129 compounds of QFPD were putatively identified. We also constructed molecular networking of mass spectrometry data to classify these compounds into 14 main clusters, in which exhibited specific patterns of flavonoids (45%), glycosides (15%), carboxylic acids (10%), and saponins (5%). The target network model of QFPD, established by predicting and collecting the targets of identified compounds, indicated a pivotal role of Ma Xing Shi Gan Decoction (MXSG) in the therapeutic efficacy of QFPD. Supportively, through transcriptomic analysis of gene expression after MXSG administration in rat model of LPS-induced pneumonia, the thrombin and Toll-like receptor (TLR) signaling pathway were suggested to be essential pathways for MXSG mediated anti-inflammatory effects. Besides, changes in content of major compounds in MXSG during decoction were found by the chemical analysis. We also validate that one major compound in MXSG, i.e. glycyrrhizic acid, inhibited TLR agonists induced IL-6 production in macrophage. In conclusion, the integration of in silico and experimental results indicated that the therapeutic effects of QFPD against COVID-19 may be attributed to the anti-inflammatory effects of MXSG, which supports the rationality of the compatibility of TCM.

negative: COVID-19 or Lung Cancer: what should we treat?

negative: Molecular mechanism of evolution and human infection with the novel coronavirus (2019-nCoV) Since December, 2019, an outbreak of pneumonia caused by the new coronavirus (2019-nCoV) has hit the city of Wuhan in the Hubei Province. With the continuous development of the epidemic, it has become a national public health crisis and calls for urgent antiviral treatments or vaccines. The spike protein on the coronavirus envelope is critical for host cell infection and virus vitality. Previous studies showed that 2019-nCoV is highly homologous to human SARS-CoV and attaches host cells though the binding of the spike receptor binding domain (RBD) domain to the angiotensin-converting enzyme II (ACE2). However, the molecular mechanisms of 2019-nCoV binding to human ACE2 and evolution of 2019-nCoV remain unclear. In this study, we have extensively studied the RBD-ACE2 complex, spike protein, and free RBD systems of 2019-nCoV and SARS-CoV using protein-protein docking and molecular dynamics (MD) simulations. It was shown that the RBD-ACE2 binding free energy for 2019-nCoV is significantly lower than that for SARS-CoV, which is consistent with the fact that 2019-nCoV is much more infectious than SARS-CoV. In addition, the spike protein of 2019-nCoV shows a significantly lower free energy than that of SARS-CoV, suggesting that 2019-nCoV is more stable and able to survive a higher temperature than SARS-CoV. This may also provide insights into the evolution of 2019-nCoV because SARS-like coronaviruses are thought to have originated in bats that are known to have a higher body-temperature than humans. It was also revealed that the RBD of 2019-nCoV is much more flexible especially near the binding site and thus will have a higher entropy penalty upon binding ACE2, compared to the RBD of SARS-CoV. That means that 2019-nCoV will be much more temperature-sensitive in terms of human infection than SARS-CoV. With the rising temperature, 2019-nCoV is expected to decrease its infection ability much faster than SARS-CoV, and get controlled more easily. The present findings are expected to be helpful for the disease prevention and control as well as drug and vaccine development of 2019-nCoV.

negative: Acute Symptomatic Seizures in Critically Ill Patients with COVID-19: Is There an Association? BACKGROUND: The coronavirus disease of 2019 (COVID-19) emerged as a global pandemic. Historically, the group of human coronaviruses can also affect the central nervous system leading to neurological symptoms; however, the causative mechanisms of the neurological manifestations of COVID-19 disease are not well known. Seizures have not been directly reported as a part of COVID-19 outside of patients with previously known brain injury or epilepsy. We report two cases of acute symptomatic seizures, in non-epileptic patients, associated with severe COVID-19 disease. CASE PRESENTATIONS: Two advanced-age, non-epileptic, male patients presented to our northeast Ohio-based health system with concern for infection in Mid-March 2020. Both had a history of lung disease and during their hospitalization tested positive for SARS-CoV-2. They developed acute encephalopathy days into their hospitalization with clinical and electrographic seizures. Resolution of seizures was achieved with levetiracetam. DISCUSSION: Patients with COVID-19 disease are at an elevated risk for seizures, and the mechanism of these seizures is likely multifactorial. Clinical (motor) seizures may not be readily detected in this population due to the expansive utilization of sedatives and paralytics for respiratory optimization strategies. Many of these patients are also not electrographically monitored for seizures due to limited resources, multifactorial risk for acute encephalopathy, and the risk of cross-contamination. Previously, several neurological symptoms were seen in patients with more advanced COVID-19 disease, and these were thought to be secondary to multi-system organ failure and/or disseminated intravascular coagulopathy-related brain injury. However, these patients may also have an advanced breakdown of the blood-brain barrier precipitated by pro-inflammatory cytokine reactions. The neurotropic effect and neuroinvasiveness of SARS-Coronavirus-2 have not been directly established. CONCLUSIONS: Acute symptomatic seizures are possible in patients with COVID-19 disease. These seizures are likely multifactorial in origin, including cortical irritation due to blood-brain barrier breakdown, precipitated by the cytokine reaction as a part of the viral infection. Patients with clinical signs of seizures or otherwise unexplained encephalopathy may benefit from electroencephalography monitoring and/or empiric anti-epileptic therapy. Further studies are needed to elucidate the risk of seizures and benefit of monitoring in this population.

negative: Social Media as a Sensor of Air Quality and Public Response in China BACKGROUND: Recent studies have demonstrated the utility of social media data sources for a wide range of public health goals, including disease surveillance, mental health trends, and health perceptions and sentiment. Most such research has focused on English-language social media for the task of disease surveillance. OBJECTIVE: We investigated the value of Chinese social media for monitoring air quality trends and related public perceptions and response. The goal was to determine if this data is suitable for learning actionable information about pollution levels and public response. METHODS: We mined a collection of 93 million messages from Sina Weibo, China’s largest microblogging service. We experimented with different filters to identify messages relevant to air quality, based on keyword matching and topic modeling. We evaluated the reliability of the data filters by comparing message volume per city to air particle pollution rates obtained from the Chinese government for 74 cities. Additionally, we performed a qualitative study of the content of pollution-related messages by coding a sample of 170 messages for relevance to air quality, and whether the message included details such as a reactive behavior or a health concern. RESULTS: The volume of pollution-related messages is highly correlated with particle pollution levels, with Pearson correlation values up to .718 (n=74, P<.001). Our qualitative results found that 67.1% (114/170) of messages were relevant to air quality and of those, 78.9% (90/114) were a firsthand report. Of firsthand reports, 28% (32/90) indicated a reactive behavior and 19% (17/90) expressed a health concern. Additionally, 3 messages of 170 requested that action be taken to improve quality. CONCLUSIONS: We have found quantitatively that message volume in Sina Weibo is indicative of true particle pollution levels, and we have found qualitatively that messages contain rich details including perceptions, behaviors, and self-reported health effects. Social media data can augment existing air pollution surveillance data, especially perception and health-related data that traditionally requires expensive surveys or interviews.

negative: Biodistribution and residence time of adenovector serotype 5 in normal and immunodeficient mice and rats detected with bioluminescent imaging As concerns increase about adenovirus type 5 (Ad5) being a safe gene transfer vector, it is important to evaluate its distribution, residence time, and possible toxicity in immunodeficient populations. To characterize the potential risk associated with different Ad5 vector delivery modes, we used immunocompetent and immunodeficient Rag2 (−/−) animals to establish mouse and rat models that could be monitored with bioluminescent imaging following intramuscular or intravascular infection with an engineered replication-incompetent Ad5 virus carrying the firefly luciferase gene (Ad5-Fluc). The Ad5 vector was less well-tolerated by Rag2 (−/−) animals than by wildtype ones, with delayed residence time, wider virus dissemination, less weight gain, and relatively severe pathological changes. In intravascularly Ad5-Fluc-infected Rag2 (−/−) mice, systemic virus dissemination extended from the abdomen to the limbs and head on day 9 post-infection. Additionally, significant increases in plasma TNF-α and IFN-γ, which may be important factors in the heightened immunopathology in the liver and brain, were detected in the Rag2 (−/−) mice 30 days after intravascular delivery. The Ad5 vector was better tolerated after intramuscular delivery than after intravascular delivery. Ad5-Fluc/Rag2 (−/−) mice and rats can be used as reliable models of an immunodeficient population in which to evaluate the safety of Ad5-vectored vaccines or gene therapy products.

negative: Transmission patterns of smallpox: systematic review of natural outbreaks in Europe and North America since World War II BACKGROUND: Because smallpox (variola major) may be used as a biological weapon, we reviewed outbreaks in post-World War II Europe and North America in order to understand smallpox transmission patterns. METHODS: A systematic review was used to identify papers from the National Library of Medicine, Embase, Biosis, Cochrane Library, Defense Technical Information Center, WorldCat, and reference lists of included publications. Two authors reviewed selected papers for smallpox outbreaks. RESULTS: 51 relevant outbreaks were identified from 1,389 publications. The median for the effective first generation reproduction rate (initial R) was 2 (range 0–38). The majority outbreaks were small (less than 5 cases) and contained within one generation. Outbreaks with few hospitalized patients had low initial R values (median of 1) and were prolonged if not initially recognized (median of 3 generations); outbreaks with mostly hospitalized patients had higher initial R values (median 12) and were shorter (median of 3 generations). Index cases with an atypical presentation of smallpox were less likely to have been diagnosed with smallpox; outbreaks in which the index case was not correctly diagnosed were larger (median of 27.5 cases) and longer (median of 3 generations) compared to outbreaks in which the index case was correctly diagnosed (median of 3 cases and 1 generation). CONCLUSION: Patterns of spread during Smallpox outbreaks varied with circumstances, but early detection and implementation of control measures is a most important influence on the magnitude of outbreaks. The majority of outbreaks studied in Europe and North America were controlled within a few generations if detected early.

negative: Acute Symptomatic Seizures in Critically Ill Patients with COVID-19: Is There an Association? BACKGROUND: The coronavirus disease of 2019 (COVID-19) emerged as a global pandemic. Historically, the group of human coronaviruses can also affect the central nervous system leading to neurological symptoms; however, the causative mechanisms of the neurological manifestations of COVID-19 disease are not well known. Seizures have not been directly reported as a part of COVID-19 outside of patients with previously known brain injury or epilepsy. We report two cases of acute symptomatic seizures, in non-epileptic patients, associated with severe COVID-19 disease. CASE PRESENTATIONS: Two advanced-age, non-epileptic, male patients presented to our northeast Ohio-based health system with concern for infection in Mid-March 2020. Both had a history of lung disease and during their hospitalization tested positive for SARS-CoV-2. They developed acute encephalopathy days into their hospitalization with clinical and electrographic seizures. Resolution of seizures was achieved with levetiracetam. DISCUSSION: Patients with COVID-19 disease are at an elevated risk for seizures, and the mechanism of these seizures is likely multifactorial. Clinical (motor) seizures may not be readily detected in this population due to the expansive utilization of sedatives and paralytics for respiratory optimization strategies. Many of these patients are also not electrographically monitored for seizures due to limited resources, multifactorial risk for acute encephalopathy, and the risk of cross-contamination. Previously, several neurological symptoms were seen in patients with more advanced COVID-19 disease, and these were thought to be secondary to multi-system organ failure and/or disseminated intravascular coagulopathy-related brain injury. However, these patients may also have an advanced breakdown of the blood–brain barrier precipitated by pro-inflammatory cytokine reactions. The neurotropic effect and neuroinvasiveness of SARS-Coronavirus-2 have not been directly established. CONCLUSIONS: Acute symptomatic seizures are possible in patients with COVID-19 disease. These seizures are likely multifactorial in origin, including cortical irritation due to blood–brain barrier breakdown, precipitated by the cytokine reaction as a part of the viral infection. Patients with clinical signs of seizures or otherwise unexplained encephalopathy may benefit from electroencephalography monitoring and/or empiric anti-epileptic therapy. Further studies are needed to elucidate the risk of seizures and benefit of monitoring in this population.

negative: Low serum 25-hydroxyvitamin D levels are associated with increased risk of viral coinfections in wheezing children

negative: Emerging Infections and Children: Influenza and Acute Necrotizing Encephalopathy Children can play a variety of roles in emerging infectious diseases. They can be victims, as in the vertical transmission of human immunodeficiency virus infection. They can be affected in a minor way compared with adults, as in West Nile virus infection, legionellosis, and coronavirus infection leading to severe acute respiratory syndrome (SARS). Sometimes, however, they play predominant roles—sources for other age groups—as do toddlers in out-of-the-home child care for transmission of penicillinresistant pneumococci and cytomegalovirus to family members. Children have a uniquely central role in transmitting the influenza viruses that cause annual seasonal outbreaks and epidemic disease and could cause global epidemic (or pandemic) disease. Children themselves suffer excessive morbidity and mortality from influenza. Continuous minor changes in virus neuraminidase and haemagglutinin components (antigenic drift) or a major change in either (antigenic shift) render naïve children especially vulnerable. Anticipating that pandemic influenza could occur at any time because of a major change in a human strain of influenza virus or through acquisition of human transmissibility of reassortant avian influenza strain(s) (Nicholson et al., 2003), the international community of healthcare experts are collaborating increasingly, and countries are drafting influenza pandemic preparedness plans. A draft by the U.S. Department of Health and Human Services of “Pandemic Influenza Preparedness and Response Plan” was released for comment in August 2004 (http://www.hhs.gov/nvpo/pandemicplan). All plans highlight the critical importance of international surveillance, openness, and rapid response to investigate and contain emergent avian or human strains.

negative: Care for patients with rheumatic diseases during COVID‐19 pandemic: A position statement from APLAR

negative: Review of Artificial Intelligence Techniques in Imaging Data Acquisition, Segmentation and Diagnosis for COVID-19 (This paper was submitted as an invited paper to IEEE Reviews in Biomedical Engineering on April 6, 2020.) The pandemic of coronavirus disease 2019 (COVID-19) is spreading all over the world. Medical imaging such as X-ray and computed tomography (CT) plays an essential role in the global fight against COVID-19, whereas the recently emerging artificial intelligence (AI) technologies further strengthen the power of the imaging tools and help medical specialists. We hereby review the rapid responses in the community of medical imaging (empowered by AI) toward COVID-19. For example, AI-empowered image acquisition can significantly help automate the scanning procedure and also reshape the workflow with minimal contact to patients, providing the best protection to the imaging technicians. Also, AI can improve work efficiency by accurate delination of infections in X-ray and CT images, facilitating subsequent quantification. Moreover, the computer-aided platforms help radiologists make clinical decisions, i.e., for disease diagnosis, tracking, and prognosis. In this review paper, we thus cover the entire pipeline of medical imaging and analysis techniques involved with COVID-19, including image acquisition, segmentation, diagnosis, and follow-up. We particularly focus on the integration of AI with X-ray and CT, both of which are widely used in the frontline hospitals, in order to depict the latest progress of medical imaging and radiology fighting against COVID-19.

negative: Rheumotologitsts’ view on the use of hydroxychloroquine to treat COVID-19 The current pandemic coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) calls urgently for effective therapies. Anti-malarial medicine chloroquine (CQ) and particularly its chemical analogue hydroxychloroquine (HCQ) have been recommended as promising candidate therapeutics that are now under either compassionate off-label use or clinical trials for the treatment of COVID-19 patients. However, there are public concerns and disputes about both the safety and efficacy of CQ and HCQ for this new application. Given the fact that for decades HCQ has been approved as an immunomodulatory drug for the long term treatment of chronic rheumatic diseases, as experienced rheumatologists, we would like to share our thoughts in this regard and trigger a brainstorm among clinical care providers for exchanging their diverse opinions on this urgent topic.

negative: Environmental factors, immune changes and respiratory diseases in troops during military activities Abstract Combat operations in contemporary theaters of war, as well as combat training, are carried out in all parts of the world, typically in a harsh environment. Specific environmental conditions, such as heat, cold, high-altitudes, desert climates, as well as chemical and biological pollution of both the atmosphere and soil, together with over-exertion, food restrictions, sleep deprivation, and psychological stress can all result in changes in the immune system and the occurrence of associated diseases. Respiratory diseases are one of the most common health problems among military personnel participating in combat training or deployed to operations in areas characterized by difficult climatic and sanitary conditions. They are, therefore, one of the main reasons for military personnel requiring ambulant and hospital treatment. The aim of the study was to discuss the influence of environmental factors and the conditions in which active duty is performed on changes in the immune system and the occurrence of respiratory tract diseases in a military environment.

negative: Impact of the COVID-19 Outbreak on the Management of Patients with Cancer The coronavirus SARS-CoV-2 (COVID-19) outbreak is having a profound impact on the management of patients with cancer. In this review, we comprehensively investigate the various aspects of cancer care during the pandemic, taking advantage of data generated in Asia and Europe at the frontline of the COVID-19 pandemic spread. Cancer wards have been subjected to several modifications to protect patients and healthcare professionals from COVID-19 infection, while attempting to maintain cancer diagnosis, therapy, and research. In this setting, the management of COVID-19 infected patients with cancer is particularly challenging. We also discuss the direct and potential remote impacts of the global pandemic on the mortality of patients with cancer. As such, the indirect impact of the pandemic on the global economy and the potential consequences in terms of cancer mortality are discussed. As the infection is spreading worldwide, we are obtaining more knowledge on the COVID-19 pandemic consequences that are currently impacting and may continue to further challenge cancer care in several countries.

negative: Risk of hospitalization and death from COVID-19 infection in patients with chronic plaque psoriasis receiving a biological treatment and renal transplanted recipients in maintenance immunosuppressive treatment

negative: Human T leukaemia Type 1 and COVID-19 In the absence of clinical data on Human T leukaemia Type 1 and COVID-19 infection, we are providing guidance to clinicians who look after people living with HTLV-1.

negative: Placental SARS-CoV-2 in a patient with mild COVID-19 disease Background: The full impact of COVID-19 on pregnancy remains uncharacterized. Current literature suggests minimal maternal, fetal, and neonatal morbidity and mortality,1 and COVID-19 manifestations appear similar between pregnant and non-pregnant women.2 We present a case of placental SARS-CoV-2 virus in a woman with an uncomplicated pregnancy and mild COVID-19 disease. Methods: A pregnant woman was evaluated at University of Missouri Women and Childrens Hospital. Institutional review board approval was obtained; information was obtained from medical records. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to detect SARS-CoV-2. A gynecological pathologist examined the placenta and performed histolopathology. Sections were formalin-fixed and paraffin-embedded; slides were cut and subjected to hematoxylin-and-eosin or immunohistochemistry (IHC) staining. IHC was performed with specific monoclonal antibodies to detect SARS-CoV-2 antigen or to identify trophoblasts. Findings: A 29 year-old multigravida presented at 40-4/7 weeks for labor induction. With myalgias two days prior, she tested positive for SARS-CoV-2. Her parents were in self-isolation for COVID-19 positivity; husband was asymptomatic and tested negative for COVID-19, but exposed to a workplace (meatpacking facility) outbreak. Prenatal course was uncomplicated, with no gestational hypertension. She was afebrile and asymptomatic with normal vital signs throughout hospitalization. Her myalgias improved prior to admission. A liveborn male infant was delivered vaginally. Newborn course was uneventful; he was appropriate for gestational age, physical was unremarkable, and he was discharged home at 36 hours. COVID-19 RT-PCR test was negative at 24 hours. At one-week follow-up, newborn was breastfeeding well, with no fevers or respiratory distress. Overall placental histology is consistent with acute uterine hypoxia (subchorionic laminar necrosis) superimposed on chronic uterine hypoxia (extra-villous trophoblasts and focal chronic villitis). IHC using SARS-CoV-2 nucleocapsid-specific monoclonal antibody demonstrated SARS-CoV-2 antigens throughout the placenta in chorionic villi endothelial cells, and rarely in CK7-expressing trophoblasts. Negative control placenta (November 2019 delivery) and ferret nasal turbinate tissues (not shown) were negative for SARS-CoV-2. Interpretation: In this report, SARS-CoV-2 was found in the placenta, but newborn was COVID-19 negative. Our case shows maternal vascular malperfusion, with no features of fetal vascular malperfusion. To our knowledge, this is the first report of placental COVID-19 despite mild COVID-19 disease in pregnancy (with no symptoms of COVID-19 aside from myalgias); specifically, this patient had no fever, cough, or shortness of breath, but only myalgias and sick contacts. Despite her having mild COVID-19 disease in pregnancy, we demonstrate placental vasculopathy and presence of SARS-CoV-2 virus across the placenta. Evidence of placental COVID-19 raises concern for possible placental vasculopathy (potentially leading to fetal growth restriction, pre-eclampsia, and other pregnancy complications) as well as for potential vertical transmission -- especially for pregnant women who may be exposed to COVID-19 in early pregnancy. Further studies are urgently needed, to determine whether women with mild, pre-symptomatic, or asymptomatic COVID-19 may have SARS-CoV-2 virus that can cross the placenta, cause fetal vascular malperfusion, and possibly affect the fetus. This raises important public health and public policy questions of whether future pregnancy guidance should include stricter pandemic precautions, such as screening for a wider array of COVID-19 symptoms, increased antenatal surveillance, and possibly routine COVID-19 testing on a regular basis throughout pregnancy.

negative: Using Partial Differential Equation with Google Mobility Data to Model COVID-19 in Arizona The outbreak of COVID-19 disrupts the life of many people in the world. The state of Arizona in the U.S. emerges as one of the country's newest COVID-19 hot spots. Accurate forecasting for COVID-19 cases will help governments to implement necessary measures and convince more people to take personal precautions to combat the virus. It is difficult to accurately predict the COVID-19 cases due to many human factors involved. This paper aims to provide a forecasting model for COVID-19 cases with the help of human activity data from the Google Community Mobility Reports. To achieve this goal, a specific partial differential equation (PDE) is developed and validated with the COVID-19 data from the New York Times at the county level in the state of Arizona in the U.S. The proposed model describes the combined effects of transboundary spread among county clusters in Arizona and human actives on the transmission of COVID-19. The results show that the prediction accuracy of this model is well acceptable (above 94\%). Furthermore, we study the effectiveness of human precautions such as wearing face masks and practicing social distancing on the decrease of COVID-19 cases at the local level. The localized analytical results can be used to help to slow down the spread of COVID-19 in Arizona. To the best of our knowledge, this work is the first attempt to apply PDE models on COVID-19 prediction with the Google Community Mobility Reports.

negative: Lessons learned from the mechanisms of posttraumatic inflammation extrapolated to the inflammatory response in COVID-19: a review Up to 20% of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) patients develop severe inflammatory complications with diffuse pulmonary inflammation, reflecting acute respiratory distress syndrome (ARDS). A similar clinical profile occurs in severe trauma cases. This review compares pathophysiological and therapeutic principles of severely injured trauma patients and severe coronavirus disease 2019 (COVID-19). The development of sequential organ failure in trauma parallels deterioration seen in severe COVID-19. Based on established pathophysiological models in the field of trauma, two complementary pathways of disease progression into severe COVID-19 have been identified. Furthermore, the transition from local contained disease into systemic and remote inflammation has been addressed. More specifically, the traumatology concept of sequential insults (‘hits’) resulting in immune dysregulation, is applied to COVID-19 disease progression modelling. Finally, similarities in post-insult humoral and cellular immune responses to severe trauma and severe COVID-19 are described. To minimize additional ‘hits’ to COVID-19 patients, we suggest postponing all elective surgery in endemic areas. Based on traumatology experience, we propose that immunoprotective protocols including lung protective ventilation, optimal thrombosis prophylaxis, secondary infection prevention and calculated antibiotic therapy are likely also beneficial in the treatment of SARS-CoV-2 infections. Finally, rising SARS-CoV-2 infection and mortality rates mandate exploration of out-of-the box treatment concepts, including experimental therapies designed for trauma care.

negative: COVID-19 in a severe eosinophilic asthmatic receiving benralizumab - a case study Introduction: Only little is known about COVID-19 in patients with asthma. There is no data on COVID-19 in patients with severe asthma or patients with asthma who are treated with monoclonal antibodies.Case Study: Here, we present the case of a severe eosinophilic asthmatic in whom benralizumab treatment, an anti-IL-5R monoclonal antibody, was initiated 2 years ago. Prior to benralizumab treatment, every viral infection had resulted in a prolonged course of oral corticosteroids (OCS). Since initiation of benralizumab, the patient has had good asthma control. Mid-March 2020, the patient developed high fever.Results: A SARS-CoV-2-PCR (nasopharyngeal swab) was positive. The patient's symptoms subsided after few days. No OCS was needed. The asthma control questionnaire 6-item scale worsened moderately in the week of the infection and returned to normal levels thereafter. The asthma control test, measuring longer term asthma control, showed no decline.Conclusion: The course of COVID-19 was very mild in this particular patient with severe eosinophilic asthma. So far, there is no evidence that would suggest a more severe course of COVID-19 in patients with asthma. It is worth noting, that prior to the initiation of benralizumab this patient had multiple exacerbations per year triggered by viral infections (4/year), which all required OCS. Whilst only anecdotal, this case study provides the first evidence to support the current recommendation of continuing monoclonal antibodies in patients with severe asthma during the COVID-19 pandemic.

negative: Emergency tracheostomy during COVID 19 Pandemic in a head and neck surgical oncology unit • Awake, Emergency, Intervention for an Unsecured 'Unable to intubate' Critical upper airway obstruction is a surgical challenge. • Aerosolization and risk COVID 19 transmission add to the already existing difficulty of surgical restoration of critical airway obstruction. • Adequate personal protection, rapid restoration of the airway with the minimum aerosol generation, and prevention of COVID 19 dissemination are keys to the success of Emergency Tracheostomy during the Pandemic.

negative: Insight into 2019 novel coronavirus — an updated intrim review and lessons from SARS-CoV and MERS-CoV Abstract Background The rapid spread of the coronavirus disease 2019 (COVID-19), caused by a zoonotic beta-coronavirus entitled 2019 novel coronavirus (2019-nCoV), has become a global threat. Awareness of the biological features of 2019-nCoV should be updated in time and needs to be comprehensively summarized to help optimize control measures and make therapeutic decisions. Methods Based on recently published literatures, official documents and selected up-to-date preprint studies, we reviewed the virology and origin, epidemiology, clinical manifestations, pathology and treatment of 2019-nCoV infection, in comparison with severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV) infection. Results The genome of 2019-nCoV partially resembled SARS-CoV and MERS-CoV, and indicating a bat origin. The COVID-19 generally had a high reproductive number, a long incubation period, a short serial interval and a low case fatality rate (much higher in patients with comorbidities) than SARS and MERS. Clinical presentation and pathology of COVID-19 greatly resembled SARS and MERS, with less upper respiratory and gastrointestinal symptoms, and more exudative lesions in post-mortems. Potential treatments included remdesivir, chloroquine, tocilizumab, convalescent plasma and vaccine immunization (when possible). Conclusion The initial experience from the current pandemic and lessons from the previous two pandemics can help improve future preparedness plans and combat disease progression.

negative: Treatment with Arbidol and Moxifloxacin in Ordinary and Severe Adult Patients Infected with COVID-19 Background An outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been widely spread. We aim to investigate the therapeutic effect of arbidol and moxifloxacin in patients infected with SARS-CoV-2. Methods We collected and analyzed data on 94 patients with COVID-19 including 27 severe patients at the Intensive Care Unit (ICU) and 74 ordinary patients at general isolation ward in Wuhan Xiehe Hospital, from February 15, 2020 to March 15, 2020. All patients were treated with arbidol (100mg each time, three times a day for 14 days) and moxifloxacin (0.4g each time, once a day for 7-14 days). Other data was also collected including demographic data, symptoms, laboratory findings, treatments and clinical outcomes. Results In basic characteristics, compared with the ordinary patients, the severe patients were older (median age was 63.0 years V.S 57.0 years, p=0.03), had higher proportion of hypertension (30% V.S 9%, p=0.03), higher possibility of getting fatigue and/or myalgia (26% V.S 6%, p=0.03), and had more obvious dyspnea symptom (26% V.S 3%, p=0.006). In regarding to laboratory results, we found the severe patients have higher white blood cell counts (p=0.003), neutrophil counts (p=0.007), higher levels of D-dimer (p<0.001), ALT (p<0.001) and AST (p=0.013) than the ordinary patients. After treatment of arbidol and moxifloxacin for one week, the rates of SARS-CoV-2 nucleic acid turning negative were 69.2% in the severe group and 77.8% in the ordinary group. A peculiar phenomenon was that IL-6 stands out among the cytokines in both groups, and higher in severe group than the ordinary one (p=0.011). After treating with arbidol and moxifloxacin for one week, IL-6 decreased significantly in severe group (p=0.023). Conclusion In summary, we proved the treatment of arbidol and moxifloxacin could be helpful in reducing viral load and inflammation during SARS-CoV2 infection, especially for negatively regulating fatal inflammation in severe COVID-19 patients. However, more evidence awaits further clinical verification.

negative: Immunosuppression drug‐related and clinical manifestation of Coronavirus disease 2019: A therapeutical hypothesis We read with interest the article of Guillen et al. 1 . Here, the authors described the management of a kidney transplanted patient infected by SARS-CoV-2 that causes novel Coronavirus disease 2019 (COVID-19). The authors stated that immunosuppressed patients might present with atypical clinical manifestation (fever, diarrhea, fatigue) without respiratory symptoms. Also Li and colleagues 2 reported SARS-CoV-2 infection in two solid organ transplanted patients. The two heart transplanted patients presented with variable severity of COVID-19 (one mild and another with more severe manifestations requiring a prolonged hospitalization), however, both survived the event.

negative: Hyperbaric oxygen therapy in preventing mechanical ventilation in COVID-19 patients: a retrospective case series. OBJECTIVE A pandemic afflicts the entire world. The highly contagious SARS-CoV-2 virus originated in Wuhan, China in late 2019 and rapidly spread across the entire globe. According to the World Health Organization (WHO), the novel Coronavirus (COVID-19)has infected more than two million people worldwide, causing over 160,000 deaths. Patients with COVID-19 disease present with a wide array of symptoms, ranging from mild flu-like complaints to life threatening pulmonary and cardiac complications. Older people and patients with underlying disease have an increased risk of developing severe acute respiratory syndrome (SARS) requiring mechanical ventilation. Once intubated, mortality increases exponentially. A number of pharmacologic regimens, including hydroxychloroquine-azithromycin, antiviral therapy (eg, remdesevir), and anti-IL-6 agents (e.g., toclizumab), have been highlighted by investigators over the course of the pandemic, based on the therapy's potential to interrupt the viral life-cycle of SARS-CoV-2 or preventing cytokine storm. At present, there have been no conclusive series of reproducible randomised clinical trials demonstrating the efficacy of any one drug or therapy for COVID-19. CASES COVID-19 positive patients (n=5) at a single institution received hyperbaric oxygen therapy (HBOT) between 13 and 20 April 2020. All the patients had tachypnoea and low oxygen saturation despite receiving high FiO2. HBOT was added to prevent the need for mechanical ventilation. A standard dive profile of 2.0ATA for 90 minutes was employed. Patients received between one and six treatments in one of two dedicated monoplace hyperbaric chambers. RESULTS All the patients recovered without the need for mechanical ventilation. Following HBOT, oxygen saturation increased, tachypnoea resolved and inflammatory markers fell. At the time of writing, three of the five patients have been discharged from the hospital and two remain in stable condition. CONCLUSION This small sample of patients exhibited dramatic improvement with HBOT. Most importantly, HBOT potentially prevented the need for mechanical ventilation. Larger studies are likely to define the role of HBOT in the treatment of this novel disease.

negative: COVID-19 Emergence and Social and Health Determinants in Colorado: A Rapid Spatial Analysis The aim of this rapid analysis was to investigate the spatial patterns of COVID-19 emergence across counties in Colorado. In the U.S. West, Colorado has the second highest number of cases and deaths, second only to California. Colorado is also reporting, like other states, that communities of color and low-income persons are disproportionately affected by COVID-19. Using GIS and correlation analysis, this study explored COVID-19 incidence and deaths from March 14 to April 8, 2020, with social determinants and chronic conditions. Preliminary results demonstrate that COVID-19 incidence intensified in mountain communities west of Denver and along the Urban Front Range, and evolved into new centers of risk in eastern Colorado. Overall, the greatest increase in COVID-19 incidence was in northern Colorado, i.e., Weld County, which reported the highest rates in the Urban Front Range. Social and health determinants associated with higher COVID-19-related deaths were population density and asthma, indicative of urban areas, and poverty and unemployment, suggestive of rural areas. Furthermore, a spatial overlap of high rates of chronic diseases with high rates of COVID-19 may suggest a broader syndemic health burden, where comorbidities intersect with inequality of social determinants of health.

negative: Response by Gheblawi et al to Letter Regarding Article, "Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2".

negative: Can We Reduce Mortality of COVID-19 if We do Better in Glucose Control? The SARS-CoV-2 has infected more than 3 million people and caused more than 240,000 death globally. Among the COVID-19 patients, the prevalence of people with other chronic diseases, such as diabetes, high blood pressure, and coronary heart disease is much higher than others. More strikingly, the survival rate of diabetic patients is also much lower than in non-diabetic patients. In addition to the general damage of high glucose to cells and tissues, a recent discovery that high glucose activates interferon regulatory factor 15 promotes influenza virus -induced cytokine storm. This discovery may shed light on the high incidence of diabetes in COVID-19. Several diabetes prevention strategies together with recent significant data-driven diabetes prediction approaches, which may help COVID-19 treatments, have been proposed.

negative: Cytokine Storm: Is it the only major death factor in COVID-19 patients? Coagulation role

negative: The position statement of the Polish Society of Gastroenterology and the Polish National Consultant in Gastroenterology regarding the management of patients with inflammatory bowel disease during the COVID-19 pandemic

negative: Pediatric Crohn's Disease and Multisystem Inflammatory Syndrome in Children (MIS-C) and COVID-19 Treated with Infliximab Coronavirus disease 2019 (COVID-19) may lead to a severe inflammatory response referred to as a cytokine storm. We describe a case of severe COVID-19 infection in a recently diagnosed pediatric Crohn's disease patient successfully treated with Tumor Necrosis Factor-alpha (TNF-α) blockade. The patient presented with five days of fever, an erythematous maculopapular facial rash, and abdominal pain without respiratory symptoms. SARS-CoV-2 PCR was positive. Despite inpatient treatment for COVID-19 and a perianal abscess, the patient acutely decompensated, with worsening fever, tachycardia, fluid-refractory hypotension, elevation of liver enzymes, and transformation of the rash into purpura extending from the face to the trunk, upper and lower extremities, including the palmar and plantar surfaces of the hands and feet. Cytokine profile revealed rising levels of interleukin (IL)-6, IL-8, and TNF-α, higher than those described in either inflammatory bowel disease (IBD) or severe COVID-19 alone. The patient was treated with infliximab for TNF-α blockade to address both moderately to severely active Crohn's disease and multisystem inflammatory syndrome in children (MIS-C) temporally related to COVID-19. Within hours of infliximab treatment, fever, tachycardia and hypotension resolved. Cytokine profile improved with normalization of TNF-α, a decrease in IL-6, and IL-8 concentrations. This case supports a role for blockade of TNF-α in the treatment of COVID-19 inflammatory cascade. The role of anti-TNF agents in patients with MIS-C temporally related to COVID-19 requires further investigation.

negative: Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage BACKGROUND: Neuroinflammation is closely associated with the poor prognosis in subarachnoid hemorrhage (SAH) patients. This study was aimed to determine the role of stimulator of IFN genes (STING), an essential regulator to innate immunity, in the context of SAH. METHODS: A total of 344 male C57BL/6 J mice were subjected to endovascular perforation to develop a model of SAH. Selective STING antagonist C-176 and STING agonist CMA were administered at 30 min or 1 h post-modeling separately. To investigate the underlying mechanism, the AMPK inhibitor compound C was administered intracerebroventricularly at 30 min before surgery. Post-SAH assessments included SAH grade, neurological test, brain water content, western blotting, RT-PCR, and immunofluorescence. Oxygenated hemoglobin was introduced into BV2 cells to establish a SAH model in vitro. RESULTS: STING was mainly distributed in microglia, and microglial STING expression was significantly increased after SAH. Administration of C-176 substantially attenuated SAH-induced brain edema and neuronal injury. More importantly, C-176 significantly alleviated both short-term and persistent neurological dysfunction after SAH. Meanwhile, STING agonist CMA remarkably exacerbated neuronal injury and deteriorated neurological impairments. Mechanically, STING activation aggravated neuroinflammation via promoting microglial activation and polarizing into M1 phenotype, evidenced by microglial morphological changes, as well as the increased level of microglial M1 markers including IL-1β, iNOS, IL-6, TNF-α, MCP-1, and NLRP3 inflammasome, while C-176 conferred a robust anti-inflammatory effect. However, all the mentioned beneficial effects of C-176 including alleviated neuroinflammation, attenuated neuronal injury and the improved neurological function were reversed by AMPK inhibitor compound C. Meanwhile, the critical role of AMPK signal in C-176 mediated anti-inflammatory effect was also confirmed in vitro. CONCLUSION: Microglial STING yielded neuroinflammation after SAH, while pharmacologic inhibition of STING could attenuate SAH-induced inflammatory injury at least partly by activating AMPK signal. These data supported the notion that STING might be a potential therapeutic target for SAH.

negative: Updates on coronavirus (COVID-19) and kidney The severe acute respiratory syndrome (SARS) is an infectious disease developed in Wuhan, China, at first. It involves the respiratory system and other organs like kidney, gastrointestinal tract and nervous system as well. The recent reports indicated that renal disorder is prevalent in coronavirus patients. The aim of this study was to provide a review of nephropathy caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and its mechanisms. The Web of Science, Scopus, and PubMed databases were systematically searched. Articles reporting nephropathy, coronavirus disease (COVID-19), coronavirus and the renal injury were included for assessment. Study designs, contrast agents, case reports and results were assessed. Of the assessed studies, suggested mechanisms include sepsis which caused cytokine storm syndrome or perhaps direct cellular injury due to the virus. In patients who were studied, albuminuria, proteinuria, and hematuria as well as an elevation in blood urea nitrogen and serum creatinine were observed. Additionally CT scan of the kidneys showed a decrease in tissue density suggestive of inflammation and interstitial edema. On the other hand, dialysis patients are a high-risk group than the general population. The current treatment for COVID-19 in acute kidney injury includes supportive management or kidney replacement therapy. All patients need to be quarantined. An N95 fit-tested mask and protective clothing and proper equipment are necessary. Some drugs can be effective to inhibit the outcome of this infection such as lopinavir/ritonavir, remdesvir, Chloroquine phosphate, convalescent plasma, tocilizumab, ACEi/ ARBs (angiotensin-converting enzyme inhibitor/angiotensin receptor blockers), and hrsACE2 (human recombinant soluble angiotensin-converting-enzyme 2).

negative: Metabolic Impacts of Confinement during the COVID-19 Pandemic Due to Modified Diet and Physical Activity Habits. While the detrimental effects of a chronic positive energy balance due to a sedentary lifestyle have been well established, the impacts of a short period of abruptly reduced physical activity and overeating arising from strict confinement due to the COVID-19 pandemic will soon start to emerge. To reasonably anticipate major consequences according to the available evidence, we hereby review the literature for studies that have explored the health impacts of several weeks of a reduction in physical activity and daily step-count combined with modified eating habits. These studies identify as main metabolic consequences increases in insulin resistance, total body fat, abdominal fat and inflammatory cytokines. All these factors have been strongly associated with the development of metabolic syndrome, which in turn increases the risk of multiple chronic diseases. A plausible mechanism involved in these impacts could be a positive energy balance promoted by maintaining usual dietary intake while reducing energy expenditure. This means that just as calorie intake restriction could help mitigate the deleterious impacts of a bout of physical inactivity, overeating under conditions of home confinement is very likely to exacerbate these consequences. Moreover, hypertension, diabetes, and cardiovascular disease have been identified as potential risk factors for more severely ill patients with COVID-19. Thus, adequate control of metabolic disorders could be important to reduce the risk of severe COVID-19.

negative: Toward Nanotechnology-Enabled Approaches against the COVID-19 Pandemic [Image: see text] The COVID-19 outbreak has fueled a global demand for effective diagnosis and treatment as well as mitigation of the spread of infection, all through large-scale approaches such as specific alternative antiviral methods and classical disinfection protocols. Based on an abundance of engineered materials identifiable by their useful physicochemical properties through versatile chemical functionalization, nanotechnology offers a number of approaches to cope with this emergency. Here, through a multidisciplinary Perspective encompassing diverse fields such as virology, biology, medicine, engineering, chemistry, materials science, and computational science, we outline how nanotechnology-based strategies can support the fight against COVID-19, as well as infectious diseases in general, including future pandemics. Considering what we know so far about the life cycle of the virus, we envision key steps where nanotechnology could counter the disease. First, nanoparticles (NPs) can offer alternative methods to classical disinfection protocols used in healthcare settings, thanks to their intrinsic antipathogenic properties and/or their ability to inactivate viruses, bacteria, fungi, or yeasts either photothermally or via photocatalysis-induced reactive oxygen species (ROS) generation. Nanotechnology tools to inactivate SARS-CoV-2 in patients could also be explored. In this case, nanomaterials could be used to deliver drugs to the pulmonary system to inhibit interaction between angiotensin-converting enzyme 2 (ACE2) receptors and viral S protein. Moreover, the concept of “nanoimmunity by design” can help us to design materials for immune modulation, either stimulating or suppressing the immune response, which would find applications in the context of vaccine development for SARS-CoV-2 or in counteracting the cytokine storm, respectively. In addition to disease prevention and therapeutic potential, nanotechnology has important roles in diagnostics, with potential to support the development of simple, fast, and cost-effective nanotechnology-based assays to monitor the presence of SARS-CoV-2 and related biomarkers. In summary, nanotechnology is critical in counteracting COVID-19 and will be vital when preparing for future pandemics.

negative: Headaches During COVID‐19: My Clinical Case and Review of the Literature OBJECTIVE: To analyze headaches related to COVID‐19 based on personal case experience. BACKGROUND: COVID‐19 is an infection caused by the new coronavirus SARS‐CoV‐2. The first reported case happened in Wuhan on December 1, 2019. At present, at least 1.8 million people are infected around the world and almost 110,000 people have died. Many studies have analyzed the clinical picture of COVID‐19, but they are focused on respiratory symptoms and headache is generically treated. METHODS: I describe and discuss my headaches during my COVID‐19 and I review the MEDLINE literature about headaches and COVID‐19. RESULTS: More than 41,000 COVID‐19 patients have been included in clinical studies and headache was present in 8%‐12% of them. However, no headache characterization was made in these studies. As a headache expert and based on my own personal clinical case, headaches related to COVID‐19 can be classified in the 2 phases of the disease. Acute headache attributed to systemic viral infection, primary cough headache, tension‐type headache and headache attributed to heterophoria can appear in the first phase (the influenza‐like phase); and headache attributed to hypoxia and a new headache, difficult to fit into the ICHD3, can appear if the second phase (the cytokine storm phase) occurs. CONCLUSIONS: Several headaches can appear during COVID‐19 infection. All of them are headaches specified in the ICHD3, except 1 that occurs from the 7th day after the clinical onset. This headache is probably related to the cytokine storm that some patients suffer and it could be framed under the ICHD3 headache of Headache attributed to other non‐infectious inflammatory intracranial disease. Although the reported prevalence of headaches as a symptom of COVID‐19 infection is low, this experience shows that, very probably, it is underestimated.

negative: Interpreting COVID-19 and Virtual Care Trends: Cohort Study BACKGROUND: The coronavirus disease (COVID-19) pandemic is rapidly spreading across the world. As of March 26, 2020, there are more than 500,000 cases and more than 25,000 deaths related to COVID-19, and the numbers are increasing by the hour. OBJECTIVE: The aim of this study was to explore the trends in confirmed COVID-19 cases in North Carolina, and to understand patterns in virtual visits related to symptoms of COVID-19. METHODS: We conducted a cohort study of confirmed COVID-19 cases and patients using an on-demand, statewide virtual urgent care center. We collected data from February 1, 2020, to March 15, 2020. Institutional Review Board exemption was obtained prior to the study. RESULTS: As of March, 18 2020, there were 92 confirmed COVID-19 cases and 733 total virtual visits. Of the total visits, 257 (35.1%) were related to COVID-19-like symptoms. Of the COVID-19-like visits, the number of females was 178 (69.2%). People in the age groups of 30-39 years (n=67, 26.1%) and 40-49 years (n=64, 24.9%) were half of the total patients. Additionally, approximately 96.9% (n=249) of the COVID-like encounters came from within the state of North Carolina. Our study shows that virtual care can provide efficient triaging in the counties with the highest number of COVID-19 cases. We also confirmed that the largest spread of the disease occurs in areas with a high population density as well as in areas with major airports. CONCLUSIONS: The use of virtual care presents promising potential in the fight against COVID-19. Virtual care is capable of reducing emergency room visits, conserving health care resources, and avoiding the spread of COVID-19 by treating patients remotely. We call for further adoption of virtual care by health systems across the United States and the world during the COVID-19 pandemic.

negative: Diabetes & Metabolic Syndrome: Clinical Research & Reviews COVID-19 and Ethnicity: A Novel Pathophysiological Role for Inflammation INTRODUCTION: There have been recent mounting concerns regarding multiple reports stating a significantly elevated relative-risk of COVID-19 mortality amongst the Black and Minority Ethnic (BAME) population. An urgent national enquiry investigating the possible reasons for this phenomenon has been issued in the UK. Inflammation is at the forefront of COVID-19 research as disease severity appears to correlate with pro-inflammatory cytokine dysregulation. This narrative review aims to shed light on the novel, pathophysiological role of inflammation in contributing towards the increased COVID-19 mortality risk amongst the BAME population. METHODS: Searches in PubMed, Medline, Scopus, medRxiv and Google Scholar were performed to identify articles published in English from inception to 18(th) June 2020. These databases were searched using keywords including: ‘COVID-19’ or ‘Black and Minority Ethnic’ or ‘Inflammation’. A narrative review was synthesized using these included articles. RESULTS: We suggest a novel pathophysiological mechanism by which acute inflammation from COVID-19 may augment existing chronic inflammation, in order to potentiate a ‘cytokine storm’ and thus the more severe disease phenotype observed in the BAME population. Obesity, insulin resistance, cardiovascular disease, psychological stress, chronic infections and genetic predispositions are all relevant factors which may be contributing to elevated chronic systemic inflammation amongst the BAME population. CONCLUSION: Overall, this review provides early insights and directions for ongoing research regarding the pathophysiological mechanisms that may explain the severe COVID-19 disease phenotype observed amongst the BAME population. We suggest ‘personalization’ of chronic disease management, which can be used with other interventions, in order to tackle this.

negative: Surviving COVID-19: A disease tolerance perspective

negative: Alveolar macrophage dysfunction and cytokine storm in the pathogenesis of two severe COVID-19 patients BACKGROUND: The novel coronavirus pneumonia COVID-19 caused by SARS-CoV-2 infection could lead to a serious of clinical symptoms and severe illness, including acute respiratory distress syndrome (ARDS) and fatal organ failure. We report the fundamental pathological investigation in the lungs and other organs of fatal cases for the mechanistic understanding of severe COVID-19 and the development of specific therapy in these cases. METHODS: The autopsy and pathological investigations of specimens were performed on bodies of two deceased cases with COVID-19. Gross anatomy and histological investigation by Hematoxylin and eosin (HE) stained were reviewed on each patient. Alcian blue/periodic acid-Schiff (AB-PAS) staining and Masson staining were performed for the examinations of mucus, fibrin and collagen fiber in lung tissues. Immunohistochemical staining were performed on the slides of lung tissues from two patients. Real-time PCR was performed to detect the infection of SARS-CoV-2. Flow cytometry analyses were performed to detect the direct binding of S protein and the expression of ACE2 on the cell surface of macrophages. FINDINGS: The main pathological features in lungs included extensive impairment of type I alveolar epithelial cells and atypical hyperplasia of type II alveolar cells, with formation of hyaline membrane, focal hemorrhage, exudation and pulmonary edema, and pulmonary consolidation. The mucous plug with fibrinous exudate in the alveoli and the dysfunction of alveolar macrophages were characteristic abnormalities. The type II alveolar epithelial cells and macrophages in alveoli and pulmonary hilum lymphoid tissue were infected by SARS-CoV-2. S protein of SARS-CoV-2 directly bound to the macrophage via the S-protein-ACE2 interaction. INTERPRETATION: Infection of Alveolar macrophage by SARS-CoV-2 might be drivers of the “cytokine storm”, which might result in damages in pulmonary tissues, heart and lung, and leading to the failure of multiple organs . FUNDING: Shanghai Guangci Translational Medical Research Development Foundation, Shanghai, China

negative: Neurological Involvement in COVID-19 and Potential Mechanisms: A Review As the current understanding of COVID-19 continues to evolve, a synthesis of the literature on the neurological impact of this novel virus may help inform clinical management and highlight potentially important avenues of investigation. Additionally, understanding the potential mechanisms of neurologic injury may guide efforts to better detect and ameliorate these complications. In this review, we synthesize a range of clinical observations and initial case series describing potential neurologic manifestations of COVID-19 and place these observations in the context of coronavirus neuro-pathophysiology as it may relate to SARS-CoV-2 infection. Reported nervous system manifestations range from anosmia and ageusia, to cerebral hemorrhage and infarction. While the volume of COVID-19-related case studies continues to grow, previous work examining related viruses suggests potential mechanisms through which the novel coronavirus may impact the CNS and result in neurological complications. Namely, animal studies examining the SARS-CoV have implicated the angiotensin-converting-enzyme-2 receptor as a mediator of coronavirus-related neuronal damage and have shown that SARS-CoV can infect cerebrovascular endothelium and brain parenchyma, the latter predominantly in the medial temporal lobe, resulting in apoptosis and necrosis. Human postmortem brain studies indicate that human coronavirus variants and SARS-CoV can infect neurons and glia, implying SARS-CoV-2 may have similar neurovirulence. Additionally, studies have demonstrated an increase in cytokine serum levels as a result of SARS-CoV infection, consistent with the notion that cytokine overproduction and toxicity may be a relevant potential mechanism of neurologic injury, paralleling a known pathway of pulmonary injury. We also discuss evidence that suggests that SARS-CoV-2 may be a vasculotropic and neurotropic virus. Early reports suggest COVID-19 may be associated with severe neurologic complications, and several plausible mechanisms exist to account for these observations. A heightened awareness of the potential for neurologic involvement and further investigation into the relevant pathophysiology will be necessary to understand and ultimately mitigate SARS-CoV-2-associated neurologic injury.

negative: COVID-19: Therapeutics and Their Toxicities SARS-CoV-2 is a novel coronavirus that emerged in 2019 and is causing the COVID-19 pandemic. There is no current standard of care. Clinicians need to be mindful of the toxicity of a wide variety of possibly unfamiliar substances being tested or repurposed to treat COVID-19. The United States Food and Drug Administration (FDA) has provided emergency authorization for the use of chloroquine and hydroxychloroquine. These two medications may precipitate ventricular dysrhythmias, necessitating cardiac and electrolyte monitoring, and in severe cases, treatment with epinephrine and high-doses of diazepam. Recombinant protein therapeutics may cause serum sickness or immune complex deposition. Nucleic acid vaccines may introduce mutations into the human genome. ACE inhibitors and ibuprofen have been suggested to exacerbate the pathogenesis of COVID-19. Here, we review the use, mechanism of action, and toxicity of proposed COVID-19 therapeutics.

negative: Study on the dynamic change law and correlation between CT imaging manifestations and cellular immunity of 2019 novel coronavirus disease PURPOSE: To explore the dynamic changes and correlation between CT imaging manifestations and cellular immunity of COVID-19. MATERIALS AND METHODS: This retrospective review analyzed 23 patients with COVID-19, including 13 males and 10 females aged 27–70 years, with an average age of 48 years. Patients were divided into two groups: group A with 11 critical-severe patients, and group B with 12 common-mild patients. Clinical, laboratory, and radiological data were collected and analyzed. RESULTS: LYM, LYM (%), CD3+, CD4+, and CD8+ decreased, while NEU (%), CRP, and CT scores increased in all patients, WBC in group A increased. In group A, on day 10–12 after disease onset, CT scores and CRP reached the highest point, and day 13–15 LYM, LYM (%) reached the lowest but NEU (%) and WBC reached the highest, CD3+, CD4+ and CD8+ were at the lowest on day 10–15. In group B, on day 7–9, CT scores, NEU (%) and CRP reached the peak, but LYM, LYM (%), CD3+, CD4+ and CD8+ reached the lowest. In all patients, CT scores had a significantly negative correlation with CD3+, CD4+, CD8+, LYM (%), and LYM (p = 0.001, r = − 0.797; p = 0.008, r = − 0.698; p = 0.002, r = − 0.775; p < 0.001, r = − 0.785; p = 0.021, r = − 0.571, respectively), and a significantly positive correlation with WBC and NEU (%) (p < 0.001, r = 0.785; p = 0.003, r = 0.691, respectively). CONCLUSION: Dynamic changes of CT manifestations and cellular immunity of patients with COVID-19 were regular and correlation was high between these two parameters.

negative: SARS-CoV-2 infection pathogenesis is related to oxidative stress as a response to aggression Since the WHO declared COVID-19 a pandemic, a great effort has been made to understand this serious disease. Thousands of studies are being devoted to understanding its epidemiology, its molecular characteristics, its mechanisms, and the clinical evolution of this viral infection. However, little has been published on its pathogenesis and the host response mechanisms in the progress of the disease. Therefore, we propose a hypothesis based on strong scientific documentation, associating oxidative stress with changes found in patients with COVID-19, such as its participation in the amplification and perpetuation of the cytokine storm, coagulopathy, and cell hypoxia. Finally, we suggest a therapeutic strategy to reduce oxidative stress using antioxidants, NFkB inhibitors, Nrf2 activators, and iron complexing agents. We believe that this hypothesis can guide new studies and therapeutic strategies on this topic.

negative: Dynamics and Control of Diseases in Networks with Community Structure The dynamics of infectious diseases spread via direct person-to-person transmission (such as influenza, smallpox, HIV/AIDS, etc.) depends on the underlying host contact network. Human contact networks exhibit strong community structure. Understanding how such community structure affects epidemics may provide insights for preventing the spread of disease between communities by changing the structure of the contact network through pharmaceutical or non-pharmaceutical interventions. We use empirical and simulated networks to investigate the spread of disease in networks with community structure. We find that community structure has a major impact on disease dynamics, and we show that in networks with strong community structure, immunization interventions targeted at individuals bridging communities are more effective than those simply targeting highly connected individuals. Because the structure of relevant contact networks is generally not known, and vaccine supply is often limited, there is great need for efficient vaccination algorithms that do not require full knowledge of the network. We developed an algorithm that acts only on locally available network information and is able to quickly identify targets for successful immunization intervention. The algorithm generally outperforms existing algorithms when vaccine supply is limited, particularly in networks with strong community structure. Understanding the spread of infectious diseases and designing optimal control strategies is a major goal of public health. Social networks show marked patterns of community structure, and our results, based on empirical and simulated data, demonstrate that community structure strongly affects disease dynamics. These results have implications for the design of control strategies.

negative: COVID-19 Clinical Research INTRODUCTION: While the global COVID-19 pandemic has challenged the entire humanity and health systems, it also triggered researchers to urgently perform clinical trials to assess the safety and efficacy of many agents and modalities to combat COVID-19. As of April 22, over 650 clinical studies have been registered both in USA and internationally. Results from these studies are also coming at a brisk pace in this unprecedented emergency. AREAS COVERED: We searched the NCI website and Medline and summarize various national and international clinical trials and summarize few of the pivotal ones in this paper, including those specific to oncology population. Two hundred and eighty four studies are actively recruiting adults and children with confirmed COVID-19, including 25 are early-phase I/phase I, 72 phase II, 58 phase III, 12 phase IV, and 31 other trials. They can be categorized into four groups: drugs that combat SARS-CoV-2, immunomodulatory agents to counteract cytokine storm, convalescence plasma therapies and vaccines trials. EXPERT OPINION: It is hoped that these efforts will results in a successful treatment to COVID-19, especially in a timely fashion before the second pandemic expected in fall. It is essential to acknowledge the devotion and hard work of the clinical research team and clinical research volunteers.

negative: COVID-19 outbreak: less stethoscope, more ultrasound

negative: COVID-19: the vasculature unleashed On the basis of emerging evidence from patients with COVID-19, we postulate that endothelial cells are essential contributors to the initiation and propagation of severe COVID-19. Here, we discuss current insights into the link between endothelial cells, viral infection and inflammatory changes and propose novel therapeutic strategies.

negative: Sex Hormones and Novel Corona Virus Infectious Disease (COVID-19) Abstract Given the rapid spread of the COVID-19 pandemic and its overwhelming impact on health care systems and the global economy, innovative therapeutic strategies are urgently needed. The proposed primary culprit of COVID-19 is the intense inflammatory response—an augmented immune response and cytokine storm—severely damaging the lung tissue and rendering some patients’ conditions severe enough to require assisted ventilation. Sex differences in the response to inflammation have been documented and can be attributed, at least in part, to sex steroid hormones. Moreover, age associated decreases in sex steroid hormones, namely estrogen and testosterone, may mediate pro-inflammatory increases in older adults that could increase their risk for COVID-19 adverse outcomes. Sex hormones can mitigate the inflammation response and might provide promising therapeutic potential for COVID-19 patients. In this article, we explore the possible anti-inflammatory effects of estrogen and testosterone and the anabolic effect of testosterone, with particular attention to the potential therapeutic role of hormone replacement therapy (HRT) in older men and women with COVID-19.

negative: Prevalence of obesity among adult inpatients with COVID-19 in France

negative: COVID-19 randomised trial protocols: rapid publication without barriers

negative: Retinal outcomes of COVID-19: Possible role of CD147 and cytokine storm in infected patients with diabetes mellitus

negative: Gendered effects on inflammation reaction and outcome of COVID‐19 patients in Wuhan BACKGROUND: The rapid outbreak of coronavirus disease 2019 (COVID‐19) has turned into a public health emergency of international concern. Epidemiological research showed that gender was associated with the severity of COVID‐19, but the underlying mechanism of gender predisposition remains poorly understood. We aim to study the gendered differences in inflammation reaction, and the association with severity and mortality of COVID‐19. METHODS: In this retrospective study, we enrolled 548 COVID‐19 inpatients from Tongji Hospital from January 26 to February 5, 2020, and followed up to March 3, 2020. Epidemiological, demographic and clinical features, and inflammatory indexes were collected and compared between males and females. Cox proportional hazard regression model was applied to identify gendered effect on mortality of COVID‐19 after adjusting age, comorbidity and smoking history. Multiple linear regression method was used to explore the influence of sex on inflammation reaction. RESULTS: Males had higher mortality than females did (22.2% vs. 10.4%), with the HR of 1.923 (95% CI, 1.181‐3.130); elder age and comorbidity were significantly associated with decease of COVID‐19 patients. Excess inflammation reaction was related to severity of COVID‐19. Male patients had greater inflammation reaction, with higher levels of IL‐10, TNF‐α, LDH, ferritin and hsCRP, but lower lymphocyte count than females adjusted by age and comorbidity. CONCLUSIONS: Gender, age, and comorbidity are critical risk factors for mortality of COVID‐19. Excess innate immunity and proinflammation activity, and deficiency in adaptive immunity response promote males especially elder males to develop cytokine storm, causing potential ARDS, multiple organ failure and decease. This article is protected by copyright. All rights reserved.

negative: From causes of aging to death from COVID-19 COVID-19 is not deadly early in life, but mortality increases exponentially with age, which is the strongest predictor of mortality. Mortality is higher in men than in women, because men age faster, and it is especially high in patients with age-related diseases, such as diabetes and hypertension, because these diseases are manifestations of aging and a measure of biological age. At its deepest level, aging (a program-like continuation of developmental growth) is driven by inappropriately high cellular functioning. The hyperfunction theory of quasi-programmed aging explains why COVID-19 vulnerability (lethality) is an age-dependent syndrome, linking it to other age-related diseases. It also explains inflammaging and immunosenescence, hyperinflammation, hyperthrombosis, and cytokine storms, all of which are associated with COVID-19 vulnerability. Anti-aging interventions, such as rapamycin, may slow aging and age-related diseases, potentially decreasing COVID-19 vulnerability.

negative: A CASE REPORT OF COVID-19 ASSOCIATED HYPERACTIVE ICU DELIRIUM WITH PROPOSED PATHOPHYSIOLOGY AND TREATMENT There have been increasing reports of neuropsychiatric presentations and symptoms of COVID-19, more commonly seen in severely ill patients. Delirium, which is highly prevalent in general intensive care unit (ICU) populations, is expected to be frequent and prominent in COVID-19 patients hospitalized with acute respiratory distress syndrome (ARDS) in ICU. In this case report with associated review, we present a case of a critically ill patient with COVID-19 managed in ICU for ARDS. Psychiatry was consulted for management of her hyperactive delirium, likely complicated by environmental factors inherent in management of COVID-19 patients as well as the use of multiple sedatives. Patient was successfully managed by psychiatry with a combination of high-dose melatonin, suvorexant, guanfacine, intravenous haloperidol, and intravenous valproic acid. In addition to case presentation, we discuss a proposed delirium pathophysiology in COVID-19 associated delirium and a systematized approach to evaluation and management of such patients.

negative: SARS-CoV-2 and viral sepsis: observations and hypotheses Summary Since the outbreak of coronavirus disease 2019 (COVID-19), clinicians have tried every effort to understand the disease, and a brief portrait of its clinical features have been identified. In clinical practice, we noticed that many severe or critically ill COVID-19 patients developed typical clinical manifestations of shock, including cold extremities and weak peripheral pulses, even in the absence of overt hypotension. Understanding the mechanism of viral sepsis in COVID-19 is warranted for exploring better clinical care for these patients. With evidence collected from autopsy studies on COVID-19 and basic science research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV, we have put forward several hypotheses about SARS-CoV-2 pathogenesis after multiple rounds of discussion among basic science researchers, pathologists, and clinicians working on COVID-19. We hypothesise that a process called viral sepsis is crucial to the disease mechanism of COVID-19. Although these ideas might be proven imperfect or even wrong later, we believe they can provide inputs and guide directions for basic research at this moment.

negative: Mild COVID-19 infection in an NMO patient treated with tocilizumab: a confirmation of anti-IL-6 protective role?

negative: A study of non-prescription usage of antibiotics in the upper respiratory tract infections in the urban population

negative: Diabetes or endocrinopathy admitted in the COVID‐19 ward The Covid‐19 pandemic confronted us with unknown clinical pictures, also in diabetology and endocrinology. Sharing clinical experiences is therefore of enormous importance. Actually, information about the care given in the Covid‐19 ward (in contrast to that provided in the Emergency Room/ICU) is still sparse. The last weeks we built experience and gathered knowledge while giving hospital care to patients who had a pre‐existent endocrine disease (and diabetes; most patients suffered from a type two diabetes). In our contribution we presented our insights obtained from this intensive period obtained in the Covid‐19 ward.

negative: Ventricular Arrhythmia Risk Based on Ethnicity in COVID-19 Patients on Hydroxychloroquine and Azithromycin Combination: Viewpoint There are many reports available now, which are mostly observational or registry trial outcomes having varied results on coronavirus 2019 (COVID-19) patients put on hydroxychloroquine and azithromycin combination. Some are showing increased in-hospital mortality and ventricular arrhythmia increase, while some are showing overall benefit with significant viral RNA load reduction. Everyday things are getting more complicated with the publication of these different outcomes. This needs to be addressed.

negative: Smell and taste symptom‐based predictive model for COVID‐19 diagnosis BACKGROUND: The presentation of COVID‐19 overlaps with common influenza symptoms. There is limited data on whether a specific symptom or collection of symptoms may be useful to predict test positivity. METHODS: An anonymous electronic survey was publicized through social media to query participants with COVID‐19 testing. Respondents were questioned regarding 10 presenting symptoms, demographic information, comorbidities and COVID‐19 test results. Stepwise logistic regression was used to identify predictors for COVID positivity. Selected classifiers were assessed for prediction performance using receiver operating characteristic analysis (ROC). RESULTS: One‐hundred and forty‐five participants with positive COVID‐19 testing and 157 with negative results were included. Participants had a mean age of 39 years, and 214 (72%) were female. Smell or taste change, fever, and body ache were associated with COVID‐19 positivity, and shortness of breath and sore throat were associated with a negative test result (p<0.05). A model using all 5 diagnostic symptoms had the highest accuracy with a predictive ability of 82% in discriminating between COVID‐19 results. To maximize sensitivity and maintain fair diagnostic accuracy, a combination of 2 symptoms, change in sense of smell or taste and fever was found to have a sensitivity of 70% and overall discrimination accuracy of 75%. CONCLUSION: Smell or taste change is a strong predictor for a COVID‐19 positive test result. Using the presence of smell or taste change with fever, this parsimonious classifier correctly predicts 75% of COVID‐19 test results. A larger cohort of respondents will be necessary to refine classifier performance. This article is protected by copyright. All rights reserved

negative: Repurposing and reshaping of hospitals during the COVID-19 outbreak in South Korea Abstract During the extensive outbreak of coronavirus disease 2019 (COVID-19) in South Korea, many strategies in the hospital setting, such as stratified patient care, the assignment of hospitals/beds by a task force team, and the establishment of dedicated COVID-19 hospitals, dedicated COVID-19 emergency centers, COVID-19 community facilities, and respiratory care split hospitals, were adopted to mitigate community transmission and prevent nosocomial infection. Most of these strategies were used during the Middle East Respiratory syndrome outbreak and were applied again successfully during the COVID-19 outbreak. The reallocation of health care capacity, repurposing of hospitals, and close collaboration between the government and the health care committee might have been the key to successfully addressing the crisis of COVID-19 given the shortage of health care resources.

negative: ASGE Bariatric Endoscopy Task Force systematic review and meta-analysis assessing the ASGE PIVI thresholds for adopting endoscopic bariatric therapies. The increasing global burden of obesity and its associated comorbidities has created an urgent need for additional treatment options to fight this pandemic. Endoscopic bariatric therapies (EBTs) provide an effective and minimally invasive treatment approach to obesity that would increase treatment options beyond surgery, medications, and lifestyle measures. This systematic review and meta-analysis were performed by the American Society for Gastrointestinal Endoscopy (ASGE) Bariatric Endoscopy Task Force comprising experts in the subject area and the ASGE Technology Committee Chair to specifically assess whether acceptable performance thresholds outlined by an ASGE Preservation and Incorporation of Valuable endoscopic Innovations (PIVI) document for clinical adoption of available EBTs have been met. After conducting a comprehensive search of several English-language databases, we performed direct meta-analyses by using random-effects models to assess whether the Orbera intragastric balloon (IGB) (Apollo Endosurgery, Austin, Tex) and the EndoBarrier duodenal-jejunal bypass sleeve (DJBS) (GI Dynamics, Lexington, Mass) have met the PIVI thresholds. The meta-analyses results indicate that the Orbera IGB meets the PIVI thresholds for both primary and nonprimary bridge obesity therapy. Based on a meta-analysis of 17 studies including 1683 patients, the percentage of excess weight loss (%EWL) with the Orbera IGB at 12 months was 25.44% (95% confidence interval [CI], 21.47%-29.41%) (random model) with a mean difference in %EWL over controls of 26.9% (95% CI, 15.66%-38.24%; P ≤ .01) in 3 randomized, controlled trials. Furthermore, the pooled percentage of total body weight loss (% TBWL) after Orbera IGB implantation was 12.3% (95% CI, 7.9%–16.73%), 13.16% (95% CI, 12.37%–13.95%), and 11.27% (95% CI, 8.17%–14.36%) at 3, 6, and 12 months after implantation, respectively, thus exceeding the PIVI threshold of 5% TBWL for nonprimary (bridge) obesity therapy. With the data available, the DJBS liner does appear to meet the %EWL PIVI threshold at 12 months, resulting in 35% EWL (95% CI, 24%-46%) but does not meet the 15% EWL over control required by the PIVI. We await review of the pivotal trial data on the efficacy and safety of this device. Data are insufficient to evaluate PIVI thresholds for any other EBT at this time. Both evaluated EBTs had ≤5% incidence of serious adverse events as set by the PIVI document to indicate acceptable safety profiles. Our task force consequently recognizes the Orbera IGB for meeting the PIVI criteria for the management of obesity. As additional data from the other EBTs become available, we will update our recommendations accordingly.

negative: Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage BACKGROUND: Neuroinflammation is closely associated with the poor prognosis in subarachnoid hemorrhage (SAH) patients. This study was aimed to determine the role of stimulator of IFN genes (STING), an essential regulator to innate immunity, in the context of SAH. METHODS: A total of 344 male C57BL/6 J mice were subjected to endovascular perforation to develop a model of SAH. Selective STING antagonist C-176 and STING agonist CMA were administered at 30 min or 1 h post-modeling separately. To investigate the underlying mechanism, the AMPK inhibitor compound C was administered intracerebroventricularly at 30 min before surgery. Post-SAH assessments included SAH grade, neurological test, brain water content, western blotting, RT-PCR, and immunofluorescence. Oxygenated hemoglobin was introduced into BV2 cells to establish a SAH model in vitro. RESULTS: STING was mainly distributed in microglia, and microglial STING expression was significantly increased after SAH. Administration of C-176 substantially attenuated SAH-induced brain edema and neuronal injury. More importantly, C-176 significantly alleviated both short-term and persistent neurological dysfunction after SAH. Meanwhile, STING agonist CMA remarkably exacerbated neuronal injury and deteriorated neurological impairments. Mechanically, STING activation aggravated neuroinflammation via promoting microglial activation and polarizing into M1 phenotype, evidenced by microglial morphological changes, as well as the increased level of microglial M1 markers including IL-1ß, iNOS, IL-6, TNF-α, MCP-1, and NLRP3 inflammasome, while C-176 conferred a robust anti-inflammatory effect. However, all the mentioned beneficial effects of C-176 including alleviated neuroinflammation, attenuated neuronal injury and the improved neurological function were reversed by AMPK inhibitor compound C. Meanwhile, the critical role of AMPK signal in C-176 mediated anti-inflammatory effect was also confirmed in vitro. CONCLUSION: Microglial STING yielded neuroinflammation after SAH, while pharmacologic inhibition of STING could attenuate SAH-induced inflammatory injury at least partly by activating AMPK signal. These data supported the notion that STING might be a potential therapeutic target for SAH.

negative: Dual Role of Th17 Cytokines, IL-17A,F, and IL-22 in Allergic Asthma The proinflammatory role of T helper (Th) 17 cells and therefore of its cytokines, IL-17 (IL-17A), IL-17F, and IL-22, in autoimmune disorders has been favored, although there is evidence that not only IL-17A but also IL-17F and IL-22 have a dual role as negative regulators. Here we review the concept of the dual function of IL-17A, IL-17F, and IL-22 in the light of recent strategies to use neutralization of these cytokines as potential alternative to neutralizing TNF and IL-1 treatments in chronic inflammatory disorders. Expectedly, in allergic lung inflammation, neutralization of IL-17A inhibited neutrophil recruitment. However, this IL-17A antibody treatment concomitantly increased eosinophil recruitment by neutralizing IL-17A’s dual role as negative regulator. IL-17A negatively regulated dendritic cell function and activation of T helper cell (Th)2 cytokine production. Furthermore, IL-17A inhibited Th2-characteristic chemokine and adhesion molecule expression. On a mechanistic level, IL-17A acted on IκB-β by preventing degradation and in turn leading to reduced NF-κB activation or IL-17A inhibited transcription factor IRF-1. Therefore, anti-IL-17A therapy, although presenting a promising lead in chronic inflammatory disorders, bears a potential risk of exacerbating allergic asthma.

negative: Nucleobase but not Sugar Fidelity is Maintained in the Sabin I RNA-Dependent RNA Polymerase The Sabin I poliovirus live, attenuated vaccine strain encodes for four amino acid changes (i.e., D53N, Y73H, K250E, and T362I) in the RNA-dependent RNA polymerase (RdRp). We have previously shown that the T362I substitution leads to a lower fidelity RdRp, and viruses encoding this variant are attenuated in a mouse model of poliovirus. Given these results, it was surprising that the nucleotide incorporation rate and nucleobase fidelity of the Sabin I RdRp is similar to that of wild-type enzyme, although the Sabin I RdRp is less selective against nucleotides with modified sugar groups. We suggest that the other Sabin amino acid changes (i.e., D53N, Y73H, K250E) help to re-establish nucleotide incorporation rates and nucleotide discrimination near wild-type levels, which may be a requirement for the propagation of the virus and its efficacy as a vaccine strain. These results also suggest that the nucleobase fidelity of the Sabin I RdRp likely does not contribute to viral attenuation.

negative: COVID-19: clinical issues from the Japan Surgical Society In this unprecedented COVID-19 pandemic, several key issues must be addressed to ensure safe treatment and prevent rapid spread of the virus and a consequential medical crisis. Careful evaluation of a patient’s condition is crucial for deciding the triage plan, based on the status of the disease and comorbidities. As functionality of the medical care system is greatly affected by the environmental situation, the treatment may differ according to the medical and infectious disease circumstances of the institution. Importantly, all medical staff must prevent nosocomial COVID-19 by minimizing the effects of aerosol spread and developing diagnostic and surgical procedures. Polymerase chain reaction (PCR) screening for COVID-19 infection, particularly in asymptomatic patients, should be encouraged as these patients are prone to postoperative respiratory failure. In this article, the Japan Surgical Society addresses the general principles of surgical treatment in relation to COVID-19 infection and advocates preventive measures against viral transmission during this unimaginable COVID-19 pandemic.

negative: Impact of SARS-CoV-2 infection on neurodegenerative and neuropsychiatric diseases: A delayed pandemic? Abstract Introduction SARS-CoV-2 was first detected in December 2019 in the Chinese city of Wuhan and has since spread across the world. At present, the virus has infected over 1.7 million people and caused over 100000 deaths worldwide. Research is currently focused on understanding the acute infection and developing effective treatment strategies. In view of the magnitude of the epidemic, we conducted a speculative review of possible medium- and long-term neurological consequences of SARS-CoV-2 infection, with particular emphasis on neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin, based on the available evidence on neurological symptoms of acute SARS-CoV-2 infection. Development We systematically reviewed the available evidence about the pathogenic mechanisms of SARS-CoV-2 infection, the immediate and lasting effects of the cytokine storm on the central nervous system, and the consequences of neuroinflammation for the central nervous system. Conclusions SARS-CoV-2 is a neuroinvasive virus capable of triggering a cytokine storm, with persistent effects in specific populations. Although our hypothesis is highly speculative, the impact of SARS-CoV-2 infection on the onset and progression of neurodegenerative and neuropsychiatric diseases of neuroinflammatory origin should be regarded as the potential cause of a delayed pandemic that may have a major public health impact in the medium to long term. Cognitive and neuropsychological function should be closely monitored in COVID-19 survivors.

negative: Statins as early therapy to mitigate COVID-19 (SARS-CoV-2)-associated ARDS and cytokine storm syndrome - time is of the essence

negative: Genetic Characterization of Coronaviruses from Domestic Ferrets, Japan We detected ferret coronaviruses in 44 (55.7%) of 79 pet ferrets tested in Japan and classified the viruses into 2 genotypes on the basis of genotype-specific PCR. Our results show that 2 ferret coronaviruses that cause feline infectious peritonitis–like disease and epizootic catarrhal enteritis are enzootic among ferrets in Japan.

negative: Prediction of clinical outcomes in individuals with chronic low back pain: a protocol for a systematic review with meta-analysis. BACKGROUND Low back pain (LBP) is one of the most prevalent and recurrent conditions in the general population, with personal, professional, social and economic impact. However, there is a lack of consistent evidence about chronic low back pain (CLBP) prognosis, especially highlighting predictors that influence CLBP outcome. Existing systematic reviews are scarce, outdated and incomplete. The primary aim of this systematic review is to identify multivariable models and/or predictors associated with clinical outcomes in subjects with CLBP (namely pain intensity, disability, return to work, psychological well-being and quality of life). METHODS We will systematically search Ovid MEDLINE (PubMed), Scopus and Web of Science databases for longitudinal studies, published until June 2017, including adults with CLBP (defined as persistent pain with ≥ 3 months duration), which studied the association between multivariable models and/or predictors with at least one of the selected clinical outcomes after ≥ 3 months of follow-up. Articles' screening and selection will be conducted by two reviewers, blindly and independently. Disagreements will be resolved by a third reviewer. Models' discriminative ability will be assessed using C-statistic. The link between multivariable models and predictors with the clinical outcome will be analysed through association measures. Qualitative and quantitative synthesis of the available evidence will be performed. Meta-analysis will be conducted to aggregate each type of measure. In the absence or in the presence of only slight to moderate of heterogeneity, we will use the fixed or random effects model, respectively. In case of moderate to severe heterogeneity, an attempt to explain variability in detail will be made through subgroups and sensitivity analyses. Subgroup analysis will be conducted according to clinical outcome, follow-up duration (≤ 6 months versus > 6 months) and type of context (pain management clinics versus other therapeutic settings). DISCUSSION We consider that it is urgent to highlight the available evidence about CLBP prognosis. This systematic review will help identify multivariable models and individual predictors that may enhance pain management success. One potential limitation will be the difficulty of aggregating quantitative measures from several prognostic models and predictors, with different clinical outcomes. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42017079233.

negative: ESICM 2013 - Abstracts of Oral Presentations and Poster Sessions

negative: Infections associated with haemophagocytic syndrome Summary Haemophagocytic syndrome or haemophagocytic lymphohistiocytosis is a rare disease that is often fatal despite treatment. Haemophagocytic syndrome is caused by a dysregulation in natural killer T-cell function, resulting in activation and proliferation of lymphocytes or histiocytes with uncontrolled haemophagocytosis and cytokine overproduction. The syndrome is characterised by fever, hepatosplenomegaly, cytopenias, liver dysfunction, and hyperferritinaemia. Haemophagocytic syndrome can be either primary, with a genetic aetiology, or secondary, associated with malignancies, autoimmune diseases, or infections. Infections associated with haemophagocytic syndrome are most frequently caused by viruses, particularly Epstein-Barr virus (EBV). We present a case of EBV-associated haemophagocytic syndrome in a young adult with no known immunosuppression. We briefly review haemophagocytic syndrome and then discuss its associated infections, particularly EBV and other herpes viruses, HIV, influenza, parvovirus, and hepatitis viruses, as well as bacterial, fungal, and parasitic organisms.

negative: Psychopharmacology of COVID-19 BACKGROUND: With the rapid, global spread of SARS-CoV-2, hospitals have become inundated with patients suffering from COVID-19. Consultation-liaison psychiatrists are actively involved in managing these patients and should familiarize themselves with how the virus and its proposed treatments can affect psychotropic management. The only FDA approved drug to treat COVID-19 is remdesivir, and other off-label medications used include chloroquine and hydroxychloroquine, tocilizumab, lopinavir/ritonavir, favipiravir, convalescent plasma therapy, azithromycin, vitamin C, corticosteroids, interferon and colchicine. PURPOSE: To provide an overview of the major safety considerations relevant to clinicians who prescribe psychotropics to patients with COVID-19, both related to the illness and its proposed treatments. METHODS: In this targeted review we performed structured literature searches in PubMed to identify articles describing the impacts of COVID-19 on different organ systems, the neuropsychiatric adverse effects of treatments, and any potential drug interactions with psychotropics. The articles most relevant to this manuscript were included. RESULTS: COVID-19 impacts multiple organ systems, including gastrointestinal, renal, cardiovascular, pulmonary, immunological, and hematological systems. This may lead to pharmacokinetic changes that impact psychotropic medications and increase sensitivity to psychotropic-related adverse effects. Additionally, several proposed treatments for COVID-19 have neuropsychiatric effects and potential interactions with commonly used psychotropics. CONCLUSION: Clinicians should be aware of the need to adjust existing psychotropics or avoid using certain medications in some COVID-19 patients. They should also be familiar with neuropsychiatric effects of medications being used to treat this disease. Further research is needed to identify strategies to manage psychiatric issues in this population.

negative: Ethical Alternatives to Experiments with Novel Potential Pandemic Pathogens Please see later in the article for the Editors' Summary

negative: A data-driven drug repositioning framework discovered a potential therapeutic agent targeting COVID-19 The global spread of SARS-CoV-2 requires an urgent need to find effective therapeutics for the treatment of COVID-19. We developed a data-driven drug repositioning framework, which applies both machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph, literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2. The retrospective study using the past SARS-CoV and MERS-CoV data demonstrated that our machine learning based method can successfully predict effective drug candidates against a specific coronavirus. Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, CVL218, currently in Phase I clinical trial, may be repurposed to treat COVID-19. Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect. In addition, we showed that CVL218 is able to suppress the CpG-induced IL-6 production in peripheral blood mononuclear cells, suggesting that it may also have anti-inflammatory effect that is highly relevant to the prevention immunopathology induced by SARS-CoV-2 infection. Further pharmacokinetic and toxicokinetic evaluation in rats and monkeys showed a high concentration of CVL218 in lung and observed no apparent signs of toxicity, indicating the appealing potential of this drug for the treatment of the pneumonia caused by SARS-CoV-2 infection. Moreover, molecular docking simulation suggested that CVL218 may bind to the N-terminal domain of nucleocapsid (N) protein of SARS-CoV-2, providing a possible model to explain its antiviral action. We also proposed several possible mechanisms to explain the antiviral activities of PARP1 inhibitors against SARS-CoV-2, based on the data present in this study and previous evidences reported in the literature. In summary, the PARP1 inhibitor CVL218 discovered by our data-driven drug repositioning framework can serve as a potential therapeutic agent for the treatment of COVID-19.

negative: Ethical rationale for better coordination of clinical research on COVID-19 Hundreds of clinical trials of potential treatments and vaccines for the “coronavirus 19 disease” (COVID-19) have been set up in record time. This is a remarkable reaction to the global pandemic, but the absence of a global coordination of clinical research efforts raises serious ethical concerns. Some COVID-19 patients might carry the burden of clinical trial involvement even though their trial cannot be completed as researchers are competing for patients. A shortage of medicines can occur when existing drugs are diverted for clinical trials. Research ethics committees are overburdened with multiple applications. A multitude of trials can also overstretch medical staff and risk neglecting non-COVID-19 patients. And finally, conflicting conclusions from a multitude of heterogeneous trials might lead to delays in public health decisions about life-saving issues. These challenges are made worse by the unpredictable evolution of epidemics, the active involvement of political decision-makers in scientific issues and the pressure of social media globally. While freedom to conduct research must be safeguarded, global health emergency situations would greatly benefit from effective international coordination mechanisms for clinical research.

negative: COVID-19 in Rheumatic Disease Patients on Immunosuppressive Agents OBJECTIVE: To analyze clinical characteristics and outcome of COVID-19 patients with underlying rheumatic diseases (RD) on immunosuppressive agents. METHOD: A case series of COVID-19 patients with RD on disease modifying anti-rheumatic drugs (DMARDs) were studied by a retrospective chart review. A literature search identified 9 similar studies of single cases and case series, which were also included. RESULTS: There were 4 COVID-19 inpatients with RD from our hospital, and the mean age was 57 ± 21 years. Two patients had a mild infection, and 2 developed severe COVID-19 related respiratory complications, including 1 patient on secukinumab requiring mechanical ventilation and 1 patient on rituximab developing viral pneumonia requiring supplemental oxygenation. All 4 patients had elevated acute phase reactants, 2 patients had mild COVID-19 with lymphopenia, and 2 patients had severe COVID-19 with normal lymphocyte counts, and high levels of IL-6. None of the patients exhibited an exacerbation of their underlying RD. In the literature, there were 9 studies of COVID-19 involving 197 cases of various inflammatory RD. Most patients were on DMARDs or biologics, of which TNFα inhibitors were most frequently used. Two tocilizumab users had a mild infection. Two patients were on rituximab with 1 severe COVID-19 requiring mechanical ventilation. Six patients were on secukinumab with 1 hospitalization. Of the total 201 cases, 12 died, with an estimated mortality of 5.9% CONCLUSION: Patients with RD are susceptible to COVID-19. Various DMARDs or biologics may affect the viral disease course differently. Patients on hydroxychloroquine, TNFα antagonists or tocilizumab may have a mild viral illness. Rituximab or secukinumab could worsen the viral disease. Further study is warranted.

negative: COVID-19 in a severe eosinophilic asthmatic receiving benralizumab - a case study. Introduction: Only little is known about COVID-19 in patients with asthma. There is no data on COVID-19 in patients with severe asthma or patients with asthma who are treated with monoclonal antibodies. Case Study: Here, we present the case of a severe eosinophilic asthmatic in whom benralizumab treatment, an anti-IL-5R monoclonal antibody, was initiated 2 years ago. Prior to benralizumab treatment, every viral infection had resulted in a prolonged course of oral corticosteroids (OCS). Since initiation of benralizumab, the patient has had good asthma control. Mid-March 2020, the patient developed high fever. Results: A SARS-CoV-2-PCR (nasopharyngeal swab) was positive. The patient's symptoms subsided after few days. No OCS was needed. The asthma control questionnaire 6-item scale worsened moderately in the week of the infection and returned to normal levels thereafter. The asthma control test, measuring longer term asthma control, showed no decline. Conclusion: The course of COVID-19 was very mild in this particular patient with severe eosinophilic asthma. So far, there is no evidence that would suggest a more severe course of COVID-19 in patients with asthma. It is worth noting, that prior to the initiation of benralizumab this patient had multiple exacerbations per year triggered by viral infections (4/year), which all required OCS. Whilst only anecdotal, this case study provides the first evidence to support the current recommendation of continuing monoclonal antibodies in patients with severe asthma during the COVID-19 pandemic.

negative: Cardiac Manifestations of Coronavirus Disease 2019 (COVID-19): A Comprehensive Review Since its origin in China, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become a pandemic and spread to 209 countries. As coronavirus disease 2019 (COVID-19) is a very rapidly emerging disease, organ-specific studies related to it have been reported. Apart from respiratory findings, some studies have highlighted inflammatory consequences in the heart, kidney, and/or liver as well. Cardiac involvement in COVID-19 seems to be a result of an inflammatory storm in response to the infection. Moreover, direct viral invasion of cardiomyocytes, as well as a myocardial injury due to oxidative stress, may account for acute cardiac injury in COVID-19. Nevertheless, the mechanism of heart injury in COVID-19 is not clear yet. However, multiple studies that highlight the clinical features, laboratory findings, and prognosis of acute myocardial injury (AMI) in COVID-19-affected individuals have been published. In this review, we have summarized the findings of all those studies as well as the clinical features and management of cardiac injury discussed by some case reports.

negative: CO.ME.T.A. -- covid-19 media textual analysis. A dashboard for media monitoring The focus of this paper is to trace how mass media, particularly newspapers, have addressed the issues about the containment of contagion or the explanation of epidemiological evolution. We propose an interactive dashboard: CO.ME.T.A.. During crises it is important to shape the best communication strategies in order to respond to critical situations. In this regard, it is important to monitor the information that mass media and social platforms convey. The dashboard allows to explore the mining of contents extracted and study the lexical structure that links the main discussion topics. The dashboard merges together four methods: text mining, sentiment analysis, textual network analysis and latent topic models. Results obtained on a subset of documents show not only a health-related semantic dimension, but it also extends to social-economic dimensions.

negative: COVID-19 Tragic Pandemic: Concerns over Unintentional “Directed Accelerated Evolution” of Novel Coronavirus (SARS-CoV-2) and Introducing a Modified Treatment Method for ARDS Global health authorities are trying to work out the current status of the novel coronavirus (COVID-19) outbreak and explore methods to reduce the rate of its transmission to healthy individuals. In this viewpoint we provide insights concerning how health care professionals can unintentionally shift the novel coronavirus type to more drug-resistant forms. It is worth noting that viruses usually have different sensitivities to physical and chemical damaging agents such antiviral drugs, UV and heat ranging from extremely sensitive (ES) to extremely resistant (ER) based on a bell-shaped curve. Given this consideration, the widespread infection of people with such ER viruses would be a real disaster. Here, we introduce a modified treatment method for COVID-19-associated pneumonia. In this proposed method, COVID-19 patients will receive a single dose of 100, 180 or 250 mSv X-ray radiation that is less than the maximum annual radiation dose of the residents of high background radiation areas of Ramsar that is up to 260 mSv. In contrast with antiviral drugs, a single dose of either 100, 180 or 250 mSv of low LET X-rays cannot exert a significant selective pressure on the novel coronavirus (SARS-CoV-2) and hence does not lead to directed accelerated evolution of these viruses. Moreover, Low Dose Radiation (LDR) has the capacity of modulating excessive inflammatory responses, regulating lymphocyte counts, and controling bacterial co-infections in patients with COVID-19.

negative: Acute myocardial injury, MINOCA, or myocarditis? Improving characterization of coronavirus-associated myocardial involvement

negative: Radiologist Reporting and Operational Management for Patients with Suspected COVID-19 Abstract Objective Evaluate adoption and outcomes of locally-designed reporting guidelines for patients with possible COVID-19. Methods We developed a departmental guideline for radiologists that specified reporting terminology and required communication for patients with imaging findings suggestive of COVID-19, based on patient test status and imaging indication. In this retrospective study, radiology reports completed 3/1/2020-5/3/2020 that mentioned COVID-19 were reviewed. Reports were divided into patients with known COVID-19, patients with “suspected” COVID-19 (having an order indication of respiratory or infectious signs or symptoms), and “unsuspected patients” (other order indications, e.g., trauma or non-chest pain). Primary outcome was percentage of COVID-19 reports using recommended terminology; secondary outcome was percentages of suspected and unsuspected patients diagnosed with COVID-19. Relationships between categorical variables were assessed with Fisher’s exact test. Results Among 77,400 total reports, 1,083 suggested COVID-19 based on imaging findings; 774 (71%) of COVID-19 reports used recommended terminology. Of 574 patients without known COVID-19 at time of interpretation, 345 (60%) were eventually diagnosed with COVID-19, including 61% (315/516) of suspected and 52% (30/58) of unsuspected patients. Nearly all (46/58) unsuspected patients were identified at CT. Discussion Radiologists rapidly adopted recommended reporting terminology for patients with suspected COVID-19. The majority of patients for whom radiologists raised concern for COVID-19 were subsequently diagnosed with the disease, including the majority of clinically unsuspected patients. Using unambiguous terminology and timely notification about previously unsuspected patients will become increasingly critical to facilitate COVID-19 testing and contact tracing as states begin to lift restrictions.

negative: Incomplete and late recovery of sudden olfactory dysfunction in COVID-19() INTRODUCTION: Sudden olfactory dysfunction is a new symptom related to COVID-19, with little data on its duration or recovery rate. OBJECTIVE: To characterize patients with sudden olfactory disfunction during the COVID-19 pandemic, especially their recovery data. METHODS: An online survey was conducted by the Brazilian Society of Otorhinolaryngology and Cervico-Facial Surgery, and Brazilian Academy of Rhinology, including doctors who assessed sudden olfactory dysfunction patients starting after February 1(st), 2020. RESULTS: 253 sudden olfactory dysfunction patients were included, of which 59.1% were females with median age of 36 years, with a median follow-up period of 31 days. 183 patients (72.3%) had been tested for COVID-19, and of those 145 (79.2%) tested positive. Patients that tested positive for COVID-19 more frequently showed non-specific inflammatory symptoms (89.7% vs. 73.7%; p = 0.02), a lower rate of total recovery of sudden olfactory dysfunction (52.6% vs. 70.3%; p = 0.05) and a longer duration to achieve total recovery (15 days vs. 10 days; p = 0.0006) than the ones who tested negative for COVID-19. Considering only positive-COVID-19 patients, individuals with sudden hyposmia completely recovered more often than the ones with sudden anosmia (68.4% vs. 50.0%; p = 0.04). CONCLUSION: Positive-COVID-19 patients with sudden olfactory dysfunction showed lower total recovery rate and longer duration than negative-COVID-19 patients. Additionally, total recovery was seen more frequently in positive-COVID-19 patients with sudden hyposmia than the ones with sudden anosmia.

negative: [Management of COVID-19: the Zhejiang experience] The current epidemic situation of coronavirus disease 2019 (COVID-19) still remained severe. As the National Clinical Research Center for Infectious Diseases, the First Affiliated Hospital of Zhejiang University School of Medicine is the primary medical care center for COVID-19 in Zhejiang province. Based on the present expert consensus carried out by National Health Commission and National Administration of Traditional Chinese Medicine, our team summarized and established an effective treatment strategy centered on "Four-Anti and Two-Balance" for clinical practice. The "Four-Anti and Two-Balance" strategy included antivirus, anti-shock, anti-hyoxemia, anti-secondary infection, and maintaining of water, electrolyte and acid base balance and microecological balance. Meanwhile, integrated multidisciplinary personalized treatment was recommended to improve therapeutic effect. The importance of early viralogical detection, dynamic monitoring of inflammatory indexes and chest radiograph was emphasized in clinical decision-making. Sputum was observed with the highest positive rate of RT-PCR results. Viral nucleic acids could be detected in 10%patients' blood samples at acute period and 50%of patients had positive RT-PCR results in their feces. We also isolated alive viral strains from feces, indicating potential infectiousness of feces.Dynamic cytokine detection was necessary to timely identifying cytokine storms and application of artificial liver blood purification system. The "Four-Anti and Two-Balance" strategy effectively increased cure rate and reduced mortality. Early antiviral treatment could alleviate disease severity and prevent illness progression, and we found lopinavir/ritonavir combined with abidol showed antiviral effects in COVID-19. Shock and hypoxemia were usually caused by cytokine storms. The artificial liver blood purification system could rapidly remove inflammatory mediators and block cytokine storm.Moreover, it also favored the balance of fluid, electrolyte and acid-base and thus improved treatment efficacy in critical illness. For cases of severe illness, early and also short period of moderate glucocorticoid was supported. Patients with oxygenation index below 200 mmHg should be transferred to intensive medical center. Conservative oxygen therapy was preferred and noninvasive ventilation was not recommended. Patients with mechanical ventilation should be strictly supervised with cluster ventilator-associated pneumonia prevention strategies. Antimicrobial prophylaxis was not recommended except for patients with long course of disease, repeated fever and elevated procalcitonin (PCT), meanwhile secondary fungal infection should be concerned.Some patients with COVID-19 showed intestinal microbial dysbiosis with decreased probiotics such as Lactobacillus and Bifidobacterium, so nutritional and gastrointestinal function should be assessed for all patients.Nutritional support and application of prebiotics or probiotics were suggested to regulate the balance of intestinal microbiota and reduce the risk of secondary infection due to bacterial translocation. Anxiety and fear were common in patients with COVID-19. Therefore,we established dynamic assessment and warning for psychological crisis. We also integrated Chinese medicine in treatment to promote disease rehabilitation through classification methods of traditional Chinese medicine. We optimized nursing process for severe patients to promote their rehabilitation. It remained unclear about viral clearance pattern after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Therefore, two weeks' quarantine for discharged patients was required and a regular following up was also needed.The Zhejiang experience and suggestions have been implemented in our center and achieved good results. However, since COVID-19 was a newly emerging disease, more work was warranted to improve strategies of prevention, diagnosis and treatment for COVID-19.

negative: ElaD, a Deubiquitinating Protease Expressed by E. coli BACKGROUND: Ubiquitin and ubiquitin-like proteins (Ubl) are designed to modify polypeptides in eukaryotes. Covalent binding of ubiquitin or Ubls to substrate proteins can be reversed by specific hydrolases. One particular set of cysteine proteases, the CE clan, which targets ubiquitin and Ubls, has homologs in eukaryotes, prokaryotes, and viruses. FINDINGS: We have cloned and analyzed the E. coli protein elaD, which is distantly related to eukaryotic CE clan members of the ULP/SENP protease family that are specific for SUMO and Nedd8. Previously misannotated as a putative sulfatase/phosphatase, elaD is an efficient and specific deubiquitinating enzyme in vitro. Interestingly, elaD is present in all intestinal pathogenic E. coli strains, but conspicuously absent from extraintestinal pathogenic strains (ExPECs). Further homologs of this protease can be found in Acanthamoeba Polyphaga Mimivirus, and in Alpha-, Beta-and Gammaproteobacteria. CONCLUSION: The expression of ULP/SENP-related hydrolases in bacteria therefore extends to plant pathogens and medically relevant strains of Escherichia coli, Legionella pneumophila, Rickettsiae, Chlamydiae, and Salmonellae, in which the elaD ortholog sseL has recently been identified as a virulence factor with deubiquitinating activity. As a counterpoint, our phylogenetic and functional examination reveals that ancient eukaryotic ULP/SENP proteases also have the potential of ubiquitin-specific hydrolysis, suggesting an early common origin of this peptidase clan.

negative: Management of a patient presenting with anterior STEMI with concomitant COVID‐19 infection early in the course of the U.S. pandemic The coronavirus disease‐2019 (COVID‐19) is a viral illness with heterogenous clinical manifestations, ranging from mild symptoms to severe acute respiratory distress syndrome and shock caused by the severe acute respiratory syndrome coronavirus‐2. The global healthcare community is rapidly learning more about the effects of COVID‐19 on the cardiovascular system, as well as the strategies for management of infected patients with cardiovascular disease. There is minimal literature available surrounding the relationship between COVID‐19 infection and acute coronary syndrome. We describe the case of a woman who presented with an acute anterior ST‐elevation myocardial infarction managed by primary percutaneous coronary intervention, who subsequently developed severe COVID‐19 infection and ultimately succumbed to multisystem organ failure.

negative: A Call to Arms, Not to Disarm: The Importance of Psychiatric Care in the Acute Medical Setting During the COVID 19 Pandemic

negative: [Novel coronavirus pneumonia related liver injury: etiological analysis and treatment strategy]. The outbreak of novel coronavirus pneumonia(NCP) caused by 2019 novel coronavirus has become a global public health challenge. Some patients accompany with liver function damage in addition to the main typical respiratory symptom. Here we analyzed the clinical features, susceptible population, potential causes and therapeutic strategies of NCP related liver injury.

negative: Percutaneous radiofrequency ablation of a bleeding pseudoaneurysm during CT-guided renal cancer treatment. A case report. We describe a new emergency interventional radiology approach in percutaneous procedure complications. We present the case of an 81-year-old male with small renal cancer, approached with percutaneous radiofrequency ablation (RTA) and complicated by pseudoaneurysm bleeding of a renal artery branch. In the emergency setting, pseudoaneurysm was treated in the CT room by the same RTA needle, without any complications or local tumor recurrence during the next 6-month follow-up.

negative: Psoriasis, biologic therapy, and the pandemic of the 21st century The pandemic known as coronavirus disease-19 (COVID-19) has quickly spread worldwide, with a significant impact on lives all over the world. The complexity related to the new coronavirus and the clinical syndrome it causes is not yet fully understood. The impact of COVID-19 on patients with psoriasis under biologic agents is continuously being observed in this rapidly changing pandemic. A case-by-case evaluation must be made by dermatologists, and the final decision should be discussed and decided by both the patient and the specialist. Observations reveal that immunosuppressive therapy may have a role in the treatment of this virus, placing emphasis on the scenario of safety through maintenance of therapy with biologic agents, especially when there are no signs or symptoms related to the infection or contact with an infected patient.

negative: Inhibition of hepatitis B virus (HBV) gene expression and replication by HBx gene silencing in a hydrodynamic injection mouse model with a new clone of HBV genotype B BACKGROUND: It has been suggested that different hepatitis B virus (HBV) genotypes may have distinct virological characteristics that correlate with clinical outcomes during antiviral therapy and the natural course of infection. Hydrodynamic injection (HI) of HBV in the mouse model is a useful tool for study of HBV replication in vivo. However, only HBV genotype A has been used for studies with HI. METHODS: We constructed 3 replication-competent clones containing 1.1, 1.2 and 1.3 fold overlength of a HBV genotype B genome and tested them both in vitro and in vivo. Moreover, A HBV genotype B clone based on the pAAV-MCS vector was constructed with the 1.3 fold HBV genome, resulting in the plasmid pAAV-HBV1.3(B) and tested by HI in C57BL/6 mice. Application of siRNA against HBx gene was tested in HBV genotype B HI mouse model. RESULTS: The 1.3 fold HBV clone showed higher replication and gene expression than the 1.1 and 1.2 fold HBV clones. Compared with pAAV-HBV1.2 (genotype A), the mice HI with pAAV-HBV1.3(B) showed higher HBsAg and HBeAg expression as well as HBV DNA replication level but a higher clearance rate. Application of two plasmids pSB-HBxi285 and pSR-HBxi285 expressing a small/short interfering RNA (siRNA) to the HBx gene in HBV genotype B HI mouse model, leading to an inhibition of HBV gene expression and replication. However, HBV gene expression may resume in some mice despite an initial delay, suggesting that transient suppression of HBV replication by siRNA may be insufficient to prevent viral spread, particularly if the gene silencing is not highly effective. CONCLUSIONS: Taken together, the HI mouse model with a HBV genotype B genome was successfully established and showed different characteristics in vivo compared with the genotype A genome. The effectiveness of gene silencing against HBx gene determines whether HBV replication may be sustainably inhibited by siRNA in vivo.

negative: Treatment of yellow fever virus with an adenovirus-vectored interferon, DEF201, in a hamster model. Interferon (IFN) is an innate immune response protein that is involved in the antiviral response during viral infection. Treatment of acute viral infections with exogenous interferon may be effective but is generally not feasible for clinical use due to many factors, including cost, stability, and availability. To overcome these limitations, an adenovirus type 5-vectored consensus alpha IFN, termed DEF201, was constructed as a potential way to deliver sustained therapeutic levels of systemic IFN. To demonstrate the efficacy of DEF201 against acute flaviviral disease, various concentrations of the construct were administered as a single intranasal dose prior to virus infection, which resulted in a dose-responsive, protective effect in a hamster model of yellow fever virus (YFV) disease. A DEF201 dose of 5×10(7) PFU/animal administered intranasally just prior to YFV challenge protected 100% of the animals, while a 10-fold lower DEF201 dose exhibited lower, although significant, levels of protection. Virus titers in the liver and serum and levels of serum alanine aminotransferase were all significantly reduced as a result of DEF201 administration at all doses tested. No toxicity, as indicated by weight loss or gross morbidity, was observed in non-YFV-infected animals treated with DEF201. Protection of YFV-infected animals was observed when DEF201 was delivered as early as 7 days prior to virus challenge and as late as 2 days after virus challenge, demonstrating effective prophylaxis and therapy in a hamster model of disease. Overall, it appears that DEF201 is effective in the treatment of YFV in a hamster model.

negative: Does high cardiorespiratory fitness confer some protection against pro‐inflammatory responses after infection by SARS‐CoV‐2? Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) originated in China in late 2019 and has since spread rapidly to every continent in the world. This pandemic continues to cause widespread personal suffering, along with severe pressure on medical and health care providers. The symtoms of SARS‐CoV‐2 and the subsequent prognosis is worsened in individuals who have pre‐exisiting comorbidities prior to infection by the virus. Individuals with obesity/overweight, insulin resistance and diabetes typically have chronic low‐grade inflammation characterized by increased levels of several pro‐inflammatory cytokines and the inflammasome: this state predisposes to greater risk for infection along with more adverse outcomes. Here we consider whether a high level of cardiorespiratory fitness induced by prior exercise training may confer some innate immune‐protection against Covid‐19 by attenuating the “cytokine storm syndrome” often experienced by “at risk” individuals.

negative: Neutrophil calprotectin identifies severe pulmonary disease in COVID-19 Severe cases of coronavirus disease 2019 (COVID-19) are regularly complicated by respiratory failure. While it has been suggested that elevated levels of blood neutrophils associate with worsening oxygenation in COVID-19, it is unknown whether neutrophils are drivers of the thrombo-inflammatory storm or simple bystanders. We now report that patients with COVID-19 (n=96) have markedly elevated levels of the neutrophil activation marker S100A8/A9 (calprotectin) in their blood. Calprotectin tracked with other acute phase reactants including C-reactive protein, D-dimer, ferritin, and absolute neutrophil count, but was superior in identifying patients requiring mechanical ventilation. In longitudinal samples, calprotectin rose as oxygenation worsened. When tested on day 1 or 2 of hospitalization (n=52 patients), calprotectin levels were significantly higher in patients who progressed to severe COVID-19 requiring mechanical ventilation (7805 +/- 7585, n=23) as compared to those who remained free of intubation (3123 +/- 2990, p=0.0059). In summary, serum calprotectin levels track closely with current and future COVID-19 severity, strongly implicating neutrophils as active perpetuators of inflammation and respiratory compromise in COVID-19.

negative: In the eye of the storm: the right ventricle in COVID-19 The corona virus disease of 2019 pandemic caused by the SARS-CoV-2 virus continues to inflict significant morbidity and mortality around the globe. A variety of cardiovascular presentations of SARS-CoV-2 infection have been described so far. However, the impact of SARS-CoV-2 on the right ventricle is largely unknown. Due to its pathophysiologic relevance, the right ventricle finds itself in the eye of the storm of corona virus disease of 2019, placing it at higher risk of failure. Increased afterload from acute respiratory distress syndrome and pulmonary embolism, negative inotropic effects of cytokines, and direct angiotensin converting enzyme 2-mediated cardiac injury from SARS-CoV-2 are potential mechanisms of right ventricle dysfunction in corona virus disease of 2019. Early detection and treatment of right ventricle dysfunction may lead to decreased mortality and improved patient outcomes in corona virus disease of 2019.

negative: A predictive model for disease progression in non-severe illness patients with Corona Virus Disease 2019 A predictive model for Corona Virus Disease 2019

negative: Taste and Smell Impairment in COVID-19: An AAO-HNS Anosmia Reporting Tool-Based Comparative Study OBJECTIVE: To identify the taste and smell impairment in coronavirus disease 2019 (COVID-19)–positive subjects and compare the findings with COVID-19–negative subjects using the American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS) Anosmia Reporting Tool. SETTING: Tertiary referral center/COVID-19 pandemic hospital. STUDY DESIGN: Comparative study. SUBJECTS AND METHODS: After power analysis, 128 subjects were divided into 2 groups according to real-time polymerase chain reaction (RT-PCR) COVID-19 testing results. Subjects were called via telephone, and the AAO-HNS Anosmia Reporting Tool was used to collect responses. RESULTS: The mean age of the study group was 38.63 ± 10.08 years. At the time of sampling, rhinorrhea was significantly high in the COVID-19–negative group, whereas those complaints described as “other” were significantly high in the COVID-19–positive group. There was a significant difference in the smell/taste impairment rates of the groups (n = 46% [71.9%] for the COVID-19–positive group vs n = 17 [26.6%] for the COVID-19–negative group, P = .001). For subjects with a smell impairment, anosmia rates did not differ between the groups. The rates of hyposmia and parosmia were significantly high in the COVID-19–positive group. For the subjects with taste impairment, ageusia rates did not differ between groups. The rate of hypogeusia and dysgeusia was significantly high in the COVID-19–positive group. Logistic regression analysis indicates that smell/taste impairment in COVID-19–positive subjects increases the odds ratio by 6.956 (95% CI, 3.16-15.29) times. CONCLUSION: COVID-19–positive subjects are strongly associated with smell/taste impairment.

negative: Collapsing Glomerulopathy in a Patient With Coronavirus Disease 2019 (COVID-19)

negative: A Survey on Applications of Artificial Intelligence in Fighting Against COVID-19 The COVID-19 pandemic caused by the SARS-CoV-2 virus has spread rapidly worldwide, leading to a global outbreak. Most governments, enterprises, and scientific research institutions are participating in the COVID-19 struggle to curb the spread of the pandemic. As a powerful tool against COVID-19, artificial intelligence (AI) technologies are widely used in combating this pandemic. In this survey, we investigate the main scope and contributions of AI in combating COVID-19 from the aspects of disease detection and diagnosis, virology and pathogenesis, drug and vaccine development, and epidemic and transmission prediction. In addition, we summarize the available data and resources that can be used for AI-based COVID-19 research. Finally, the main challenges and potential directions of AI in fighting against COVID-19 are discussed. Currently, AI mainly focuses on medical image inspection, genomics, drug development, and transmission prediction, and thus AI still has great potential in this field. This survey presents medical and AI researchers with a comprehensive view of the existing and potential applications of AI technology in combating COVID-19 with the goal of inspiring researches to continue to maximize the advantages of AI and big data to fight COVID-19.

negative: Surgical Oncologists and the COVID-19 Pandemic: Guiding Cancer Patients Effectively through Turbulence and Change BACKGROUND: The COVID-19 pandemic has posed extraordinary demands from patients, providers, and health care systems. Despite this, surgical oncologists must maintain focus on providing high-quality, empathetic care for the almost 2 million patients nationally who will be diagnosed with operable cancer this year. The focus of hospitals is transitioning from initial COVID-19 preparedness activities to a more sustained approach to cancer care. METHODS: Editorial Board members provided observations of the implications of the pandemic on providing care to surgical oncology patients. RESULTS: Strategies are presented that have allowed institutions to successfully prepare for cancer care during COVID-19, as well as other strategies that will help hospitals and surgical oncologists manage anticipated challenges in the near term. Perspectives are provided on: (1) maintaining a safe environment for surgical oncology care; (2) redirecting the multidisciplinary model to guide surgical decisions; (3) harnessing telemedicine to accommodate requisite physical distancing; (4) understanding interactions between SARS CoV-2 and cancer therapy; (5) considering the ethical impact of professional guidelines for surgery prioritization; and (6) advocating for our patients who require oncologic surgery in the midst of the COVID-19 pandemic. CONCLUSIONS: Until an effective vaccine becomes available for widespread use, it is imperative that surgical oncologists remain focused on providing optimal care for our cancer patients while managing the demands that the COVID-19 pandemic will continue to impose on all of us.

negative: Handling and Processing of Blood Specimens from Patients with COVID‐19 for Safe Studies on Cell Phenotype and Cytokine Storm The pandemic caused by severe acute respiratory syndrome coronavirus 2 heavily involves all those working in a laboratory. Samples from known infected patients or donors who are considered healthy can arrive, and a colleague might be asymptomatic but able to transmit the virus. Working in a clinical laboratory is posing several safety challenges. Few years ago, International Society for Advancement of Cytometry published guidelines to safely analyze and sort human samples that were revised in these days. We describe the procedures that we have been following since the first patient appeared in Italy, which have only slightly modified our standard one, being all human samples associated with risks. © 2020 International Society for Advancement of Cytometry

negative: Emergency and Urgent Orthopaedic Surgeries in non covid patients during the COVID 19 pandemic: Perspective from India OBJECTIVES: To Evaluate the results and the protocols of our Institution for 18 Emergency and Urgent Non Covid Surgeries during the Covid 19 Pandemic METHODS: 18 patients underwent Emergency and Urgent Orthopaedic Surgeries at institution. The Protocol was Screening, Segregation, Selection, Isolation, theatre modification, and Online Follow. RESULTS: Two adverse events including, one death and one intensive care admission due to underlying morbidity were recorded. Average Hospital stay was 2.5 days with no patients becoming covid positive at follow up. CONCLUSION: Strict Surgical protocols need to be followed for surgery during the Covid19 pandemic.

negative: Epidemiological, clinical, and immunological features of a cluster of COVID-19 contracted hemodialysis patients BACKGROUND: The outbreak of highly contagious COVID-19 has posed a serious threat to human life and health, especially for those with underlying diseases. However, the impact of COVID-19 epidemic on HD center and HD patients has not been reported. METHODS: We reviewed the whole course of the COVID-19 in the HD center of Renmin Hospital, Wuhan University (from January 14, 2020 till March 12, 2020). We compared the clinical manifestation and immune profiles among different patient groups with healthy individuals. RESULTS: 42 out of 230 HD patients (18.26%) and 4 out of 33 medical staff (12.12%) were diagnosed with COVID-19 during the study period. 15 HD patients (6.52%), including 10 COVID-19 diagnosed, died. Only 2 deaths of the COVID-19 HD patients were associated with pneumonia/lung failure, others were ascribed to cardiovascular/cerebrovascular diseases or hyperkalemia. Except for 3 patients who were admitted to ICU for severe condition (8.11%), including 2 dead, most COVID-19 diagnosed patients presented mild or non-respiratory symptoms. The flow cytometric analysis of peripheral blood showed that multiple lymphocyte populations in HD patients were significantly decreased. HD patients with COVID-19 even displayed more remarkable reduction of serum inflammatory cytokines than other COVID-19 patients. CONCLUSIONS: Compared with the general population, HD patients and health care professionals are the highly susceptible population and HD centers are high risk area during the outbreak. A majority of HD Patients with COVID-19 exhibited mild clinical symptoms and did not progress to severe pneumonia likely due to the impaired cellular immune function and incapability of mounting cytokines storm. More attention should be paid to prevent cardiovascular events, which may be the collateral impacts of COVID-19 epidemic on HD patients.

negative: RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders Repeat-associated disorders caused by expansions of short sequences have been classified as coding and noncoding and are thought to be caused by protein gain-of-function and RNA gain-of-function mechanisms, respectively. The boundary between such classifications has recently been blurred by the discovery of repeat-associated non-AUG (RAN) translation reported in spinocerebellar ataxia type 8, myotonic dystrophy type 1, fragile X tremor/ataxia syndrome and C9ORF72 amyotrophic lateral sclerosis and frontotemporal dementia. This noncanonical translation requires no AUG start codon and can initiate in multiple frames of CAG, CGG and GGGGCC repeats of the sense and antisense strands of disease-relevant transcripts. RNA structures formed by the repeats have been suggested as possible triggers; however, the precise mechanism of the translation initiation remains elusive. Templates containing expansions of microsatellites have also been shown to challenge translation elongation, as frameshifting has been recognized across CAG repeats in spinocerebellar ataxia type 3 and Huntington's disease. Determining the critical requirements for RAN translation and frameshifting is essential to decipher the mechanisms that govern these processes. The contribution of unusual translation products to pathogenesis needs to be better understood. In this review, we present current knowledge regarding RAN translation and frameshifting and discuss the proposed mechanisms of translational challenges imposed by simple repeat expansions.

negative: Head and neck cancer cannot wait for this pandemic to end: Risks, challenges and perspectives of oral-maxillofacial surgeon during COVID-19

negative: Noninvasive ventilation in acute respiratory failure due to H1N1 influenza: A word of caution

negative: Treatments Administered to the First 9152 Reported Cases of COVID-19: A Systematic Review The emergence of SARS-CoV-2/2019 novel coronavirus (COVID-19) has created a global pandemic with no approved treatments or vaccines. Many treatments have already been administered to COVID-19 patients but have not been systematically evaluated. We performed a systematic literature review to identify all treatments reported to be administered to COVID-19 patients and to assess time to clinically meaningful response for treatments with sufficient data. We searched PubMed, BioRxiv, MedRxiv, and ChinaXiv for articles reporting treatments for COVID-19 patients published between 1 December 2019 and 27 March 2020. Data were analyzed descriptively. Of the 2706 articles identified, 155 studies met the inclusion criteria, comprising 9152 patients. The cohort was 45.4% female and 98.3% hospitalized, and mean (SD) age was 44.4 years (SD 21.0). The most frequently administered drug classes were antivirals, antibiotics, and corticosteroids, and of the 115 reported drugs, the most frequently administered was combination lopinavir/ritonavir, which was associated with a time to clinically meaningful response (complete symptom resolution or hospital discharge) of 11.7 (1.09) days. There were insufficient data to compare across treatments. Many treatments have been administered to the first 9152 reported cases of COVID-19. These data serve as the basis for an open-source registry of all reported treatments given to COVID-19 patients at www.CDCN.org/CORONA. Further work is needed to prioritize drugs for investigation in well-controlled clinical trials and treatment protocols. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40121-020-00303-8) contains supplementary material, which is available to authorized users.

negative: Management of acute kidney injury in patients with COVID-19 The outbreak of coronavirus disease 2019 (COVID-19) has rapidly evolved into a global pandemic. Most patients with COVID-19 have mild symptoms, but about 5% develop severe symptoms, which can include acute respiratory distress syndrome, septic shock, and multiple organ failure. Kidney involvement is frequent, with clinical presentation ranging from mild proteinuria to progressive acute kidney injury (AKI) necessitating renal replacement therapy (RRT). An understanding of the pathophysiology and mechanisms of kidney damage and AKI in the setting of critical illness and COVID-19 is emerging, although further research is needed to identify patients at risk of AKI and to guide management strategies. As no specific treatment options exist for AKI secondary to COVID-19, intensive care is largely supportive. Current approaches to prevention and management of AKI, and identification of potential indications for use of RRT and sequential extracorporeal therapies, are based mainly on clinical experience, and AKI strategies are adapted empirically to patients with COVID-19. International collaborative and cross-disciplinary research is needed to obtain adequate evidence to support current clinical approaches and to develop new approaches to management.

negative: Bead-Based Flow Cytometric Assays: A Multiplex Assay Platform with Applications in Diagnostic Microbiology Researchers have focused on developing specific assays for conclusively identifying and measuring the levels of bacteria, fungi, protozoa, viruses (microbes), and their associated products (biomarkers) that cause disease in humans and animals (Murray et al., 2003). Traditional methods using microscopy and chemical or immunological stains, test cultures with selective media or target cells, or serological assays have been used effectively to identify infectious agents in biological specimens or environmental samples. However, due to increasing veterinary, medical, and public health concerns, faster and more accurate diagnostic tools have been sought. Multiplex array-based assays allow for a range of biomarkers to be rapidly and simultaneously measured within specimens (Robertson and Nicholson, 2005). Recently, multiplex bead-based flow cytometric immunoassays have been developed and applied that show great promise for improving the study, diagnosis, and therapeutic management of infectious diseases (Alvarez-Barrientos et al., 2000; Jani et al., 2002).

negative: Serine Proteases in the Lectin Pathway of the Complement System The complement system plays a crucial role in host defense against pathogen infections and in the recognition and removal of damaged or altered self-components. Complement system activation can be initiated by three different pathways—classical, alternative, and lectin pathways—resulting in a proteolytic cascade, which culminates in multiple biological processes including opsonization and phagocytosis of intruders, inflammation, cell lysis, and removal of immune complexes and apoptotic cells. Furthermore, it also functions as a link between the innate and adaptive immune responses. The lectin pathway (LP) activation is mediated by serine proteases, termed mannan-binding lectin (MBL)-associated serine proteases (MASPs), which are associated with the pattern recognition molecules (PRMs) that recognize carbohydrates or acetylated compounds on surfaces of pathogens or apoptotic cells. These result in the proteolysis of complement C2 and C4 generating C3 convertase (C4b2a), which carries forward the activation cascade of complements, culminating in the elimination of foreign molecules. This chapter presents an overview of the complement system focusing on the characterization of MASPs and its genes, as well as its functions in the immune response.

negative: Clinical characteristics and predictors of survival in adults with coronavirus disease 2019 receiving tocilizumab Coronavirus disease 2019 (COVID-19) can progress to cytokine storm that is associated with organ dysfunction and death. The purpose of the present study is to determine clinical characteristics associated with 28 day in-hospital survival in patients with coronavirus disease 2019 (COVID-19) that received tocilizumab. This was a retrospective observational cohort study conducted at a five hospital health system in Michigan, United States. Adult patients with confirmed COVID-19 that were admitted to the hospital and received tocilizumab for cytokine storm from March 1, 2020 through April 3, 2020 were included. Patients were grouped into survivors and non-survivors based on 28 day in-hospital mortality. Study day 0 was defined as the day tocilizumab was administered. Factors independently associated with in-hospital survival at 28 days after tocilizumab administration were assessed. Epidemiologic, demographic, laboratory, prognostic scores, treatment, and outcome data were collected and analyzed. Clinical response was collected and defined as a decline of two levels on a six-point ordinal scale of clinical status or discharged alive from the hospital. Of the 81 patients included, the median age was 64 (58–71) years and 56 (69.1%) were male. The 28 day in-hospital mortality was 43.2%. There were 46 (56.8%) patients in the survivors and 35 (43.2%) in the non-survivors group. On study day 0 no differences were noted in demographics, clinical characteristics, severity of illness scores, or treatments received between survivors and non-survivors. C-reactive protein was significantly higher in the non-survivors compared to survivors. Compared to non-survivors, recipients of tocilizumab within 12 days of symptom onset was independently associated with survival (adjusted OR: 0.296, 95% CI: 0.098–0.889). SOFA score ≥8 on day 0 was independently associated with mortality (adjusted OR: 2.842, 95% CI: 1.042–7.753). Clinical response occurred more commonly in survivors than non-survivors (80.4% vs. 5.7%; p < 0.001). Improvements in the six-point ordinal scale and SOFA score were observed in survivors after tocilizumab. Early receipt of tocilizumab in patients with severe COVID-19 was an independent predictor for in-hospital survival at 28 days.

negative: Cytokine cascade and networks among MSM HIV seroconverters: implications for early immunotherapy The timing, intensity and duration of the cytokine cascade and reorganized interrelations in cytokine networks are not fully understood during acute HIV-1 infection (AHI). Using sequential plasma samples collected over three years post-infection in a cohort of MSM HIV-1 seroconvertors, we determined the early kinetics of cytokine levels during FiebigI-IV stages using Luminex-based multiplex assays. Cytokines were quantified and relationships between cytokines were assessed by Spearman correlation. Compared with HIV-negative MSM, HIV-infected individuals had significantly increased multiple plasma cytokines, including GM-CSF, IFN-α2, IL-12p70, IP-10 and VEGF, during both acute and chronic stages of infection. Furthermore, rapid disease progressors (RDPs) had earlier and more robust cytokine storms, compared with slow disease progressors (SDPs) (49.6 days vs. 74.9 days, respectively; 6.7-fold vs. 3.7-fold change of cytokines, respectively), suggesting the faster and stronger cytokine storm during AHI could promote disease progression. On the other hand, HIV-1 infection induced more interlocked cytokines network, establishing new strong correlations and imposing a higher rigidity. There were, respectively, 146 (44.9%) statistically significant correlations of cytokines in RDPs and 241 (74.2%) in SDPs (p < 0.001). This study suggests that immunomodulatory interventions aimed at controlling cytokine storm in AHI may be beneficial to slow eventual disease progression.

negative: The Nucleocapsid Protein of Human Coronavirus NL63 Human coronavirus (HCoV) NL63 was first described in 2004 and is associated with respiratory tract disease of varying severity. At the genetic and structural level, HCoV-NL63 is similar to other members of the Coronavirinae subfamily, especially human coronavirus 229E (HCoV-229E). Detailed analysis, however, reveals several unique features of the pathogen. The coronaviral nucleocapsid protein is abundantly present in infected cells. It is a multi-domain, multi-functional protein important for viral replication and a number of cellular processes. The aim of the present study was to characterize the HCoV-NL63 nucleocapsid protein. Biochemical analyses revealed that the protein shares characteristics with homologous proteins encoded in other coronaviral genomes, with the N-terminal domain responsible for nucleic acid binding and the C-terminal domain involved in protein oligomerization. Surprisingly, analysis of the subcellular localization of the N protein of HCoV-NL63 revealed that, differently than homologous proteins from other coronaviral species except for SARS-CoV, it is not present in the nucleus of infected or transfected cells. Furthermore, no significant alteration in cell cycle progression in cells expressing the protein was observed. This is in stark contrast with results obtained for other coronaviruses, except for the SARS-CoV.

negative: The COVID-19 Pandemic and its Impact on the Cardio-Oncology Population PURPOSE OF REVIEW: The novel Coronavirus (2019-nCoV, COVID-19) is historically one of the most severe acute respiratory syndromes and pandemics to affect the globe in the twenty-first century. Originating in Wuhan, the virus rapidly spread and impacted subsets of populations with initial unclear risk factors contributing to worsening morbidity and mortality. Patients with diagnosis of cancer and undergoing treatment further represent a population at risk for worsening cardiopulmonary outcomes. This review explores specific risk factors, diagnoses, and treatment options that impact cardio-oncologic patients with COVID-19. RECENT FINDINGS: Multiple studies globally, including Italy, China, and the USA, have documented severe outcomes. Cancer patients are at increased risk of cardiac injury which itself is a risk factor for mortality. Additionally, elderly cancer patients undergoing recent anti-cancer treatment may be at greater risk for sustaining worse outcomes, although data remains suboptimal in this population. Major gaps remain regarding risk associated with type of cancer and type of anti-cancer treatment, as well as the layered risk of cardiovascular disease and cancer. Immunomodulatory therapies used to treat cytokine release syndrome secondary to anti-cancer therapies, as well as other agents being traditionally used to treat cardiovascular and cancer disease states, are being investigated for treatment of COVID-19. SUMMARY: Hypertension, cardiovascular disease, diabetes, and cancer have been associated with more severe COVID-19 infection and worse outcomes. Patients undergoing anti-cancer therapy or those who have suffered from coronavirus infection may develop long-standing changes, not limited to pulmonary fibrosis, hyperlipidemia, and worsening atherosclerosis. Those undergoing anti-cancer therapy are at theoretically increased susceptibility for infection, with type of cancer not necessarily dictating outcome. A review of the literature of patients with cardiovascular and/or cancer disease is presented, as well as proposed strategies to attenuate risk regarding treatment, management, and surveillance in this vulnerable population.

negative: How to handle patients with autoimmune rheumatic and inflammatory bowel diseases in the COVID-19 era: An expert opinion • A correct patient risk stratification is of paramount importance for the proper management of economic and human resources. • It's fundamental to prioritize clinical trials evaluating dosing, prophylaxis, and treatment with immunosuppressant in COVID-19 in order to avoid either an overuse and a treatment shortage. • Future controlled studies may highlight in our patients a potential preventive role of immunosuppressant therapies in the development of severe forms of Covid-19. • Despite the overall risk of infection in rheumatic and gastroenterological diseases a conclusive association between these diseases and COVID −19 remains questionable.

negative: Medical imaging informatics research and development trends—an editorial

negative: Psychosocial impact of COVID-19 outbreak on international students living in Hubei province, China

negative: Age groups and spread of influenza: implications for vaccination strategy BACKGROUND: The unpredictable nature of the potentially devastating impact of 2009 pH1N1 influenza pandemic highlights the need for pandemic preparedness planning, where modeling studies could be most useful for simulations of possible future scenarios. METHODS: A compartmental model with pre-symptomatic and asymptomatic influenza infections is proposed which incorporates age groups as well as intervention measures such as age-specific vaccination, in order to study spread of influenza in a community. RESULTS: We derive the basic reproduction number and other effective reproduction numbers under various intervention measures. For illustration, we make use of the Pneumonia and Influenza (P&I) mortality data and vaccination data of the very young (age 0-2) and the very old (age >64) during 2004-2005 Taiwan winter influenza season to fit our model and to compute the relevant reproduction numbers. The reproduction number for this winter flu season is estimated to be slightly above one (~1.0001). CONCLUSIONS: Comparatively large errors in fitting the P&I mortality data of the elderly (>64) were observed shortly after winter school closings in January, which may indicate the impact of younger, more active age groups transmitting influenza to other age groups outside of the school settings; in particular, to the elderly in the households. Pre-symptomatic infections seemed to have little effect on the model fit, while asymptomatic infection by asymptomatic infectives has a more pronounced impact on the model fit for the elderly mortality, perhaps indicating a larger role in disease transmission by asymptomatic infection. Simulations indicate that the impact of vaccination on the disease incidence might not be fully revealed in the change (or the lack thereof) in the effective reproduction number with interventions, but could still be substantial. The estimated per contact transmission probability for susceptible elderly is significantly higher than that of any other age group, perhaps highlighting the vulnerability of the elderly due to close contacts with their caretakers from other age groups. The relative impact of targeting the very young and the very old for vaccination was weakened by their relative inactivity, thus giving evidence of the lack of impact of vaccinating these two groups on the overall transmissibility of the disease in the community. This further underscores the need for morbidity-based strategy to prevent elderly mortality.

negative: COVID-19 Pandemic in India: What Lies Ahead

negative: MicroR‐9‐5p suppresses EV71 replication through targeting NFκB of the RIG‐I‐mediated innate immune response Accumulating evidence demonstrates that there is a causative link between hsa‐microRNA‐9‐5p (miR‐9) and pathophysiological processes. Enterovirus 71 (EV71) has been found to contribute to numerous severe clinical symptoms which result in death. The exact mechanism by which EV71 influences miR‐9 expression is unknown, and the relationship between miR‐9 and EV71 is still unclear. Here, miR‐9 expression was found to be impaired upon EV71 infection in several cell lines and in an EV71 infection mouse model. Additionally, we confirmed that EV71 infection induces robust expression of pro‐inflammatory cytokines (TNF‐α, IL‐6, and IL‐1) and interferons (IFN‐α and IFN‐β). Overexpression of miR‐9 attenuated EV71 proliferation and reduced protein and gene expressions of virion protein 1 (VP1) of EV71. Furthermore, we observed that the inflammation caused by EV71 infection was restored to a moderate level via miR‐9 overexpression. Nuclear factor kappa B (NFκB) in the retinoic acid‐induced gene 1 (RIG‐I) signaling pathway, but not interferon regulating factor 3 (IRF3), was significantly decreased and inactivated by ectopic miR‐9 expression. Moreover, in mouse infection experiments, administration of miR‐9 agomirs caused a significant decrease in VP1 levels and pro‐inflammatory cytokine production after viral inoculation. Taken together, the present data demonstrate that miR‐9 exerts an anti‐EV71 effect in cells and a mouse model via mediating NFκB activity of the RIG‐I signal pathway, thereby suggesting a new candidate for antiviral drug development.

negative: Treatment of Covid19 ‐ Repurposing drugs commonly used in dermatology For the last two decades, the outbreaks of diseases caused by coronaviruses and intermittent worldwide public health emergences have reminded us that they still represent a severe threat to global health. The recent outbreak of Corona Virus disease 19 (COVID‐19) highlighted the urgent need for effective treatment, and initiated rapid search for therapies, able to counter the most severe disease effects. Many aspects of COVID‐19 pathogenesis are unknown, but complex interplay of direct viral damage and immune response dysregulation is underline. Intensive research is undergoing for therapeutic targets of virus and high‐efficiency and low toxicity targeted drugs. There is no available specific antiviral treatment of this disease, therefore repurposing of drugs already available for the treatment of other viral and autoimmune diseases has been a part of research efforts. Well known anti‐inflammatory properties of Chloroquine and Hydroxychloroquine, agents widely used in dermatology, made them potential candidates for the treatment of COVID‐19. We review pathogenesis and clinical characteristic of COVID‐19, as well as treatment options that have been under evaluation in past several months. In addition, we focus more on Chloroquine and Hydroxychloroquine, their pharmacological properties, clinical utility, and current recommendations for their use in COVID‐19. This article is protected by copyright. All rights reserved.

negative: Managing emerging infectious diseases: Is a federal system an impediment to effective laws? In the 1980's and 1990's HIV/AIDS was the emerging infectious disease. In 2003–2004 we saw the emergence of SARS, Avian influenza and Anthrax in a man made form used for bioterrorism. Emergency powers legislation in Australia is a patchwork of Commonwealth quarantine laws and State and Territory based emergency powers in public health legislation. It is time for a review of such legislation and time for consideration of the efficacy of such legislation from a country wide perspective in an age when we have to consider the possibility of mass outbreaks of communicable diseases which ignore jurisdictional boundaries.

negative: The diagnostic value of detecting sudden smell loss among asymptomatic COVID-19 patients in early stage: The possible early sign of COVID-19 IMPORTANCE: The newly emerged coronavirus disease 19 (COVID-19), is threatening the world. Olfactory or gustatory dysfunction is reported as one of the symptoms worldwide. As reported so far, different clinical features have been reported according to outbreak sites and gender; most of the patients, who complained of anosmia or hyposmia, were Europeans. We had a fast review for novel articles about COVID-19 infection and olfactory function. OBSERVATIONS: Rapid reviews for COVID-19 or other viral infection and olfactory and/or gustatory dysfunctions were done in this review. Up to date, a lot of reports have shown that olfactory dysfunction is related to viral infections but no exact mechanism, clinical course, and definite treatment have been discovered, which is also same in COVID-19. In general, intranasal steroid (INS) and oral steroid for short time help improve the recovery of the olfactory function in case of olfactory dysfunction after virus infection. Considering severe respiratory complications and immunocompromised state of COVID-19, the use of steroid should be limited and cautious because we do not have enough data to support the usage of steroid to treat olfactory dysfunction in the clinical course of COVID-19. CONCLUSIONS AND RELEVANCE: In the days of pandemic COVID-19, we should keep in mind that olfactory dysfunctions, even without other upper respiratory infection or otolaryngologic symptoms, might be the early signs of COVID-19.

negative: Immune-Related Adverse Events: Pneumonitis Checkpoint inhibitors are part of the family of immunotherapies and are increasingly being used in a wide variety of cancers. Immune-related adverse events pose a major challenge in the treatment of cancer patients. Pneumonitis is a rare immune-related adverse event that presents in distinct patterns. The goal of this chapter is to instruct readers on the incidence and clinical manifestations of pneumonitis and to offer guidance in the evaluation and treatment of patients with pneumonitis.

negative: Infectious Diseases and Microbiological Threats “The time to close the book on infectious disease” is far from near. Infections seem to be here to stay and have increased in importance in spite of enormous success in the field of prophylactic efforts, hygiene, vaccinology, and treatment. A large number of new agents and infections have appeared during the last decades. Conditions earlier thought to have other etiologies are today known to be distinct and have been proven to be of infectious origin. Infections alone can constitute major incidents, or they can be part of or a consequence of an incident. Even in the relatively new incident category of terrorism, infections must be seriously considered. Climate change and other changes in nature today constitute major threats of increasing infectious incidents. The increasing problem with antimicrobial resistance is, at present, considered to be one of the strongest disease threats. Infectious incidents are unique in the sense that they usually have an insidious onset, have a time span before they are detected as present or even as serious. Once the infection has started to spread, the development and increase can be extremely quick, even logarithmic. The extent of infectious incidents can be larger than that of most other disasters, and is best exemplified through different pandemics. The most important weapon to control infectious outbreaks or epidemics is active surveillance, leading to different kind of actions.

negative: Microarray analysis of MicroRNA expression in peripheral blood mononuclear cells of critically ill patients with influenza A (H1N1) BACKGROUND: With concerns about the disastrous health and economic consequences caused by the influenza pandemic, comprehensively understanding the global host response to influenza virus infection is urgent. The role of microRNA (miRNA) has recently been highlighted in pathogen-host interactions. However, the precise role of miRNAs in the pathogenesis of influenza virus infection in humans, especially in critically ill patients is still unclear. METHODS: We identified cellular miRNAs involved in the host response to influenza virus infection by performing comprehensive miRNA profiling in peripheral blood mononuclear cells (PBMCs) from critically ill patients with swine-origin influenza pandemic H1N1 (2009) virus infection via miRNA microarray and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) assays. Receiver operator characteristic (ROC) curve analysis was conducted and area under the ROC curve (AUC) was calculated to evaluate the diagnostic accuracy of severe H1N1 influenza virus infection. Furthermore, an integrative network of miRNA-mediated host-influenza virus protein interactions was constructed by integrating the predicted and validated miRNA-gene interaction data with influenza virus and host-protein-protein interaction information using Cytoscape software. Moreover, several hub genes in the network were selected and validated by qRT-PCR. RESULTS: Forty-one significantly differentially expressed miRNAs were found by miRNA microarray; nine were selected and validated by qRT-PCR. QRT-PCR assay and ROC curve analyses revealed that miR-31, miR-29a and miR-148a all had significant potential diagnostic value for critically ill patients infected with H1N1 influenza virus, which yielded AUC of 0.9510, 0.8951 and 0.8811, respectively. We subsequently constructed an integrative network of miRNA-mediated host-influenza virus protein interactions, wherein we found that miRNAs are involved in regulating important pathways, such as mitogen-activated protein kinase signaling pathway, epidermal growth factor receptor signaling pathway, and Toll-like receptor signaling pathway, during influenza virus infection. Some of differentially expressed miRNAs via in silico analysis targeted mRNAs of several key genes in these pathways. The mRNA expression level of tumor protein T53 and transforming growth factor beta receptor 1 were found significantly reduced in critically ill patients, whereas the expression of Janus kinase 2, caspase 3 apoptosis-related cysteine peptidase, interleukin 10, and myxovirus resistance 1 were extremely increased in critically ill patients. CONCLUSIONS: Our data suggest that the dysregulation of miRNAs in the PBMCs of H1N1 critically ill patients can regulate a number of key genes in the major signaling pathways associated with influenza virus infection. These differentially expressed miRNAs could be potential therapeutic targets or biomarkers for severe influenza virus infection.

negative: Cardiac and arrhythmic complications in patients with COVID‐19 In December 2019, the world started to face a new pandemic situation, the severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). Although coronavirus disease (COVID‐19) clinical manifestations are mainly respiratory, major cardiac complications are being reported. Cardiac manifestations etiology seems to be multifactorial, comprising direct viral myocardial damage, hypoxia, hypotension, enhanced inflammatory status, ACE2‐receptors downregulation, drug toxicity, endogenous catecholamine adrenergic status, among others. Studies evaluating patients with COVID‐19 presenting cardiac injury markers show that it is associated with poorer outcomes, and arrhythmic events are not uncommon. Besides, drugs currently used to treat the COVID‐19 are known to prolong the QT interval and can have a proarrhythmic propensity. This review focus on COVID‐19 cardiac and arrhythmic manifestations and, in parallel, makes an appraisal of other virus epidemics as SARS‐CoV, Middle East respiratory syndrome coronavirus, and H1N1 influenza.

negative: Nutrition, immunity and COVID-19 The immune system protects the host from pathogenic organisms (bacteria, viruses, fungi, parasites). To deal with this array of threats, the immune system has evolved to include a myriad of specialised cell types, communicating molecules and functional responses. The immune system is always active, carrying out surveillance, but its activity is enhanced if an individual becomes infected. This heightened activity is accompanied by an increased rate of metabolism, requiring energy sources, substrates for biosynthesis and regulatory molecules, which are all ultimately derived from the diet. A number of vitamins (A, B(6), B(12), folate, C, D and E) and trace elements (zinc, copper, selenium, iron) have been demonstrated to have key roles in supporting the human immune system and reducing risk of infections. Other essential nutrients including other vitamins and trace elements, amino acids and fatty acids are also important. Each of the nutrients named above has roles in supporting antibacterial and antiviral defence, but zinc and selenium seem to be particularly important for the latter. It would seem prudent for individuals to consume sufficient amounts of essential nutrients to support their immune system to help them deal with pathogens should they become infected. The gut microbiota plays a role in educating and regulating the immune system. Gut dysbiosis is a feature of disease including many infectious diseases and has been described in COVID-19. Dietary approaches to achieve a healthy microbiota can also benefit the immune system. Severe infection of the respiratory epithelium can lead to acute respiratory distress syndrome (ARDS), characterised by excessive and damaging host inflammation, termed a cytokine storm. This is seen in cases of severe COVID-19. There is evidence from ARDS in other settings that the cytokine storm can be controlled by n-3 fatty acids, possibly through their metabolism to specialised pro-resolving mediators.

negative: Review on the potential action mechanisms of Chinese medicines in treating Coronavirus Disease 2019 (COVID-19) [Figure: see text] The Coronavirus Disease 2019 (COVID-19) has been declared as a global pandemic, but specific medicines and vaccines are still being developed. In China, interventional therapies with traditional Chinese medicine for COVID-19 have achieved significant clinical efficacies, but the underlying pharmacological mechanisms are still unclear. This article reviewed the etiology of COVID-19 and clinical efficacy. Both network pharmacological study and literature search were used to demonstrate the possible action mechanisms of Chinese medicines in treating COVID-19. We found that Chinese medicines played the role of antivirus, anti-inflammation and immunoregulation, and target organs protection in the management of COVID-19 by multiple components acting on multiple targets at multiple pathways. AEC2 and 3CL protein could be the direct targets for inhibiting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Quercetin, kaempferol, luteolin, isorhamnetin, baicalein, naringenin, and wogonin could be the main active ingredients of Chinese medicines for the management of COVID-19 by targeting on AEC2 and 3CL protein and inhibiting inflammatory mediators, regulating immunity, and eliminating free radicals through COX-2, CASP3, IL-6, MAPK1, MAPK14, MAPK8, and REAL in the signaling pathways of IL-17, arachidonic acid, HIF-1, NF-κB, Ras, and TNF. This study may provide meaningful and useful information on further research to investigate the action mechanisms of Chinese medicines against SARS-CoV-2 and also provide a basis for sharing the “China scheme" for COVID-19 treatment.

negative: ENT manifestation in COVID-19 patients OBJECTIVE: to detect, analyze and discuss the different ear nose throat (ENT) manifestations those were reported in COVID19 positive patients in the reviewed and published literatures. METHODS: We performed a search in the PubMed databases, Web of Science, LILACS, MEDLINE, SciELO, and Cochrane Library using the keywords; COVID-19, Novel coronavirus, corona, 2019-nCoV, SARS-CoV-2, ENT, ear, nose, throat, otorhinolaryngology, ORL, pharynx, ORL, smell, larynx, different ENT related symptoms. We reviewed published and peer reviewed studies that reported the ENT manifestations in COVID-19 laboratory-confirmed positive patients. RESULTS: within the included 1773 COVID-19 laboratory-confirmed positive patients, the most common ENT manifestations of COVID-19 were sore throat (11.3%) and headache (10.7%). While the other reported ENT manifestations were pharyngeal erythema (5.3%), nasal congestion (4.1%), runny nose or rhinorrhea (2.1%), upper respiratory tract infection (URTI) (1.9%), and tonsil enlargement (1.3%). CONCLUSION: ENT manifestations for COVID-19 are not common as fever and cough. But, a universal questionnaire using well-defined COVID-19 manifestations is needed to make the COVID-19 data precisely defined, complete and homogenous.

negative: Forty years with coronaviruses I have been researching coronaviruses for more than forty years. This viewpoint summarizes some of the major findings in coronavirus research made before the SARS epidemic and how they inform current research on the newly emerged SARS-CoV-2.

negative: Recommendations on management of gynecological malignancies during the COVID-19 pandemic: perspectives from Chinese gynecological oncologists The outbreak of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 has rapidly spread globally. Cancer patients are at a higher risk of being infected with the coronavirus and are more likely to develop severe complications, as compared to the general population. The increasing spread of COVID-19 presents challenges for the clinical care of patients with gynecological malignancies. Concerted efforts should be put into managing gynecological malignancies in an orderly manner by strictly implementing the measures that are specifically developed for controlling the spread of COVID-19. We have drafted Recommendations on Management of Gynecological Malignancies during the COVID-19 Pandemic based on our experience on controlling COVID-19 pandemic in China. We recommend that patients with gynecological malignancies should be managed in hierarchical and individualized manners in combination with local conditions related to COVID-19. Medical care decision should be balanced between controlling COVID-19 pandemic spread and timely diagnosis and treatment for gynecologic oncology patients.

negative: COVID-19 in a tertiary hospital from Romania: Epidemiology, preparedness and clinical challenges

negative: The neurological insights of the emerging coronaviruses Emerging Viral diseases are incredibly infectious and proficient in inducing pandemics. Unlike the previous emerging coronaviruses (ECoVs) which neurological complexities were uncommon, with neurological features exhibition at 14-25 days post-onset, yet with critical outcomes exhibiting > 50% mortality in central nervous(CNS) presenting pathologies. The COVID 19 neurological consequences occur more frequently even in mild cases, presenting with CNS involvement in up to 25%, musculoskeletal and peripheral manifestation(PNM). Through preceding ECoVs case reports, the PNM not linked to fatal outcomes, however, required, repeated neuro-imaging as notable CT and MRI changes appeared as late as 21 days while the likelihood of Cerebrospinal fluid to test positive for ECoV was 25%, only in the CNS presenting cases. Owing to 44-60% myalgia presentation, risk of the high inflammatory state, and coagulation cascade abnormalities reported in ECoVs, testing for C-reactive protein, serum creatine kinase, and D-dimer level is mandatory. Presently, there is no antiviral medication or vaccination for the ECoVs, early induction of antiviral drugs remains the backbone of management. Neurologically, the therapeutic dosages of anticoagulants are linked to the high incidence of thrombotic complexities, while methylprednisolone is associated with myopathy. Future studies expected to apply more neuro-imaging techniques for CNS exploration and further explore the pathogenesis of the COVID 19 myalgia, anosmia/ageusia reported in the majority of the initial cases.

negative: SARS-CoV-2 Transmission in Patients With Cancer at a Tertiary Care Hospital in Wuhan, China

negative: Human monoclonal IgG selection of Plasmodium falciparum for the expression of placental malaria-specific variant surface antigens Pregnancy-associatedPlasmodium falciparum malaria (PAM) is a major cause of morbidity and mortality in African women and their offspring. PAM is characterized by accumulation of infected erythrocytes (IEs) that adhere to chondroitin sulphate A (CSA) in the placental intervillous space. We show here that human monoclonal IgG antibodies with specificity for variant surface antigens (VSA) specifically expressed by CSA-adhering IEs (VSA(PAM)) can be used in vitro to select parasites from nonpregnant donors to express VSA(PAM) and that this selection for VSA(PAM) expression results in preferential transcription of var2csa. The results corroborate current efforts to develop PAM-specific vaccines based on VAR2CSA.

negative: SARS-CoV-2 and cardiovascular complications: From molecular mechanisms to pharmaceutical management The coronavirus disease 2019 (COVID-19), elicited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is a pandemic public health emergency of global concern. Other than the profound severe pulmonary damage, SARS-CoV-2 infection also leads to a series of cardiovascular abnormalities, including myocardial injury, myocarditis and pericarditis, arrhythmia and cardiac arrest, cardiomyopathy, heart failure, cardiogenic shock, and coagulation abnormalities. Meanwhile, COVID-19 patients with preexisting cardiovascular diseases are often at a much higher risk of increased morbidity and mortality. Up-to-date, a number of mechanisms have been postulated for COVID-19-associated cardiovascular damage including SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) activation, cytokine storm, hypoxemia, stress and cardiotoxicity of antiviral drugs. In this context, special attention should be given towards COVID-19 patients with concurrent cardiovascular diseases, and special cardiovascular attention is warranted for treatment of COVID-19.

negative: The Cytokine Response to Physical Activity and Training Cytokines are soluble glycoproteins that are produced by and mediate communication between and within immune and nonimmune cells, organs and organ systems throughout the body. Pro- and anti-inflammatory mediators constitute the inflammatory cytokines, which are modulated by various stimuli, including physical activity, trauma and infection. Physical activity affects local and systemic cytokine production at different levels, often exhibiting striking similarity to the cytokine response to trauma and infection. The present review examines the cytokine response to short term exercise stress, with an emphasis on the balance between pro- and anti-inflammatory mechanisms and modulation of both innate and specific immune parameters through cytokine regulation. The effects of long term exercise on cytokine responses and the possible impact on various facets of the immune system are also discussed, with reference to both cross-sectional and longitudinal studies of exercise training. Finally, the validity of using exercise as a model for trauma and sepsis is scrutinised in the light of physiological changes, symptomatology and outcome, and limitations of the model are addressed. Further studies, examining the effect of exercise, trauma and infection on novel cytokines and cytokine systems are needed to elucidate the significance of cytokine regulation by physical activity and, more importantly, to clarify the health implications of short and long term physical activity with respect to overall immune function and resistance to infection.

negative: Association of chemosensory dysfunction and Covid‐19 in patients presenting with influenza‐like symptoms BACKGROUND: Rapid spread of the SARS‐CoV‐2 virus and concern for viral transmission by ambulatory patients with minimal to no symptoms underline the importance of identifying early or subclinical symptoms of Covid‐19 infection. Two such candidate symptoms include anecdotally reported loss of smell and taste. Understanding the timing and association of smell/taste loss in Covid‐19 may help facilitate screening and early isolation of cases. METHODS: A single‐institution, cross‐sectional study evaluating patient‐reported symptoms with a focus on smell and taste was conducted using an internet‐based platform on adult subjects who underwent testing for Covid‐19. Logistic regression was employed to identify symptoms associated with Covid‐19 positivity. RESULTS: A total of 1480 patients with influenza‐like symptoms underwent Covid‐19 testing between March 3 through 29, 2020. Our study captured 59 of 102 (58%) Covid‐19‐positive patients and 203 of 1378 (15%) Covid‐19‐negative patients. Smell and taste loss were reported in 68% (40/59) and 71% (42/59) of Covid‐19‐positive subjects, respectively, compared to 16% (33/203) and 17% (35/203) of Covid‐19‐negative patients (p<0.001). Smell and taste impairment were independently and strongly associated with Covid‐19‐positivity (anosmia: adjusted odds ratio [aOR] 10.9, 95%CI:5.08‐23.5; ageusia: aOR 10.2 95%CI:4.74‐22.1); whereas, sore throat was associated with Covid‐19‐negativity (aOR 0.23, 95%CI:0.11‐0.50). Of patients who reported Covid‐19‐associated loss of smell, 74% (28/38) reported resolution of anosmia with clinical resolution of illness. CONCLUSIONS: In ambulatory individuals with influenza‐like symptoms, chemosensory dysfunction was strongly associated with Covid‐19 infection and should be considered when screening symptoms. Most will recover chemosensory function within weeks paralleling resolution of other disease‐related symptoms. This article is protected by copyright. All rights reserved

negative: Identifying novel factors associated with COVID-19 transmission and fatality using the machine learning approach The COVID-19 virus has infected millions of people and resulted in hundreds of thousands of deaths worldwide. By using the logistic regression model, we identified novel critical factors associated with COVID19 cases, death, and case fatality rates in 154 countries and in the 50 U.S. states. Among numerous factors associated with COVID-19 risk, we found that the unitary state system was counter-intuitively positively associated with increased COVID-19 cases and deaths. Blood type B was a protective factor for COVID-19 risk, while blood type A was a risk factor. The prevalence of HIV, influenza and pneumonia, and chronic lower respiratory diseases was associated with reduced COVID-19 risk. Obesity and the condition of unimproved water sources were associated with increased COVID-19 risk. Other factors included temperature, humidity, social distancing, smoking, and vitamin D intake. Our comprehensive identification of the factors affecting COVID-19 transmission and fatality may provide new insights into the COVID-19 pandemic and advise effective strategies for preventing and migrating COVID-19 spread.

negative: Mesenchymal Stem Cell Derived Exosomes: a Nano Platform for Therapeutics and Drug Delivery in Combating COVID-19 The recent pandemic situation transpired due to coronavirus novel strain SARS-CoV-2 has become a global concern. This human coronavirus (HCov-19) has put the world on high alert as the numbers of confirmed cases are continuously increasing. The world is now fighting against this deadly virus and is leaving no stone unturned to find effective treatments through testing of various available drugs, including those effective against flu, malaria, etc. With an urgent need for the development of potential strategies, two recent studies from China using Mesenchymal Stem Cells (MSCs) to treat COVID-19 pneumonia have shed some light on a potential cure for the COVID-19 infected patients. However, MSCs, despite being used in various other clinical trials have always been questioned for their tendency to aggregate or form clumps in the injured or disease microenvironment. It has also been reported in various studies that exosomes secreted by these MSCs, contribute towards the cell’s biological and therapeutic efficacy. There have been reports evaluating the safety and feasibility of these exosomes in various lung diseases, thereby proposing them as a cell-free therapeutic agent. Also, attractive features like cell targeting, low-immunogenicity, safety, and high biocompatibility distinguish these exosomes from other synthetic nano-vesicles and thus potentiate their role as a drug delivery nano-platform. Building upon these observations, herein, efforts are made to give an overview of stem cell-derived exosomes as an appealing therapeutic agent and drug delivery nano-carrier. In this review, we briefly recapitulate the recent evidence and developments in understanding exosomes as a promising candidate for novel nano-intervention in the current pandemic scenario. Furthermore, this review will highlight and discuss mechanistic role of exosomes to combat severe lung pathological conditions. We have also attempted to dwell into the nano-formulation of exosomes for its better applicability, storage, and stability thereby conferring them as off the shelf therapeutic.

negative: Identification and Characterization of a Ribose 2'-O-Methyltransferase Encoded by the Ronivirus Branch of Nidovirales. UNLABELLED The order Nidovirales currently comprises four virus families: Arteriviridae, Coronaviridae (divided into the subfamilies Coronavirinae and Torovirinae), Roniviridae, and the recently recognized Mesoniviridae RNA cap formation and methylation have been best studied for coronaviruses, with emphasis on the identification and characterization of two virus-encoded methyltransferases (MTases) involved in RNA capping, a guanine-N7-MTase and a ribose-2'-O-MTase. Although bioinformatics analyses suggest that these MTases may also be encoded by other nidoviruses with large genomes, such as toroviruses and roniviruses, no experimental evidence has been reported thus far. In this study, we show that a ronivirus, gill-associated virus (GAV), encodes the 2'-O-MTase activity, although we could not detect 2'-O-MTase activity for the homologous protein of a torovirus, equine torovirus, which is more closely related to coronaviruses. Like the coronavirus 2'-O-MTase, the roniviral 2'-O-MTase harbors a catalytic K-D-K-E tetrad that is conserved among 2'-O-MTases and can target only the N7-methylated cap structure of adenylate-primed RNA substrates. However, in contrast with the coronavirus protein, roniviral 2'-O-MTase does not require a protein cofactor for stimulation of its activity and differs in its preference for several biochemical parameters, such as reaction temperature and pH. Furthermore, the ronivirus 2'-O-MTase can be targeted by MTase inhibitors. These results extend our current understanding of nidovirus RNA cap formation and methylation beyond the coronavirus family. IMPORTANCE Methylation of the 5'-cap structure of viral RNAs plays important roles in genome replication and evasion of innate recognition of viral RNAs by cellular sensors. It is known that coronavirus nsp14 acts as an N7-(guanine)-methyltransferase (MTase) and nsp16 as a 2'-O-MTase, which are involved in the modification of RNA cap structure. However, these enzymatic activities have not been shown for any other nidoviruses beyond coronaviruses in the order Nidovirales In this study, we identified a 2'-O-methyltransferase encoded by ronivirus that shows common and unique features in comparison with that of coronaviruses. Ronivirus 2'-O-MTase does not need a protein cofactor for MTase activity, whereas coronavirus nsp16 needs the stimulating factor nsp10 for its full activity. The conserved K-D-K-E catalytic tetrad is identified in ronivirus 2'-O-MTase. These results extend our understanding of nidovirus RNA capping and methylation beyond coronaviruses and also strengthen the evolutionary and functional links between roniviruses and coronaviruses.

negative: A predictive model and scoring system combining clinical and CT characteristics for the diagnosis of COVID-19 OBJECTIVES: To develop a predictive model and scoring system to enhance the diagnostic efficiency for coronavirus disease 2019 (COVID-19). METHODS: From January 19 to February 6, 2020, 88 confirmed COVID-19 patients presenting with pneumonia and 80 non-COVID-19 patients suffering from pneumonia of other origins were retrospectively enrolled. Clinical data and laboratory results were collected. CT features and scores were evaluated at the segmental level according to the lesions’ position, attenuation, and form. Scores were calculated based on the size of the pneumonia lesion, which graded at the range of 1 to 4. Air bronchogram, tree-in-bud sign, crazy-paving pattern, subpleural curvilinear line, bronchiectasis, air space, pleural effusion, and mediastinal and/or hilar lymphadenopathy were also evaluated. RESULTS: Multivariate logistic regression analysis showed that history of exposure (β = 3.095, odds ratio (OR) = 22.088), leukocyte count (β = − 1.495, OR = 0.224), number of segments with peripheral lesions (β = 1.604, OR = 1.604), and crazy-paving pattern (β = 2.836, OR = 2.836) were used for establishing the predictive model to identify COVID-19-positive patients (p < 0.05). In this model, values of area under curve (AUC) in the training and testing groups were 0.910 and 0.914, respectively (p < 0.001). A predicted score for COVID-19 (PSC-19) was calculated based on the predictive model by the following formula: PSC-19 = 2 × history of exposure (0–1 point) − 1 × leukocyte count (0–2 points) + 1 × peripheral lesions (0–1 point) + 2 × crazy-paving pattern (0–1 point), with an optimal cutoff point of 1 (sensitivity, 88.5%; specificity, 91.7%). CONCLUSIONS: Our predictive model and PSC-19 can be applied for identification of COVID-19-positive cases, assisting physicians and radiologists until receiving the results of reverse transcription–polymerase chain reaction (RT-PCR) tests. KEY POINTS: • Prediction of RT-PCR positivity is crucial for fast diagnosis of patients suspected of having coronavirus disease 2019 (COVID-19). • Typical CT manifestations are advantageous for diagnosing COVID-19 and differentiation of COVID-19 from other types of pneumonia. • A predictive model and scoring system combining both clinical and CT features were herein developed to enable high diagnostic efficiency for COVID-19.

negative: Emerging Influenza and Psychosis: An Important Story in Psychological Medicine

negative: Good or bad: Application of RAAS inhibitors in COVID-19 patients with cardiovascular comorbidities The coronavirus disease 2019 (COVID-19) pandemic is caused by a newly emerged coronavirus (CoV) called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). COVID-19 patients with cardiovascular disease (CVD) comorbidities have significantly increased morbidity and mortality. The use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor type 1 blockers (ARBs) improve CVD outcomes; however, there is concern that they may worsen the prognosis of CVD patients that become infected with SARS-CoV-2 because the virus uses the ACE2 receptor to bind to and subsequently infect host cells. Thus, some health care providers and media sources have questioned the continued use of ACE inhibitors and ARBs. In this brief review, we discuss the effect of ACE inhibitor-induced bradykinin on the cardiovascular system, on the renin–angiotensin–aldosterone system (RAAS) regulation in COVID-19 patients, and analyze recent clinical studies regarding patients treated with RAAS inhibitors. We propose that the application of RAAS inhibitors for COVID-19 patients with CVDs may be beneficial rather than harmful.

negative: Pathophysiological characteristics and therapeutic approaches for pulmonary injury and cardiovascular complications of coronavirus disease 2019 The pandemic of coronavirus disease 2019 (COVID-19) has emerged as a major health crisis, with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) having infected over a million people around the world within a few months of its identification as a human pathogen. Initially, SARS-CoV-2 infects cells in the respiratory system and causes inflammation and cell death. Subsequently, the virus spreads out and damages other vital organs and tissues, triggering a complicated spectrum of pathophysiological changes and symptoms, including cardiovascular complications. Acting as the receptor for SARS-CoV entering mammalian cells, angiotensin converting enzyme-2 (ACE2) plays a pivotal role in the regulation of cardiovascular cell function. Diverse clinical manifestations and laboratory abnormalities occur in patients with cardiovascular injury in COVID-19, characterizing the development of this complication, as well as providing clues to diagnosis and treatment. This review provides a summary of the rapidly appearing laboratory and clinical evidence for the pathophysiology and therapeutic approaches to COVID-19 pulmonary and cardiovascular complications.

negative: Epinephrine use in COVID-19: friend or foe?

negative: The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management The 2019 coronavirus disease (COVID-19) presents with a large variety of clinical manifestations ranging from asymptomatic carrier state to severe respiratory distress, multiple organ dysfunction and death. While it was initially considered primarily a respiratory illness, rapidly accumulating data suggests that COVID-19 results in a unique, profoundly prothrombotic milieu leading to both arterial and venous thrombosis. Consistently, elevated D-dimer level has emerged as an independent risk factor for poor outcomes, including death. Several other laboratory markers and blood counts have also been associated with poor prognosis, possibly due to their connection to thrombosis. At present, the pathophysiology underlying the hypercoagulable state is poorly understood. However, a growing body of data suggests that the initial events occur in the lung. A severe inflammatory response, originating in the alveoli, triggers a dysfunctional cascade of inflammatory thrombosis in the pulmonary vasculature, leading to a state of local coagulopathy. This is followed, in patients with more severe disease, by a generalized hypercoagulable state that results in macro- and microvascular thrombosis. Of concern, is the observation that anticoagulation may be inadequate in many circumstances, highlighting the need for alternative or additional therapies. Numerous ongoing studies investigating the pathophysiology of the COVID-19 associated coagulopathy may provide mechanistic insights that can direct appropriate interventional strategies.

negative: Will the antimalarial drug take over to combat COVID-19? BACKGROUND: China has been fighting the epidemic of pneumonia-like diseases first detected for over a month in the city of Wuhan in December 2019. The disease epidemic is caused by a novel coronavirus, called COVID-19, which has now infected more than 700,000 people worldwide. With a death toll approaching that of China’s SARS-CoV outbreak in 2002 and 2003, 2019-nCoV has contributed to an international emergency in public health, placing all health organizations on high alert. Such large numbers of infected and deceased people require an urgent need for reliable, inexpensive, and cheap drugs to control and reduce the outbreak. OBJECTIVE: To systematically review and evaluate the pattern of COVID-19 and the treatment plans. METHODS: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The articles were searched from databases like PubMed, the Cochrane Library, ScienceDirect, and the Health Research and Development Information Network (HERDIN) combining MeSH and free-text terms. RESULTS: This analysis highlights the agent of COVID-19 and the possible transmission. The current research taking place to overcome this complex disease and the urgent need to develop improved therapeutics are also discussed. CONCLUSION: Herein, we present an epidemiological overview of the currently available information on the treatment claimed to have helped to bring the situation under control.

negative: A serological survey of human coronavirus in pigs of the Tohoku District of Japan. A total of 2496 swine sera from 60 farms in the Tohoku District of Japan was examined for hemagglutination inhibiting (HI) antibodies to human coronavirus (HCV), swine hemagglutinating encephalomyelitis virus (HEV) and bovine coronavirus (BCV). HI antibodies to HCV OC43 strain and HEV 67N strain were highly prevalent with positivity rates of 91.4 and 82.1%, respectively, while the BCV Kakegawa strain was 44.2% positive. Farm D in Miyagi Prefecture showed the highest antibody titers to HCV OC43 strain with geometric mean titers (GMT) of 1:200. These results suggest that pigs might be infected with HCV or an antigenetically related virus as well as HEV.

negative: Extrapulmonary and atypical clinical presentations of COVID‐19 The novel coronavirus (SARS‐CoV2) has led to outbreak of multiple cases of pneumonia in Wuhan city in December 2019. The disease caused by this virus was named coronavirus disease 2019 or “COVID‐19”, which was declared by WHO as a global pandemic in March 2020. It typically presents with respiratory symptoms and febrile illness. However, there are few reported extrapulmonary and atypical presentations, such as haemoptysis, cardiac, neurological, gastrointestinal, ocular and cutaneous manifestations, as well as venous and arterial thrombosis. Lack of awareness of these presentations might lead to misdiagnosis, delayed diagnosis and isolation of suspected patients which increases the risk of transmission of infection between patients and doctors. All these issues will be discussed in this review. This article is protected by copyright. All rights reserved.

negative: Knowledge, attitudes, and practices towards COVID-19 among Chinese residents during the rapid rise period of the COVID-19 outbreak: a quick online cross-sectional survey Unprecedented measures have been adopted to control the rapid spread of the ongoing COVID-19 epidemic in China. People's adherence to control measures is affected by their knowledge, attitudes, and practices (KAP) towards COVID-19. In this study, we investigated Chinese residents' KAP towards COVID-19 during the rapid rise period of the outbreak. An online sample of Chinese residents was successfully recruited via the authors' networks with residents and popular media in Hubei, China. A self-developed online KAP questionnaire was completed by the participants. The knowledge questionnaire consisted of 12 questions regarding the clinical characteristics and prevention of COVID-19. Assessments on residents' attitudes and practices towards COVID-19 included questions on confidence in winning the battle against COVID-19 and wearing masks when going out in recent days. Among the survey completers (n=6910), 65.7% were women, 63.5% held a bachelor degree or above, and 56.2% engaged in mental labor. The overall correct rate of the knowledge questionnaire was 90%. The majority of the respondents (97.1%) had confidence that China can win the battle against COVID-19. Nearly all of the participants (98.0%) wore masks when going out in recent days. In multiple logistic regression analyses, the COVID-19 knowledge score (OR: 0.75-0.90, P<0.001) was significantly associated with a lower likelihood of negative attitudes and preventive practices towards COVID-2019. Most Chinese residents of a relatively high socioeconomic status, in particular women, are knowledgeable about COVID-19, hold optimistic attitudes, and have appropriate practices towards COVID-19. Health education programs aimed at improving COVID-19 knowledge are helpful for Chinese residents to hold optimistic attitudes and maintain appropriate practices. Due to the limited sample representativeness, we must be cautious when generalizing these findings to populations of a low socioeconomic status.