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Research priorities for the primordial prevention of acute rheumatic fever and rheumatic heart disease by modifying the social determinants of health
  1. Michael G Baker1,
  2. Mary Y Masterson2,
  3. Maylene Shung-King3,
  4. Andrea Beaton4,5,
  5. Asha C Bowen6,7,
  6. Geetha P Bansal8,
  7. Jonathan R Carapetis6,7
  1. 1Public Health, University of Otago Wellington, Wellington, New Zealand
  2. 2Center for Translation Research and Implementation Science (CTRIS), National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
  3. 3Health Policy and Systems Division, School of Public Health, University of Cape Town, Rondebosch, Western Cape, South Africa
  4. 4Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  5. 5Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
  6. 6Department of Infectious Diseases, Perth Children's Hospital, Nedlands, Western Australia, Australia
  7. 7Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, University of Western Australia, Nedlands, Western Australia, Australia
  8. 8HIV Research and Training Program, John E Fogarty International Center, Bethesda, Maryland, USA
  1. Correspondence to Professor Michael G Baker; michael.baker{at}otago.ac.nz

Abstract

The social determinants of health (SDH), such as access to income, education, housing and healthcare, strongly shape the occurrence of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) at the household, community and national levels. The SDH are systemic factors that privilege some more than others and result in poverty and inequitable access to resources to support health and well-being. Primordial prevention is the modification of SDH to improve health and reduce the risk of disease acquisition and the subsequent progression to RHD. Modifying these determinants using primordial prevention strategies can reduce the risk of exposure to Group A Streptococcus, a causative agent of throat and skin infections, thereby lowering the risk of initiating ARF and its subsequent progression to RHD.

This report summarises the findings of the Primordial Prevention Working Group-SDH, which was convened in November 2021 by the National Heart, Lung, and Blood Institute to assess how SDH influence the risk of developing RHD. Working group members identified a series of knowledge gaps and proposed research priorities, while recognising that community engagement and partnerships with those with lived experience will be integral to the success of these activities. Specifically, members emphasised the need for: (1) global analysis of disease incidence, prevalence and SDH characteristics concurrently to inform policy and interventions, (2) global assessment of legacy primordial prevention programmes to help inform the co-design of interventions alongside affected communities, (3) research to develop, implement and evaluate scalable primordial prevention interventions in diverse settings and (4) research to improve access to and equity of services across the RHD continuum. Addressing SDH, through the implementation of primordial prevention strategies, could have broader implications, not only improving RHD-related health outcomes but also impacting other neglected diseases in low-resource settings.

  • Prevention strategies
  • Review
  • Public Health
  • Cardiovascular disease
  • Treatment

Data availability statement

There are no data in this work.

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Summary box

  • Social determinants of health (SDH) impact all facets of the rheumatic heart disease (RHD) continuum from primordial prevention, through the initial diagnosis/treatment of Group A Streptococcus (primary prevention), to the screening/treatment of acute rheumatic fever (ARF) (secondary prevention) and the long-term care and management of RHD (tertiary care).

  • Declines in ARF and RHD have been observed across many high-income countries (HICs) during the 20th century due in large part to improvements to SDH. Similar trends have not been seen in low- and middle-income countries, or impoverished populations in HICs.

  • There is a need for global analysis of disease incidence, prevalence and SDH characteristics concurrently to inform policy and interventions for RHD. Also to learn from legacy primordial prevention programmes for RHD developed in partnerships with affected communities.

  • There is a need to co-design, implement and evaluate scalable primordial prevention interventions for ARF and RHD alongside affected communities in diverse settings. Also to examine access to services across the care continuum from ARF to RHD to help guide improved equity of care and outcomes.

Introduction

Rheumatic heart disease (RHD), a neglected, preventable cardiovascular illness, is characterised by permanent valvular heart damage with high morbidity and mortality if left untreated.1 RHD is preceded by one or more episodes of acute rheumatic fever (ARF), an immune-mediated illness that follows Group A Streptococcus (GAS) infections of the throat or skin. ARF typically occurs in children and adolescents (aged 5–15).2 In 2019, the Global Burden of Disease Study estimated that there were 2.8 (2.2–3.5) million new cases of RHD annually, with 40.5 (32.1–50.1) million total cases, leading to 310 000 deaths, the vast majority occurring in low and middle-income countries (LMICs).3 While there was a decline in RHD deaths and lost disability-adjusted life years (DALYs) from 1990 to 2019,4 the burden of disease remains substantial, suggesting that considerable effort should be applied to the prevention and control of this disease.

The social determinants of health (SDH) fundamentally impact the incidence and distribution of GAS, ARF and RHD.5 6 The WHO defines SDH as ‘…the non-medical factors that influence health outcomes. They are the conditions in which people are born, grow, work, live and age, and the wider set of forces and systems shaping the conditions of daily life’.7 These factors include income, employment, social protection, education, food security, housing and amenities, the quality of the physical environment, and access to appropriate, affordable, adequate and effective health services.

SDH impact all facets of the RHD continuum from primordial prevention, through the initial diagnosis/treatment of GAS (primary prevention), to the screening/treatment of ARF (secondary prevention) and the long-term care and management of RHD (tertiary care) (figure 1). Primordial prevention is defined as the modification of SDH to improve health and reduce the risk of disease acquisition and the subsequent progression to RHD. These modifications can include broad SDH such as income and education, as well as more proximal factors such as the level of social contacts, housing conditions, overall health status, health literacy and access to healthcare services.

Figure 1

Hypothesised pathways by which SDH influence the risk of GAS exposure and progression to ARF and RHD, adapted from Baker et al.6 ARF, acute rheumatic fever; GAS, Group A Streptococcus; RHD, rheumatic heart disease.

Over the past century, high-income countries (HICs) and some LMICs have significantly reduced RHD incidence,8 partially attributable to improved economic stability9 and directed interventions.10 11 However, RHD remains a persistent public health problem in many LMICs as well as in some populations in HICs, all of which are characterised by health inequities, poverty and social disadvantage. This pattern suggests that SDH are a major driver of RHD persistence.

In 2021, the National Heart, Lung, and Blood Institute invited global experts to discuss issues related to RHD elimination. In this report, the Primordial Prevention Working Group-SDH (PPWG-SDH) was charged with evaluating the current state of SDH research and identifying a list of opportunities that could address research gaps within this space. Note that in a companion article, the PPGW-vaccine group discusses vaccine development efforts. Access to vaccination is one of the United Nations Sustainable Development Goals (SDGs).12 Assuming an effective GAS vaccine becomes available, it will be important to distribute it equitably to those most in need.

A fundamental question asked by the PPWG-SDH is whether the current literature supporting specific modifiable SDH interventions is generalisable to different resource settings. The role and contribution of specific SDH will likely vary across these different contexts. Methods used to deliver interventions are also likely to differ considerably for HICs with pockets of RHD compared with LMICs with more widespread RHD and limited resources. Therefore, it was essential also to examine potential micro-level directed small-scale interventions versus macro-level interventions, which require structured collaborations with government and non-government entities to be used in diverse settings. Collaboration with community partners and policymakers will be essential to ensure strategies are feasible, acceptable and sustainable within affected populations.

The PPWG-SDH’s findings can be summarised around four topics for researching this disease (GAS/ARF/RHD), which are further described below.

  1. Global analysis of disease incidence, prevalence and SDH characteristics to inform policy and interventions.

  2. Global assessment and learning from the legacy primordial prevention programmes developed in partnerships with affected communities.

  3. Research to develop and implement scalable primordial prevention interventions in diverse settings.

  4. Research to guide improved access to and equity of services across the RHD continuum.

Key research topic 1: global analysis of disease incidence, prevalence and SDH characteristics to inform policy and interventions

Major social determinants such as income, employment and education strongly influence exposure pathways that alter the risk of acquiring GAS and subsequently developing ARF or RHD (figure 1). The most extensive evidence of the impact of major social determinants is arguably from the decline in ARF/RHD observed across many HICs during the 20th century as economic development lifted populations out of poverty.5 8 13 During 1990–2019, the distribution of RHD varied markedly across the globe. In some LMICs, RHD risk is widespread, with only pockets of the population protected from infection.3 At the other extreme are HICs, where RHD has largely disappeared.9 However, in some HICs, while the risk is generally low, RHD remains a health problem for small groups living in relative poverty and/or facing health disparities due to systemic inequities.14–17 Within such countries, disease risk differs, depending on the level of economic deprivation seen at the community level.16 18 Beyond such deprivation there are also marked differences in risk across ethnic groups, which may reflect multiple intergenerational factors such as the enduring impact of systemic racism, colonisation and inherited genetic factors resulting in a family history of RHD.16 Primordial factors and their contribution to continued RHD incidences are thus complex and multilayered, and despite years of research in this area, they are still not fully understood.

To further understand the interplay of SDH with disease incidence and prevalence, the PPWG-SDH identified the following priorities:

  1. Develop internationally comparable surveillance and screening strategies for GAS, ARF and RHD in partnership with affected communities through the establishment of sentinel surveillance sites/networks.

  2. Assess and map the distribution of GAS infection, ARF incidence and RHD prevalence in countries and geographical regions in relation to SDH (notably income, employment, education, housing, healthcare), particularly in LMICs to learn from their experience.19

  3. Identify differences in GAS/ARF/RHD occurrence by population group, including the association with SDH and inherited and intergenerational factors (eg, genetics, family history, effects of colonisation, systemic racism).

  4. Determine how policy changes and multidisciplinary efforts have resulted in meaningful improvements in socioeconomic status and whether this has led to a reduction in ARF/RHD occurrence.4

  5. Perform longitudinal studies evaluating the mechanisms of GAS transmission and immunopathogenesis impacted by SDH in various settings (eg, social crowding, poor housing conditions, access to education for girls and overall health status).

Key research topic 2: global assessment of the legacy primordial prevention programmes developed in partnerships with affected communities

In 1981, Martinique and Guadeloupe launched a 10-year RHD prevention programme.11 Five years later, under a similar premise, Cuba implemented a comprehensive 10-year prevention programme.10 Both campaigns involved multilevel interactions with community partners and health providers. In addition, there was a strong emphasis on health promotion and education in combination with surveillance leading to considerable improvements in overall standards of living, access to healthcare and reductions in ARF incidences. Since these studies, funded through WHO initiatives,20 the global RHD field has seen relatively few macro-level interventions with country-level impacts. Cost-effectiveness analyses have been performed for the Cuban 10-year RHD prevention programme.10 From their analysis, the programme resulted in a reduction in DALYs and overall cost savings due to the primary and secondary prevention strategies deployed.21 Beyond surveillance and prevention strategies, future research programmes should consider the inclusion of total value economic assessments to support investment case studies to prevent ARF/RHD.

Based on lessons learnt from the legacy programmes of primordial prevention, data and studies are needed to address questions and information gaps, such as:

  1. Identify success factors for effective prevention of GAS/ARF/RHD, including:

    • Documenting successful models of good prevention practice, particularly those that are likely to be generalisable.

    • Identifying which stakeholders need to be engaged and at what levels and timeframes in the process.

    • Identifying settings (including communities, homes and schools) where programmes are co-designed alongside affected communities and delivered effectively.

    • Identifying surveillance methods for monitoring and documenting the impact of prevention programmes.

    • Assessing effectiveness across a full range of resource settings (HIC to LMIC).

  2. Discern optimal methods for engaging with communities on prevention of GAS/ARF/RHD, including:

    • Supporting the leadership of prevention programs by affected communities.

    • Understanding community priorities in order to co-design prevention programs.

    • Supporting community ownership of the behavioral aspects of SDH that are relevant to reducing disease.

Key research topic 3: research to develop and implement scalable primordial prevention interventions in diverse settings

Social crowding

GAS infection initiates and potentially primes the dysregulated immune response that causes ARF. GAS may be transmitted through respiratory droplets, direct contact with skin sores and contaminated surfaces.22 The disease is moderately to highly infectious based on evidence from outbreaks, with humans being the only reservoir.22 23 Although there appears to be strong evidence associating social crowding (eg, home,24 school23 and social contacts25) with increased GAS incidence, a large proportion of the data has come from HICs, and may be influenced by socioeconomic status.5

Several observational studies have demonstrated a clear relationship between structural household crowding (number of household members in relationship to dwelling size) and risk of GAS infection (eg, GAS skin infection26) and ARF.5 6 27 There is also evidence that functional household crowding (notably people crowding together for warmth) and bedsharing (eg, children sharing a bed with another child or adult out of necessity) are also associated with an increased risk of ARF.6 27 A high number of contacts outside the household (eg, crowded schools, care facilities or attendance at large gatherings) is also a risk factor for GAS infection identified in some studies.22 25 GAS transmission has also been demonstrated in HICs, where homelessness leads to social crowding and limited access to healthcare.22

Most of these observations have been made in HIC settings, with limited studies from LMICs. Further studies are needed to understand the association of social crowding with disease incidence in low-resource settings. These studies could include qualitative evaluations of the value of social crowding within communities compared with the value placed on disease prevention. Based on these findings, researchers and community members can define metrics to inform policymakers and community partners about the health implications of social crowding. Additional studies in endemic LMIC settings of GAS transmission using molecular tools, much like those performed within Indigenous populations of northern Australia,25 are warranted to determine the role of household and community-level crowding on GAS transmission. This information would enable multidisciplinary teams to select contextually relevant interventions with the potential for sustainability.

Despite the strong observational evidence, robust intervention studies focused on addressing social crowding have yet to be performed. Opportunities exist to support the development of meaningful interventions in resource-limited settings, through partnerships with researchers, community leaders, policymakers and other key players.

Housing conditions

The environments where children and young people interact can influence the risk of GAS transmission. The characteristics of these environments (including dampness, poor ventilation and indoor pollution) may directly influence the survival and transmission of GAS organisms.22 Access to adequate resources for washing bodies, clothing and bedding may increase the removal of GAS organisms from the skin22 and hence can be an important strategy to reduce transmission. The absence of these resources and facilities has been shown to increase ARF risk.5 6 In healthcare settings, GAS outbreaks have also been associated with poor infection control practices demonstrating that effective hand washing by healthcare workers reduces the chance of GAS passing from one person to another in such environments.28–30

Overall health status

Health status and immune functioning are inter-related in complex ways. There is increasing evidence that immune priming driven by the cumulative effect of repeated GAS exposures and responses to GAS infection is integral in ARF pathogenesis.31 These repeated exposures to GAS are more likely in conditions of social crowding, poverty and limited access to healthcare, as described in the housing conditions and social crowding sections above and the health literacy and access and equity to healthcare services sections below.

Nutrition has multiple effects on health status, immunity and potentially the oral microbiome, although there are inconsistent findings around nutritional factors and the risk of ARF and RHD.5 A recent case–control study found a strong association between a high intake of sugar-sweetened beverages and the risk of ARF, even after adjusting for multiple other risk factors.27 A subsequent laboratory study in mice found evidence that a high sucrose intake might promote GAS growth and/or survival in the nasopharynx.32 Other groups have demonstrated that there may be a causal relationship between iron and albumin deficiency with ARF risk.33 Poverty and malnutrition are closely linked. Hence, it is possible that malnutrition of macronutrients and micronutrients also contributes to ARF risk. Specifically, understanding the influence of body mass index as well as micronutrient deficiency for ARF disease risk may enable the development of feasible interventions in collaboration with community partners. Of note, researchers in New Zealand have also assessed the relationship between poor oral health (based on questionnaire data and linked dental records) and ARF incidence and found no association between the two.27

Health literacy and effective health communication

Health literacy has been described as ‘…cognitive and social skills that determine the motivation and ability to understand and use health information, and adequate health literacy is seen as a prerequisite for healthy behaviors.34 Health literacy and health-seeking behaviours are individual characteristics, which are significantly influenced by structural factors that drive inequities in healthcare system.35 36 Service providers have an important role to appropriately disseminate health information in an effective manner.37 While GAS throat and skin infections pass from child to child and have a known syndrome in childhood, widespread awareness of the interconnection between these common childhood infections and ARF/RHD has been poorly communicated. Knowledge about common childhood illnesses, including sore throats and skin sores, and the connection between these common infections and more severe outcomes, notably ARF and RHD, will help caregivers and older children recognise and manage these infections early to prevent the more severe and permanent consequences of ARF and RHD. This awareness may be achieved by widespread education and appropriate storytelling to ensure that the community and providers are prepared to prevent ARF using guideline-based care.38–40 Until poverty alleviation is achieved, awareness raising remains a critical strategy that communities can partner in to prevent ARF and RHD.

For children and young people who have had ARF, a high level of caregiver ARF/RHD knowledge and primary/secondary prevention strategies to prevent new infections (antibiotic prophylaxis with monthly benzathine penicillin G (BPG)), reduces the likelihood of progression to RHD. An even greater level of knowledge is needed to support the care of people who are being treated for RHD. While access to this secondary prevention level is more widespread in HICs, knowledge of its importance and adherence to the monthly injections remains challenging.

Economic basis for interventions

In many countries, there is a need for health economic assessments to demonstrate the benefit of investment in primordial, primary and secondary prevention activities.41 These strategies, in turn, would lower the costs and DALYs associated with tertiary care for people living with RHD.42 Importantly, advocates should consider contextual factors when interpreting country-level health economic assessments to ensure the appropriate evidence is presented and acted on. Advocacy for this approach at the country level requires adequate health economic assessments based on burden of diseases.

Data and studies needed to address questions and information gaps include:

  1. Quantify the impact of housing improvement and crowding reduction on suitable ARF end points (eg, GAS transmission, immune priming).

  2. Quantify the impact of community-level environmental health improvements (including in schools and social meeting places, access to washing facilities) on suitable ARF end points (eg, GAS transmission, immune priming).

  3. Quantify the impact of interventions to ensure sustained reduction in exposure to GAS (reduction in skin abrasions, scabies treatment, self-care of skin infections, improved washing and other hygiene behaviours) on suitable ARF end points (eg, GAS transmission, immune priming).

  4. Quantify the impact of other potential interventions (eg, improved nutrition) on suitable ARF end points (eg, GAS transmission, immune priming).

  5. Quantify how prevention measures for ARF/RHD also reduce the burden of other infectious diseases in the settings described here (eg, gastroenteritis, pneumonia) as well as other health and economic benefits.

Key research topic 4: research to improve access and equity of services across the RHD continuum

Access to adequate healthcare services is a crucial social determinant in reducing the development of ARF and RHD at every stage in the causal pathway. The question of equitable access to ARF/RHD prevention and treatment is also covered in related research reviews within this supplement that focus on vaccine access and coverage, primary prevention of ARF, secondary prevention of progression to RHD and tertiary treatment of RHD.

Several countries reported successful reductions in ARF/RHD with healthcare interventions focused on delivering improved treatment of sore throats with injected penicillin. The widespread availability of affordable, comprehensive care clinics for sore throat treatment coincided with significant reductions in ARF rates in the USA,43 Cuba10 and Costa Rica.44 However, the relative contributions of increased penicillin uptake, access to comprehensive care clinics and other factors such as improved housing or economic development are difficult to determine from these descriptive reports. Barriers to accessing primary healthcare for such interventions are significant risk factors for GAS26 and ARF.27

In recent years, studies have demonstrated that improving access to primary care services for the treatment of GAS infections may prevent ARF. A large school-based sore throat management programme was developed to improve access to healthcare for under-served populations in New Zealand. The intervention included testing of symptomatic children for GAS pharyngitis, and prescribed short courses of oral antibiotics to those who were infected. Multiple studies demonstrated that this programme provided effective access to antibiotics for children in resource-limited settings but declines in ARF were highly variable.6 45–48 More intensive treatment interventions (eg, injected antibiotics) may be needed to conclusively demonstrate a relationship with ARF prevention. There is also increasing evidence that treating skin infections in children may provide an important intervention for preventing ARF.27 49 50 Studies in LMIC settings are also needed to determine whether treatment of GAS infections is a high-priority strategy for health agencies to consider for ARF prevention.

These studies can be further supported by molecular GAS testing, however, this is currently cost-prohibitive for many countries.51 In addition, to improving access to care, community-based frameworks will need to be adapted (contextually) or developed to appropriately monitor access to primary care services, outcomes and performance improvement.

Similarly, there is a need for directed interventions to improve the prevention of RHD through early detection of ARF, which is often not diagnosed.52 Research from Uganda53 and New Zealand54 has also shown a familial risk of RHD, supporting screening for undetected RHD in family members of ARF patients. Regular BPG prophylaxis can prevent the progression of latent RHD detected by such screening.52 Within the Australian context, research has been performed to assess service delivery barriers,39 40 55 56 however, additional research in other endemic settings is needed to understand and address situational barriers impacting access to ARF and RHD services at a community and national level. Data and studies needed to address questions and information gaps include:

  1. Quantify the impact of improved primary care access for diagnosis and treatment of GAS infections, including targeting of services and potential of early treatment to prevent immune priming, and the monitoring of equity of outcomes of services (eg, development of low-cost GAS detection tests to facilitate screening in low-resource settings).

  2. Quantify the impact of improved equity of access to services for effective diagnosis and management of ARF and RHD generally, and the monitoring of equity of outcomes of services.

  3. Measure the level of knowledge and health literacy in communities affected by RHD, across the disease spectrum, so that this knowledge can assist in guiding intervention programmes to improve equity of healthcare assessment and outcomes.

Conclusions

Globally, where ARF and RHD incidences have declined, there is an association with significant improvements to the SDH. Arguably, this is the most robust evidence we have to address modifiable SDH in order to reduce the global burden of RHD. Despite this knowledge, we have very little systematic evidence from the multitude of longitudinal interventions and studies that have occurred over the last century, predominantly in HICs. Consequently, the first major research theme the PPWG-SDH identified was to conduct a global analysis of ARF/RHD occurrence in relation to SDH. As part of this analysis, we are proposing a global assessment and learning from the legacy primordial prevention programmes developed in partnerships with affected communities and their effectiveness.

The PPWG-SDH recognises that there is a need for research to develop and implement scalable primordial prevention interventions in diverse settings, both at a macro-intervention and a micro-intervention level. There do not appear to be any controlled trials focusing on primordial prevention of ARF. However, there is sufficient observational data to support trials of such measures including household crowding reduction, improved nutrition and better access to household washing facilities. There are also research opportunities to specifically look at access to services across the care continuum, including remote and difficult to access regions. Such research could help guide improved access to and equity of services and outcomes across the RHD continuum.

Ultimately, ARF and RHD are likely to decrease in burden if standards of living continue to improve and poverty is reduced across the globe. Investment in the United Nations SDGs will certainly contribute to the goal of eliminating RHD at a global level. However, specific and targeted addressing of the SDH that are associated with ARF and RHD is needed in local, regional and global contexts to reduce the inequitable burden and human impact of these diseases on communities already weighed down with other diseases of poverty.

Data availability statement

There are no data in this work.

Ethics statements

Patient consent for publication

Ethics approval

Not applicable.

References

Footnotes

  • Handling editor Seye Abimbola

  • Contributors All authors contributed to the development of this manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Disclaimer The contents and views expressed in this report are those of the authors and do not necessarily reflect the official views of the National Heart, Lung, and Blood Institute, Fogarty International Center, National Institutes of Health, United States Government or the affiliated institutions.

  • Competing interests AB received funding support from the National Institutes of Health, American Heart Association, Leducq Foundation, Edwards Lifesciences—Every Heartbeat Matters, The Philips Foundation and Thrasher Pediatric Research Fund.

  • Provenance and peer review Not commissioned; externally peer reviewed.