Research priorities for the primordial prevention of acute rheumatic fever and rheumatic heart disease by modifying the social determinants of health

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.

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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

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.