BMC Public Health A global framework for action to improve the primary care response to chronic non-communicable diseases: a solution to a neglected problem

Dermot Maher email@example.com
Medical Research Council
Virus Research Institute (MRC/UVRI) Uganda Research Unit on AIDS
PO Box 49EntebbeUganda, Uganda

Anthony D Harries email@example.com
International Union Against Tuberculosis and Lung Disease
Old Inn Cottage
Colden Common
Vears LaneSO21 1TQWinchesterUK

Rony Zachariah firstname.lastname@example.com
Medical Department
Medecins Sans Frontieres
Brussels Operational Centre
BrusselsBelgium

Don Enarson email@example.com
International Union Against Tuberculosis and Lung Disease
ParisFrance

BMC Public Health A global framework for action to improve the primary care response to chronic non-communicable diseases: a solution to a neglected problem
10.1186/1471-2458-9-355BioMed Central Page 1 of 7 (page number not for citation purposes) Correspondence * Corresponding author
Background: Although in developing countries the burden of morbidity and mortality due to infectious diseases has often overshadowed that due to chronic non-communicable diseases (NCDs), there is evidence now of a shift of attention to NCDs.Discussion:Decreasing the chronic NCD burden requires a two-pronged approach: implementation of the multisectoral policies aimed at decreasing population-level risks for NCDs, and effective and affordable delivery of primary care interventions for patients with chronic NCDs. The primary care response to common NCDs is often unstructured and inadequate. We therefore propose a programmatic, standardized approach to the delivery of primary care interventions for patients with NCDs, with a focus on hypertension, diabetes mellitus, chronic airflow obstruction, and obesity. The benefits of this approach will extend to patients with related conditions, e.g. those with chronic kidney disease caused by hypertension or diabetes. This framework for a "public health approach" is informed by experience of scaling up interventions for chronic infectious diseases (tuberculosis and HIV). The lessons learned from progress in rolling out these interventions include the importance of gaining political commitment, developing a robust strategy, delivering standardised interventions, and ensuring rigorous monitoring and evaluation of progress towards defined targets.The goal of the framework is to reduce the burden of morbidity, disability and premature mortality related to NCDs through a primary care strategy which has three elements: 1) identify and address modifiable risk factors, 2) screen for common NCDs and 3) and diagnose, treat and follow-up patients with common NCDs using standard protocols. The proposed framework for NCDs borrows the same elements as those developed for tuberculosis control, comprising a goal, strategy and targets for NCD control, a package of interventions for quality care, key operations for national implementation of these interventions (political commitment, case-finding among people attending primary care services, standardised diagnostic and treatment protocols, regular drug supply, and systematic monitoring and evaluation), and indicators to measure progress towards increasing the impact of primary care interventions on chronic NCDs. The framework needs evaluation, then adaptation in different settings.Summary: A framework for a programmatic "public health approach" has the potential to improve on the current unstructured approach to primary care of people with chronic NCDs. Research to establish the cost, value and feasibility of implementing the framework will pave the way for international support to extend the benefit of this approach to the millions of people worldwide with chronic NCDs.

Background

The international health focus in the past two decades has been on the problem of infectious diseases, with noncommunicable diseases (NCDs) given a low priority at global level [1]. However recognition is increasing of the double burden in developing countries of chronic communicable diseases (e.g. tuberculosis and HIV) and chronic NCDs [2], based on emerging country-level evidence [3]. Attention to chronic NCDs is now increasing for several reasons: 1) they have a huge negative economic impact [4] and represent a significant impediment to human development [5]; 2) the effects of globalisation are likely to have a particular impact on chronic NCDs, including diabetes, hypertension, smoking-related conditions and obesity; and 3) recent progress in mobilising funds and improving the response to infectious diseases (especially HIV/AIDS, tuberculosis and malaria) has enabled a shift to a broader global health outlook.

The main international focus is on those chronic NCDs (diabetes, hypertension, chronic airflow obstruction and obesity) which share the following characteristics: 1) they are becoming more common as a consequence of the effects of globalisation; 2) enough preliminary data on these conditions are available to justify the conclusion that they are contributing to epidemiological transition (a double burden of communicable diseases and non-communicable diseases) in a wide range of low-and middleincome countries; 3) they share common risk factors which are potentially amenable to behavioural modification (tobacco use, unhealthy diets, physical inactivity, and harmful use of alcohol) [6]; 4) they can be detected using simple tests available (or potentially readily available) in primary care settings in low-income countries: hypertension (sphygmomanometer), chronic airflow obstruction (peak expiratory flow meter), diabetes (urine or blood glucose) and obesity (weight and height); 5) they can be managed in typical primary care settings in middle-and low-income countries; 6) the benefits of prevention and care extend to related conditions of public health importance, e.g. chronic kidney disease (often caused by hypertension or diabetes); and 7) they are the focus of World Health Organization efforts, such as the launch of the new global initiative in July 2009, to try to ensure that NCDs are urgently accorded greater priority in the health and development policies of poor nations and on global aid agendas [8]. If the framework for the selected chronic NCDs proves useful, it may pave the way for structured approaches to the prevention and management of other chronic NCDs such as chronic kidney disease, chronic liver disease and chronic organic brain syndromes (e.g. the dementias).

Recent estimates and projections have revealed the extent of the global burden of chronic NCDs. The World Health Organization (WHO) predicts a 17% increase in global NCD deaths over the next decade, with the greatest increase in Africa (27%) [8]. In 2007, it was estimated that there were 246 million people living with diabetes mellitus, 6 million new cases and 3.8 million deaths, with 70% of these patients living in the developing world [9]. In 2000, there were an estimated 972 million people with hypertension, 65% of whom lived in the developing world, with the number predicted to grow to 1.5 billion by 2025 [10]. Chronic obstructive pulmonary disease similarly affects large numbers of people with an estimated 300 million living with asthma [11] and 61 million living with chronic airflow obstruction [12], with three-quarters of the patients living in Asia and Africa. The chronic NCD burden is likely to increase further as scaled-up programmes of antiretroviral treatment (ART) of HIVinfected people lead to reduced HIV/AIDS mortality and to possible metabolic side-effects resulting from life-long ART [13].

A worldwide goal for the prevention and control of NCDs has been proposed to complement the Millennium Development Goals, with the accompanying target of an additional 2% per year reduction in death rates attributable to the main chronic diseases (heart disease, stroke, cancer, diabetes, and chronic respiratory diseases) [14]. WHO has developed a global strategy and action plan for the prevention and control of NCDs [8]. This comprehensive multisectoral approach covers the development of national policy frameworks, establishment of programmes, building of capacity for an effective national response, monitoring and evaluation at different levels, and promotion of research, but does not include a framework for action to improve the primary care response to chronic NCDs. Although primary care is the health service entry point for the vast majority of people with NCDs and therefore plays a key role in the delivery of prevention and care interventions [15], the primary care response to common NCDs is often unstructured and inadequate. There is an urgent need for an effective and affordable framework for use and adaptation by countries to improve the delivery of interventions for patients with chronic NCDs by primary care providers, including those in the government services (whether Ministry of Health services or not, e.g., social-security schemes, prisons, military) and non-government services (e.g., non-governmental organisations, and private practitioners). In practice in many developing countries, secondary and tertiary care institutions often also provide primary care.

Chronic NCDs in developing countries have often been neglected despite their huge burden of morbidity and mortality. Efforts to decrease population-level risks for NCDs need to be accompanied by action to improve the delivery of primary care interventions for people with NCDs. We propose a framework for action to ensure an effective and affordable primary care response to chronic NCDs.

Discussion

Rationale for a global framework for action to improve the primary care response to chronic NCDs

Health care delivery systems in developing countries are generally less well oriented towards dealing with chronic NCDs than with infectious diseases. The approach is often unstructured, lacks systematic follow-up and monitoring of chronic clinical care, and provides little information about morbidity or mortality. Moreover, access to essential supplies is often limited and comes at a relatively high cost [16]. This situation is common in developing countries in sub-Saharan Africa [17] and other regions. A lack of quality health information is one of the main obstacles in developing national strategies for an effective response to NCDs [18]. There is a need to document the baseline and future trends in burden of NCDs which may be exacerbated by the effects of globalisation, including global climate change. This information on NCDs is needed for purposes of planning local, national and international responses to changing patterns of disease burden, and monitoring the impact of these responses on disease burden.

Suggested ways to improve the primary health care response to chronic NCDs include: a) the integrated management of chronic NCDs with that of chronic communicable diseases [19], e.g. as demonstrated in Cambodia with HIV, diabetes and hypertension [20]; b) the development of chronic care services that cut across conventional categories of infectious diseases and NCDs [21]; and c) the incorporation of indicators of programme performance and access to services [22]. The standard approach to diagnosis and treatment, and evaluation and reporting of treatment outcomes, which has been a cornerstone of the international strategy to control tuberculosis [23], can be adapted for NCDs -simple systems can be established for monitoring and evaluation of outcomes of patients and of programme performance (through quarterly and cumulative cohort analyses of the numbers of cases registered and their outcomes), as has been shown with the reporting of ART scale-up in Malawi [24]. The importance of this approach to monitoring and evaluation is reflected by Objective 6 of the WHO Action Plan "to monitor noncommunicable diseases and their determinants and evaluate progress..." [8]. The establishment of multidisciplinary chronic disease clinics using standardised approaches to patient management could bring efficiency gains, especially in providing continuity of care [25] (an important element of quality care), long-term adherence support [26] and social support, and may help to decrease the stigma often associated with HIV and tuberculosis. Improvements on the current situation are likely with a programmatic, standardized approach to the delivery of primary care interventions for patients with NCDs, incorporating the above suggestions. The framework for this "public health approach" is designed to improve the management of the vast majority of people with NCDs who can be managed satisfactorily in primary care. The framework also incorporates referral of people with NCDs needing more complex management in secondary or tertiary care. The proposed framework is informed by experience of scaling up interventions for chronic infectious diseases [24]. The lessons learned from progress in rolling out interventions for the diagnosis and treatment of tuberculosis [27] and HIV infection [28] include the importance of gaining political commitment, developing a robust strategy, delivering standardised interventions, ensuring rigorous monitoring and evaluation of progress towards defined targets, and setting ambitious targets which serve as an aspiration for rallying stakeholders in their efforts and helping to increase resources for the global response. The proposed framework for NCDs borrows the same elements as those developed for tuberculosis control [29], comprising a goal, strategy and targets for NCD control, a package of interventions for quality care, key operations for national implementation of these interventions, and indicators to measure progress towards increasing the impact of primary care interventions on chronic NCDs. The generic global framework can be adapted at national level and validated for particular settings, with operational evaluation of feasibility, effectiveness, cost and cost-effectiveness.

A proposed global framework for the primary care response to chronic NCDs Goal

To reduce the burden of morbidity, disability and premature mortality related to NCDs.

Strategy for the primary care contribution to NCD control Among all those seen in primary care, 1) identify and address modifiable risk factors, 2) screen for common NCDs and 3) diagnose, treat, follow-up and when necessary refer patients with common NCDs using standard protocols.

In many countries, a substantial proportion of the population accesses the primary care system each year. Primary care is an important site for chronic disease prevention as well as care, and those accessing primary care represent a target group for delivery of prevention and care interventions. To complement the multisectoral measures aimed at primary prevention of NCDs, everyone seen in primary care should be assessed for common risk factors such as smoking, alcohol and obesity, and counseled on lifestyle modification. Low-cost, rapid and reliable means of screening are available for common NCDs, e.g. hypertension (automatic sphygmomanometer), chronic airflow obstruction (peak expiratory flow meter), diabetes (urine or finger-prick dipsticks) and obesity (weighing scales and height measuring rod to enable calculation of body mass index). A structured approach to delivering quality care for patients with common NCDs involves the use of simple standard protocols for diagnosis, treatment, follow-up and referral. Targets 1. To assess 90% of patients presenting to primary health care facilities for three common modifiable risk factors for NCD -namely, cigarette smoking, alcohol and obesityand to address those risk factors when present.

2. To screen 90% of all patients presenting to primary health care facilities at least once each year for common NCDs using simple tests for hypertension (automatic sphygmomanometer), chronic airflow obstruction (peak expiratory flow meter), diabetes (urine or blood glucose, with proteinuria also detectable by dipstick testing of the urine) and obesity (weight and height).

3. To ensure that 90% of patients diagnosed with hypertension, diabetes, obesity, and chronic airflow obstruction are managed and continue within life-long structured and monitored primary care.

Package of interventions for quality care 1. Political commitment

Chronic diseases require a (chronic) sustained response and political commitment. Sustained government commitment to comprehensive health system strengthening should include commitment to addressing the problem of NCDs. The government has several key roles, including leadership, stewardship, resource mobilisation and allocation, policy development and implementation, and health workforce development.

Case-finding among people attending primary care services

This is a central part of the strategy for the primary care contribution to NCD control. Those accessing primary care represent a target group for delivery of prevention and care interventions. The linked delivery of prevention and care interventions is important: providing care without prevention and vice versa represent missed opportunities.

Standardised diagnostic and treatment protocols

The use of simple standard protocols for diagnosis, treatment, follow-up and, when necessary, referral of patients with common NCDs can ensure a structured approach to delivering quality care. Generic protocols for standard case management, using simple and inexpensive tools and drugs, should be adapted at national level and validated for the particular circumstances in particular settings.

Regular drug supply

A regular supply of essential drugs is necessary for the quality care of people with NCDs, since an individual patient's clinical course will deteriorate if treatment is interrupted.

Systematic monitoring and evaluation

Quarterly and cumulative cohort analyses of the numbers of cases registered and their outcomes are the vital signs of NCD management. Key indicators are: the numbers of patients registered and retained on treatment, and the primary outcomes of alive, dead, stopped treatment, lost to follow-up and transferred to another facility. The number of new cases started on treatment in any given time period represents the new incident cases, and provides a gauge of access to treatment and case detection if the number of expected cases is known or estimated. The cumulative number of patients retained alive and on treatment represents the burden of disease, the data being essential for proper planning of logistics and accurate drug forecasting. Cumulative numbers who have died, have been lost to follow-up or who have stopped treatment provide a measure of programme performance.

Key operations for national implementation of these interventions

1. Political commitment 1.1 Establish an adequately staffed and funded NCDs and health promotion unit within the Ministry of Health, with guidance on evidence-based policy from a National Advisory Committee. Health promotion includes community sensitisation on NCDs.

1.2 Mobilise and coordinate the investment of funds in strengthening the primary care system to enable delivery of quality care for people with NCDs. Areas of investment include human resources, health care infrastructure, secure supply of materials for diagnosis and of drugs, and record-keeping.

1.3 Develop and disseminate a manual for the strengthened primary care response to NCDs, to be used as a policy reference guide and training tool.

2. Case-finding among people attending primary care services 2.1 Train primary care staff to be able to deliver the strategy for the primary care response to NCDs. Staff should take the opportunity when people are seen in primary care to: 1) identify and address modifiable risk factors, 2) screen for common NCDs, and 3) diagnose, treat and fol-low-up patients with common NCDs using standard protocols.

2.2 Ensure the availability of the essential materials for diagnosis, treatment and record-keeping which primary care staff need to deliver the strategy.

3. Standardised diagnostic and treatment protocols 3.1 Develop or apply established simple standard protocols for diagnosis, treatment, follow-up and, when necessary, referral of patients with common NCDs which can ensure a structured approach to delivering quality care.

3.2 Ensure the protocols are validated to reflect the approach which is relevant to those NCDs which are common in a particular country, and updated to reflect changing circumstances.

Regular drug supply

4.1 Strengthen the national system of drug procurement and delivery to ensure regular and reliable delivery of essential drugs to primary care facilities.

4.2 Base the forecasting of drug requirements on the systematic registration of patients and recording and reporting of their outcomes.

4.3

Obtain access to quality-assured, affordable drugs through manufacture of appropriate generic formulations (suitable for storage under local conditions) and pooled procurement mechanisms. The success of the drug supply system established along these lines through the Global Drug Facility for anti-tuberculosis drugs [30] is now being extended to the supply of drugs for chronic respiratory diseases through the Asthma Drug Facility and may be further extended to drugs for other NCDs.

Systematic monitoring and evaluation

5.1 Ensure an efficient system for data collection, entry and management, which enables assessment of clinical progress of individual patients and a comprehensive assessment of the burden of chronic NCDs and its response to health system interventions.

5.2 Design and implement a patient-held record (e.g. "health passport") which indicates the essential information for chronic care -the key clinical findings, main diagnoses, treatments, and appointments for review (including referral) -to complement the recommended record-keeping system for health facilities (as a fail-safe in case the health facility system doesn't work and as an aidememoire for the patient).

5.3

Design and implement a user-friendly and reliable record-keeping system for health facilities, which may be entirely paper-based, paper-based with a computer-based system for data aggregation and cohort reporting, or entirely computer-based. Introduction of robust, easy-touse, touch screen computer systems in primary care facilities could enable rapid and efficient record-keeping by staff, and ready access to data for analysis.

5.4 Use strategic information (obtained from routine recording and reporting) to guide improvement in the quality of patient care at the point of care delivery (as is the case, for example, for the recommended system of routine recording and reporting of patients' response to anti-tuberculosis treatment) [31].

Indicators to measure progress towards increased impact of primary care interventions on chronic NCDs

Proposed indicators that could be used at country level to measure progress in NCD management include: 1) a national NCD policy framework that is available in the Ministry of Health;

2) the number of administrative areas in the country that regularly report on the incidence and prevalence of NCD cases reported in primary care;

3) the number of new incident cases reported in primary care over defined time periods; 4) the number of patients alive and on standardised nationally approved therapy (i.e. prevalence of those receiving care) at defined moments in time.

Next steps

The proposed framework needs to be evaluated and implementation priorities determined in different settings according to the prevailing NCD epidemiology. A programme of health system research is urgently needed to establish the feasibility of implementation, and its cost, cost-effectiveness and acceptability [32]. Such research is responsive to the needs of developing countries [33], and is in line with that proposed by the representatives of health policy and research agencies who developed the "Grand challenges in chronic non-communicable diseases" [34]. Research on local implementation, e.g. at district level, is necessary to support effective national scaleup [35]. The approach in a particular setting depends on assessment of the local health structure, e.g. regarding the role of district hospitals in supporting local primary care facilities, and of human resources. A research approach of "learning by doing" will help to address the many practical issues concerning the required human and infrastructure resources, especially in handling increased NCD casefinding, and the acceptability and logistics of providing integrated care, e.g. clinics for chronic NCDs and chronic infectious diseases. In addition to the information generated by the proposed framework on NCDs among people accessing primary care, NCD epidemiological surveillance is needed to establish the population-level burden of NCDs and assess the proportion of cases detected and managed by the health system.

The Director-General of WHO has recently highlighted the importance of strengthened health systems based on primary care as "the route to greater efficiency and fairness in health care and greater security in the health sector and beyond" [36]. This vision of primary care must encompass improved delivery of interventions for the many people with NCDs seen in primary care. Providing affordable and effective primary care to the often large and increasing numbers of people with NCDs in developing countries will be an immense challenge. The scale of this challenge should be taken not as discouragement, but as a reason for action, in mobilising the wide range of stakeholders involved, finding the resources, and taking the necessary steps to meet the challenge. Implementation of the framework should capitalise on synergies with other disease control efforts in addressing the necessary human and infrastructure resources required to provide quality care, as part of strengthening health systems. Set against the cost of action, the cost of inaction on NCDs is measured in terms of the human toll of illness, disability and death, and the economic toll of lost productivity and development potential.

Summary

• In many developing countries the current approach to delivery of primary care interventions for people with chronic NCDs is often unstructured and inadequate.

• Informed by lessons learned from progress in scaling up interventions for tuberculosis and HIV, a framework for a "public health approach" has the potential to provide an effective and affordable solution to this neglected problem.

• The elements of the proposed framework for NCDs comprise a goal, strategy and targets, a package of interventions for quality care, key operations for national implementation of these interventions, and indicators to measure progress towards increasing the impact of primary care interventions on chronic NCDs.

• If implementation of the proposed framework is found to be feasible, effective and cost-effective, international support can be mobilised to extend the benefit of this approach to the millions of people worldwide with chronic NCDs.
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Competing interestsThe authors declare that they have no competing interests.Authors' contributionsDM had the idea for the paper and drafted the manuscript. AH, RZ and DE helped to develop the idea and to draft the manuscript. All authors read and approved the final manuscript.Pre-publication historyThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/9/355/pre pub
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Grand challenges in chronic non-communicable diseases. A S Daar, P A Singer, D L Persad, S K Pramming, D R Matthews, R Beaglehole, A Bernstein, L K Borysiewicz, S Colagiuri, N Ganguly, R I Glass, D T Finegood, J Koplan, E G Nabel, G Sarna, N Sarrafzadegan, R Smith, D Yach, J Bell, Nature. 450Daar AS, Singer PA, Persad DL, Pramming SK, Matthews DR, Beagle- hole R, Bernstein A, Borysiewicz LK, Colagiuri S, Ganguly N, Glass RI, Finegood DT, Koplan J, Nabel EG, Sarna G, Sarrafzadegan N, Smith R, Yach D, Bell J: Grand challenges in chronic non-communicable diseases. Nature 2007, 450:494-6.

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Primary health care as a route to health security. M Chan, Lancet. 373Chan M: Primary health care as a route to health security. Lancet 2009, 373:1586-7.


Equal contributors

Jiayu Hu
Shanghai Centers for Disease Control and Prevention
1380 Zhongshan West Road200336ShanghaiChina

†
Xiaodong Sun
Shanghai Centers for Disease Control and Prevention
1380 Zhongshan West Road200336ShanghaiChina

†
Zhuoying Huang
Shanghai Centers for Disease Control and Prevention
1380 Zhongshan West Road200336ShanghaiChina

Abram L Wagner
Department of Epidemiology
University of Michigan
1415 Washington Heights

SPH II
48109Ann ArborMIUSA

Bradley Carlson
Department of Epidemiology
University of Michigan
1415 Washington Heights

SPH II
48109Ann ArborMIUSA

Jianping Yang
Shanghai Centers for Disease Control and Prevention
1380 Zhongshan West Road200336ShanghaiChina

Suwen Tang
Shanghai Centers for Disease Control and Prevention
1380 Zhongshan West Road200336ShanghaiChina

Yunyi Li
Shanghai Centers for Disease Control and Prevention
1380 Zhongshan West Road200336ShanghaiChina

Matthew L Boulton email@example.com
Department of Epidemiology
University of Michigan
1415 Washington Heights

SPH II
48109Ann ArborMIUSA

Zhengan Yuan email@example.com†
Shanghai Centers for Disease Control and Prevention
1380 Zhongshan West Road200336ShanghaiChina

Equal contributors
10.1186/s12879-016-1485-3R E S E A R C H A R T I C L E Open Access Streptococcus pneumoniae and Haemophilus influenzae type b carriage in Chinese children aged 12-18 months in Shanghai, China: a cross-sectional study * Correspondence:Streptococcus pneumoniaeHaemophilus influenzae type bSeroprevalenceAntimicrobial susceptibilityChina
Background: The bacteria Streptococcus pneumoniae (pneumococcus) and Haemophilus influenzae type b (Hib) are leading causes of childhood pneumonia and meningitis and are major contributors to worldwide mortality in children younger than 5 years of age. Asymptomatic nasopharyngeal carriage of pneumococcus and Hib was determined for healthy children in Shanghai in 2009. Methods: Children from 5 immunization clinics were enrolled in this study. Specimens from the nasopharynx were collected and cultured in Columbia and chocolate agar to identify pneumococcal and Hib carriage. Pneumococcal specimens were serotyped with the Neufeld test, and antibiotic resistance for pneumococcal and Hib specimens used the E-test method. Significance of risk factors for carriage was assessed through chi-square tests. Results: Among 614 children, 16.6 % had pneumococcal carriage and 8.0 % Hib carriage. The predominant serotype of pneumococcus that was isolated was 19 F (52.9 %); serotype coverage was 68.6 % for both 7-valent pneumococcal conjugate vaccine (PCV) and PCV-10, and 82.3 % for PCV-13. Household residency and father's education were both significantly related to pneumococcal and Hib carriage. The majority of S. pneumoniae isolates were sensitive to most antimicrobials but there were high levels of resistance to azithromycin (51.0 %) and erythromycin (51.0 %). Haemophilus influenzae isolates were sensitive to almost all antimicrobials tested although 12.2 % of isolates were resistant to ampicillin. Conclusions: The pneumococcal and Hib vaccines require payment, and the children with the highest burden of disease may not be receiving these vaccines. Moreover, the presence of high antibiotic susceptibility towards pneumococcus, and to a lesser extent towards Hib, underscores the need for preventive protection against these diseases. Public funding of pneumococcal and Hib vaccines would be one mechanism to increase uptake of these vaccines.

Background

The bacteria Streptococcus pneumoniae (pneumococcus) and Haemophilus influenzae type b (Hib) are leading causes of childhood pneumonia and meningitis and are major contributors to worldwide mortality in children younger than 5 years of age. In 2011, an estimated 411,000 deaths occurred worldwide due to pneumococcal pneumonia and 197,000 due to Hib pneumonia [1]. In China, it is estimated that there are 261,000 cases and 11,000 deaths each year in children under 5 years of age due to pneumococcal pneumonia and meningitis [2], and 19,000 childhood deaths result from Hib infection [3].

Pneumococcus and Hib colonize the upper airways. Asymptomatic carriers can still transmit to other individuals, with disease resulting if the pathogens descend the airway into the lower respiratory tract [4,5]. Over 90 different serotypes of pneumococcus have been found, and vaccinations need to strike a reasonable balance between the financial cost against the value of including more serotypes known to cause disease [6]. In contrast to the serotypic diversity with pneumococcus, Hib is a much more predominant cause of disease than non-type b H. influenzae [7].

The Hib conjugate vaccine has been available since 1987 in the US [7] and 2000 in China [8], and a pneumococcal conjugate vaccine (PCV) was licensed in the US in 2000 [9] and introduced to China in 2008 [10], although it was taken off the market in China in 2014 [11]. Neither the Hib vaccine nor PCV are included on the publically-funded Expanded Program on Immunization (EPI) in China, but they are available at immunization clinics for a fee. The Hib vaccine costs $13-$17 whereas PCV is much more expensive ($127) [10]. As a result coverage of Hib vaccine is much higher than PCV (50.9 % versus 11.4 % in Shanghai); moreover, although infants as young as 6 weeks are eligible for Hib vaccine and PCV administration, vaccination is typically delayed until after 1 year of age. Coverage at 12 months is around 20 % for Hib vaccine and <5 % for PCV and at 24 months, coverage is approximately 40 % for Hib vaccine and 5 % for PCV [12].

The first PCV protected against 7 serotypes of pneumococcus (PCV-7), but more recently, 10-valent (PCV-10) and 13-valent (PCV-13) vaccines have been licensed [6], and a 15-valent vaccine (PCV-15) is under development [13]. The World Health Organization (WHO) recommends that countries choose a PCV depending on the distribution of serotypes within their population, along with vaccine supply and costeffectiveness considerations [6]. Two studies in China have previously evaluated the coverage between PCVs and serotypes in the population. A study of clinical isolates from 8 cities in China during 2005 and 2006 found coverage of PCV-7 was 62.6 %, PCV-10 was 64.8 %, and PCV-13 was 79.6 % [14]. Similarly, a study of clinical isolates from 2006 to 2008 found coverage of 60.3, 66.7 and 87.8 % for the 3 vaccines, respectively [15]. Because the distribution of pneumococcal serotypes may vary geographically, however, these findings may not be representative of potential coverage from vaccines in all areas.

Few studies have been published from China in the English literature looking at Hib and pneumococcal carriage. This information is important for modeling the burden of disease and underscoring the importance of vaccination, particularly in a country with low coverage of Hib and pneumococcal vaccines but with widespread resistance to antibiotics [16,17]. In this study, we calculate the prevalence of nasopharyngeal carriage of Hib and pneumococcus (including specific pneumococcal serotypes), describe the prevalence of antimicrobial resistance in children with carriage, and examine risk factors for nasopharyngeal colonization with pneumococcus or Hib.

Methods

In 2009, April and May for spring, October and November for autumn, healthy children aged 12-18 months were recruited from a total of 5 immunization clinics in Shanghai. We purposely sampled in both the spring and autumn in order to determine if there was a seasonal fluctuation in carriage (although this has not been borne out in previous studies in the UK [18] or Italy [19]). These clinics purposefully selected from 3 districts (Huangpu, Xuhui, and Pudong) to represent different areas of the city. For 1 or 2 days, research staff from the municipal Centers for Disease Control and Prevention (CDC) and district CDCs attended these clinics, and enrolled children between 12 and 18 months who attended the clinic on those days. Children were excluded for the following reasons: 1) antibiotic use within 15 days of enrollment; 2) congenital anomalies of the nasopharynx; 3) existence of a long-term infectious disease (such as chronic otitis media, or chronic sinusitis); 4) previous immunization for pneumococcal disease; 5) coagolopathy; or 6) body temperature over 38°C at time of enrollment.

Parents of the children were asked about their residency status (local or Shanghai residency vs non-local residency), their household monthly income, daycare attendance, household size, number of children, highest educational level attainment of father and mother, smoking in the household,, if child was breastfed, child history of serious disease, and number of doses of Hib vaccine the child had received.

Research staff obtained a nasopharyngeal sample using one infant-sized calcium alginate swab (Thermo Fisher Scientific, Hampton, NH, USA) for each child. These specimens were streaked on Columbia agar and chocolate agar immediately upon collection, then transported in 12 h to the Shanghai Municipal CDC for culturing and preliminary pathogen identification. The swabs were streaked directly onto the plates. Positive isolates were stored at −70°C, then transported to a centralized laboratory in Beijing for pathogen confirmation, pneumococcal serotyping, and antibiotic resistance testing. The site of specimen collection (nasopharynx), swab material (calcium alginate fiber), storage temperature (−70°C), and choice of agar (5 % sheep blood) followed standard methods [20].

Isolate confirmation

The specimens streaked on the Columbia and chocolate agar were incubated at 37°C in 5 % CO 2 -enriched atmosphere for 24-48 h. Identification of pneumococcal colonies was based on the following conventional microbiological methods: colony morphology, growth on Columbia agar, susceptibility to optochin, and bile solubility. Colony morphology, growth on chocolate agar, and the X + V factor were requirements for identification of H. influenzae colonies. For both pneumococcus and Hib, a diameter in the inhibition zone >7 mm was recorded as a positive result. S. pneumoniae isolates were serotyped by the Neufeld (Quellung) reaction, by inoculating a broth with culture from the agar plate, and then mixing a selection from the broth with antiserum and determining if a reaction occurred.

Antimicrobial susceptibility tests

Minimum inhibitory concentrations (MICs) of antimicrobial agents were determined by E-test method. The pneumococcal and Hib isolates were tested for susceptibility to azithromycin, cefuroxime, ceftriaxone, levofloxacin, and moxifloxacin. Pneumococcal isolates were additionally tested for resistance to amoxicillin/clavulanic acid, erythromycin, and penicillin. H. influenzae isolates were tested for susceptibility to ampicillin. Standard references were included for quality control.

Statistical analysis

Descriptive statistics were used to illustrate the prevalence of Hib and pneumococcal carriage, antibiotic resistance, S. pneumoniae serotypes, season of enrollment, and other demographic characteristics of the enrolled children. For bivariate analyses, the Pearson chi-square test was used to test the association between dichotomous demographic factors and 1) carriage of S. pneumoniae and 2) carriage of Hib. The Cochran-Armitage Trend Test was used to compute P-values for ordinal variables (age of child, age of mother at childbirth, urbanicity, household income, size of house, mother's education, father's education, feeding pattern, and Hib vaccine history). Exact tests were used if any cell counts were ≤5. Correction for multiple testing was done through the sequential Holm-Bonferroni Method.

For the multivariable analysis, the explanatory variables input into the logistic regression model were either related due to (1) a priori considerations (age of child), (2) selection criteria (season, urbanicity), or (3) variables found to be significant (P-value <0.05) in the bivariate analysis. Mother's education level and father's education level were not placed in the same model together because of concerns about multicollinearity. Analyses were performed in SAS version 9.3 (SAS Institute, Inc, Cary, NC, USA). P-value correction for multiple testing was computed in R version 3.0.3 (R Foundation for Statistical Computing, Vienna, Austria).

Results

In this study, 6 parents refused to participate, leaving a total of 614 children aged 12 to 18 months enrolled: 308 in the spring and 306 in the autumn. Table 1 highlights the demographic and carrier state risk factors; 338 were male, and 160 were local residents, whereas 454 were non-local children whose family had relocated to Shanghai from another province. Children with PCV already administered were excluded from participating in the study, but 80.7 % of children had received at least one dose of Hib vaccine. No child in the study attended a daycare.

Overall, 137 (22.3 %) of participants were carriers of one or more pathogen. More children were carriers of pneumococcus (16.6 %) than Hib (8.0 %). Household residency and father's education were the two significant risk factors for pneumococcal carriage: more non-locals (20.0 %) than locals (6.9 %) were carriers (P = 0.0009), and children having a father with less education were more likely to be carriers (P = 0.0406). For Hib carriage, in addition to household residency and father's education, urbanicity, household income, size of house, and mother's education were significant risk factors. Urban dwellers had lower carriage (5.9 %) than those in suburban (9.5 %) or rural areas (18.2 %) (P = 0.0077), and having greater income and a larger house were protective against Hib carriage. Hib vaccination was not associated Hib carriage status (P = 0.3392).

The most common pneumococcal serotype was 19 F, which was in 54 children. In descending order of prevalence, the other isolated serotypes present in the sample were 19A (n = 8), 6A (n = 6), 6B (n = 5), 6A/6B crossreactive (n = 5), 23 F (n = 4), 15 (n = 4), 14 (n = 2), and 1 each for 17 and 22Twelve specimens were untypeable. The prevalences we found correspond to a coverage of 68.6 % (70) for PCV-7 and PCV-10, 82.3 % (84) for PCV-13, and 83.3 % (85) for PCV-15.  Table 2 shows the frequency of antimicrobial resistance for each pathogen. All 102 pneumococcal isolates were sensitive to levofloxacin and moxifloxacin. Highest levels of resistance were to azithromycin (51.0 %) and erythromycin (51.0 %). Most Hib isolates were sensitive to all antibiotics, except 12.2 % were resistant to ampicillin.

Results of a multivariable analysis are shown in Table 3. Pneumococcal carriage was significantly lower in the spring compared to autumn (odds ratio (OR) = 0.46, 95 % confidence interval (CI) = 0.27, 0.78). Locals had 0.30 times the odds of pneumococcal carriage compared to non-locals (95 % CI = 0.13, 0.69). No significant predictors of Hib carriage were found; a more parsimonious model of Hib carriage, only including the covariates from the pneumococcal carriage model, also revealed no statistically significant predictors (results not shown).

Discussion

In a study of a group of otherwise healthy children 12-18 months of age attending immunization clinics in Shanghai, we found a substantial number had asymptomatic nasopharyngeal colonization with either pneumococcus (16.6 %) or Hib (8.0 %). Carriage of Haemophilus influenzae type b in Shanghai was higher compared to concurrent studies taking place in Dongguan and Beijing [21,22]. Pneumococcal carriage was lower in this study than that in Dongguan [21], but higher than that in Beijing [22]. The rate of pneumococcal carriage we found is slightly lower than what has been found in the United States (29 %) and Australia (26 %) prior to widespread pneumococcal vaccination [23,24], and it is much lower than what has been found in other developing countries before vaccination introduction; for example almost all infants are colonized with pneumococcus in Papua New Guinea and The Gambia [25]. Low carriage of these pathogens among persons in Shanghai may result from high levels of antibiotic overuse [16], and Hib carriage might be lower than pneumococcal carriage because children with a history of PCV administration were excluded, whereas most children in the study had received at least one dose of Hib vaccine. There may be a substantial reduction in carriage due to Hib vaccine coverage in the population; a study in The Gambia found nasopharyngeal carriage decreased from 12 to 0.5 % after the Hib vaccine was introduced [26]. It has been hypothesized that crowding, having more children in the family, and exposure to smoking are reasons why carriage is higher in developing countries than developed countries [25]. We found an inverse association between household size and Hib (but not pneumococcal) carriage, and carriage was higher (but not significantly so) for children with siblings compared to single children, indicating possible effects from human crowding. However, families in this study showed similar characteristics to families throughout China-they had Approximately two-thirds of the pneumococcal isolates identified are included in the current PCV-7 formulation, and there is increased coverage, to about fourfifths, with PCV-13. In contrast, the additional serotypes in PCV-10 and PCV-15, which build upon PCV-7 and PCV-13, respectively, do not appear to be highly prevalent in Shanghai children. This suggests that PCV-13 is an appropriately comprehensive vaccine for use in Shanghai.

Antibiotic resistance tests are important to ensure that the clinical treatment is effective. We encountered high resistance to erythromycin and azithromycin among pneumococcal isolates in this study, and previous studies have even higher levels of antibiotic resistance to erythromycin and penicillin [27]. Antibiotic resistance in the Hib isolates was lower than in the pneumococcal isolates, but the relatively high resistance rate for Hib (12.2 %) is concerning. Hib and pneumococcus can cause a similar spectrum of invasive disease-pneumonia, meningitis, or septicemia; and doctors in China often do not identify the causative agent of disease or assess for antimicrobial susceptibility before prescribing a course of treatment. High antibiotic resistance in the population can therefore prevent a child from receiving an effective treatment. As Hib and pneumococcal vaccination coverage increases in China, sustained laboratory investigations of antibiotic resistance will be necessary to ensure that the standard of care for invasive disease is effective. Because penicillin sensitivity was still quite high in this population, it may be the antibiotic of choice for physicians in Shanghai treating pneumococcal disease.

This study has several limitations. We collected specimens from asymptomatic children, and, theoretically, the pneumococcal serotypes in healthy children may differ from those with invasive pneumococcal disease. However, previous studies in China have found some concordance between the serotype distribution in invasive and noninvasive cases [14]. We also did not test an individual child for multiple carriage of pneumococcal serotypes, although previous studies have found a large proportion of children may be colonized in this manner [28]. Additionally, our small sample size may limit our ability to identify important risk factors for pneumococcal and Hib colonization. Lastly, it is difficult to compare the distribution of risk factors for Hib carriage to those for pneumococcal carriage because we did not exclude participants based on Hib vaccination, and Hib vaccine coverage may be high enough in Shanghai to effectively lower Hib carriage [26].

Conclusions

We found a substantial proportion of children with asymptomatic pneumococcal and Hib colonization. In recent years, there have been for-fee vaccines available in China to protect against pneumococcal and Hib disease. Because carriage of these bacteria was higher in more disadvantaged children, indicating a higher burden of disease in these children, these vaccines may not be reaching the children who have the highest burden of disease. Moreover, the presence of high antibiotic susceptibility towards pneumococcus, and to a lesser extent towards Hib, underscores the need for preventive protection against these diseases. Public funding of pneumococcal and Hib vaccines would be one mechanism to increase uptake of these vaccines.

Ethics approval and consent to participate

The Shanghai CDC Ethics Committee approved this study. Informed consent was obtained from each child's parents prior to participation.

Table 1
1Prevalence of nasopharyngeal carriage of pneumococcus and Haemophilus influenzae type b (Hib) and demographic and medical correlates among children inShanghai, 2009    Count
Pneumococcal carriage (%)
P-value a
Hib carriage (%)
P-value a

Overall
614
102 (16.6 %)
49 (8.0 %)

Season of enrollment
0.0780
1.0000

Autumn
306
38 (12.4 %)
23 (7.5 %)

Spring
308
64 (20.8 %)
26 (8.4 %)

Sex
1.0000
1.0000

Male
338
60 (17.8 %)
30 (8.9 %)

Female
276
42 (15.2 %)
19 (6.9 %)

Age of child
0.1530
1.0000

12 months
170
35 (20.6 %)
14 (8.2 %)

13-14 months
184
35 (19.0 %)
16 (8.7 %)

15-16 months
158
20 (12.7 %)
12 (7.6 %)

17-18 months
102
12 (11.8 %)
7 (6.9 %)

Age of mother at childbirth
0.3984
1.0000

18-24 years
179
35 (19.6 %)
18 (10.1 %)

25-29 years
257
44 (17.1 %)
18 (7.0 %)

30-34 years
123
18 (14.6 %)
9 (7.3 %)

35-44 years
55
5 (9.1 %)
4 (7.3 %)

Household residency
0.0009
0.0008

Local
160
11 (6.9 %)
2 (1.3 %)

Non-local
454
91 (20.0 %)
47 (10.4 %)

Urbanicity
0.1530
0.0077

Urban
422
62 (14.7 %)
25 (5.9 %)

Suburban
126
22 (17.5 %)
12 (9.5 %)

Rural
66
18 (27.3 %)
12 (18.2 %)

Household income
0.1166
0.0490

<2000 yuan ($292)
232
47 (20.3 %)
26 (11.2 %)

2000-4999 yuan ($292-$730)
286
47 (16.4 %)
21 (7.3 %)

≥5000 yuan ($731)
96
8 (8.3 %)
2 (2.1 %)

Size of house
0.2163
0.0008

<18 m 2
145
32 (22.1 %)
17 (11.7 %)

18-29 m 2
120
20 (16.7 %)
19 (15.8 %)

30-69 m 2
156
25 (16.0 %)
8 (5.1 %)

≥70 m 2
193
25 (13.0 %)
5 (2.6 %)

Siblings
0.1530
0.0999

No
407
57 (14.0 %)
24 (5.9 %)

Yes
207
45 (21.7 %)
25 (12.1 %)

Mother's education
0.0650
0.0008

Primary school or less
73
18 (24.7 %)
9 (12.3 %)

Junior high
286
54 (18.9 %)
32 (11.2 %)

High school/vocational
134
16 (11.9 %)
8 (6.0 %)

College or more
121
14 (11.6 %)
0 (0.0 %)

Table 1
1Prevalence of nasopharyngeal carriage of pneumococcus and Haemophilus influenzae type b (Hib) and demographic and medical correlates among children in Shanghai, 2009 (Continued) Hib vaccine history, which were from Cochran-Armitage Trend Test. Exact tests were used if cell counts were ≤5. P-values were corrected for multiple testing through the sequential Holm-Bonferroni MethodFather's education

Table 2
2Antibiotic Resistance among S. pneumoniae, and H. Influenzae type b isolates in 614 Shanghai children, 2009Antibiotic
S. pneumoniae (n = 102)
H. influenzae type b (n = 49)

Sensitive
Intermediary
Resistant
Sensitive
Intermediary
Resistant

Amoxicillin/Clavulanic Acid
96 (94.1 %)
5 (4.

Table 3
3Odds ratios and 95 % confidence intervals for risk factors of nasopharyngeal carriage of pneumococcus or Haemophilus influenzae type b (Hib) among 614 children in Shanghai, 2009 community daycare facilities. Accordingly, risk factors (like large families and daycare use) common in other places throughout the world may have a low prevalence in China and may not be as important for describing the overall distribution of nasopharyngeal carriage in the population.Pneumococcal carriage
P-value a
Hib carriage
P-value a

Spring vs autumn
0.46 (0.27, 0.78)
0.0044
0.78 (0.37, 1.64)
0.5166

Age of child
0.4703
0.9533

12 months
1.46 (0.69, 3.09)
0.95 (0.34, 2.65)

13-14 months
1.34 (0.64, 2.84)
1.08 (0.39, 2.94)

15-16 months
0.94 (0.42, 2.09)
1.21 (0.43, 3.40)

17-18 months
ref
ref

Local vs non-local residency
0.30 (0.13, 0.69)
0.0048
0.45 (0.09, 2.32)
0.3388

Urbanicity
0.1773
0.1067

Urban
0.66 (0.34, 1.25)
0.43 (0.19, 0.97)

Suburban
1.06 (0.46, 2.44)
0.63 (0.21, 1.85)

Rural
ref
ref

Father's education
0.4037
0.4163

Primary school or less
0.79 (0.21, 2.90)
8.53 (0.70, 103.52)

Junior high
1.10 (0.52, 2.34)
5.61 (0.60, 52.28)

High school/vocational
0.66 (0.29, 1.52)
5.29 (0.58, 48.43)

College or more
ref
ref

Household income
0.5869

<2000 yuan
2.21 (0.48, 10.18)

2000-4999 yuan
2.19 (0.47, 10.18)

≥5000 yuan
ref

Size of house
0.1010

<18 m 2
2.06 (0.67, 6.32)

18-29 m 2
2.96 (0.99, 8.85)

30-69 m 2
1.17 (0.35, 3.88)

≥70 m 2
ref

≥1 dose Hib vaccine vs no doses
0.55 (0.24, 1.27)
0.1607

a P-value from Wald Chi-square test of Type 3 Analysis

AcknowledgementsWe appreciate the work of the research staff who contributed time and effort to this project.Consent for publicationNot applicable.Availability of data and materialsPlease contact the corresponding author for details about the data. Data access is subject to approval from the Shanghai CDC.Competing interestsThe authors declare that they have no competing interests.Authors' contributions JH contributed to the conception and design of study, and acquisition of data. XS contributed to analysis of data, interpretation of results, and critically reviewed and revised the manuscript. ZH acquired data, analyzed and cleaned the data, interpreted results, and drafted the manuscript. AW analyzed the data, contributed to interpretation of results, and drafted the manuscript. BC contributed to interpretation of results, and critical review of the manuscript. JY participated in collection and management of data. ST was responsible for experiments and data analysis. YL participated in experiments, and data analysis. MB contributed to interpretation of results ad critical review of the manuscript. ZY contributed to conception and design of study, and critical review of the manuscript. All authors read and approved the final manuscript. Submit your next manuscript to BioMed Central and we will help you at every step:
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