Research opportunities for the primary prevention and management of acute rheumatic fever and rheumatic heart disease: a National Heart, Lung, and Blood Institute workshop report

Abstract

Primary prevention of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) encompasses the timely diagnosis and adequate treatment of the superficial group A Streptococcus (GAS) infections pharyngitis and impetigo. GAS is the only known inciting agent in the pathophysiology of the disease. However, sufficient evidence indicates that the uptake and delivery of primary prevention approaches in RHD-endemic regions are significantly suboptimal. This report presents expert deliberations on priority research and implementation opportunities for primary prevention of ARF/RHD that were developed as part of a workshop convened by the US National Heart, Lung, and Blood Institute in November 2021. The opportunities identified by the Primary Prevention Working Group encompass epidemiological, laboratory, clinical, implementation and dissemination research domains and are anchored on five pillars including: (A) to gain a better understanding of superficial GAS infection epidemiology to guide programmes and policies; (B) to improve diagnosis of superficial GAS infections in RHD endemic settings; (C) to develop scalable and sustainable models for delivery of primary prevention; (D) to understand potential downstream effects of the scale-up of primary prevention and (E) to develop and conduct economic evaluations of primary prevention strategies in RHD endemic settings. In view of the multisectoral stakeholders in primary prevention strategies, we emphasise the need for community co-design and government engagement, especially in the implementation and dissemination research arena. We present these opportunities as a reference point for research organisations and sponsors who aim to contribute to the increasing momentum towards the global control and prevention of RHD.

Summary box.

• A significant knowledge gap globally for health consumers is the link between a sore throat or skin sores and subsequent ARF/rheumatic heart disease (RHD). Health literacy campaigns co-designed with communities to ensure sociocultural acceptability to increase health-seeking behaviour are needed.

• There are significant opportunities to improve the uptake and delivery of primary prevention through targeted campaigns for treatment of sore throats and skin sores in RHD-endemic regions.

• Implementation research to optimise primary prevention of ARF/RHD is a key focus and spans epidemiological, laboratory, clinical, translation and dissemination research specialties.

• Achieving improvements in primary prevention will require multisectoral stakeholder collaboration, emphasising the need to engage local communities, government agencies, non-governmental organisations and local, regional and international advocacy groups.

• There is a great need in low-resource regions for high-quality, affordable, available and implementable point-of-care methods for group A Streptococcus diagnosis.

Introduction

Rheumatic heart disease (RHD) continues to be endemic with devastating health and socioeconomic consequences in low-to-middle-income countries (LMICs)^{1 2} and among Indigenous populations within high-income countries (HICs), despite the disease’s decline and near-elimination from HIC half a century ago.^{3 4} Primary prevention of acute rheumatic fever (ARF) and RHD encompasses the timely diagnosis and adequate treatment of superficial group A Streptococcus (GAS) infections, namely pharyngitis and impetigo,^{3 5} the only known inciting agent in the pathophysiology of the disease.

In the last two decades, there has been increasing momentum to improve early diagnosis and reduce and possibly eradicate RHD globally.⁶ The landmark 2018 World Health Assembly resolution to end RHD^{7 8} was a culmination of several regional and international statements and calls to action,^9–12 and set the stage for heightened coordination and further onboarding¹³ of global efforts in the fight against this preventable disease.

In November 2021, in line with these concerted efforts, the National Heart, Lung, and Blood Institute (NHLBI), part of the US National Institutes of Health, convened a global stakeholders’ workshop entitled ‘Eradication of Rheumatic Heart Disease: Assessing Research Challenges and Opportunities’. This paper provides a summary of the proceedings of the NHLBI Primary Prevention Working Group (PPWG) and the outcomes of this report are intended to inform and provide guidance for a global audience. The PPWG proposes a list of key opportunities for improving primary prevention uptake and delivery. These can be summarised around five areas, further described below.

1. Obtain a better understanding of the epidemiology of superficial GAS infection to guide the development and implementation of programmes and policies.

2. Improve diagnosis of superficial GAS infections in RHD endemic settings.

3. Develop scalable and sustainable models for delivery of primary prevention.

4. Understand potential downstream effects of the scale-up of primary prevention.

5. Develop and conduct economic evaluations of primary prevention strategies in RHD endemic settings.

Key research topic 1: Obtain a better understanding of GAS epidemiology to guide programmes and policies

The correlation between episodes of GAS pharyngitis and subsequent development of ARF is well described.¹⁴ Oral antibiotic treatment within 9 days of symptom onset given to patients with suspected GAS pharyngitis (primary prophylaxis) is an effective and safe option for reducing the attack rate of ARF by up to 70%,^{15 16} while intramuscular (IM) benzathine penicillin (PCN) G appears to extend this reduction to 80%.¹⁵ However, GAS pharyngitis may frequently be either asymptomatic or so mild that medical attention is not sought, hampering the effectiveness of primary prophylaxis for the prevention of ARF and RHD. Recent longitudinal studies highlight the increased transmissibility of GAS in crowded settings and the need for effective interventions to hamper bacterial shedding that promotes outbreaks.¹⁷ Additional assessments of transmission are warranted to better understand the frequency of GAS transmission in diverse settings and populations. Community knowledge of the link between a sore throat and the development of ARF remains low—addressing this in partnership with communities to ensure culturally appropriate health awareness materials are developed is needed to increase healthcare-seeking behaviour. Similarly, the overlap between GAS pharyngitis and viral infection in the era of antimicrobial resistance, sometimes leads to under treatment of GAS pharyngitis. In addition, the potential roles of asymptomatic, pharyngeal GAS carriage and group C and G streptococci carriage or pharyngitis in the pathogenesis and progression to ARF/RHD remain unclear.^18–21

Recent evidence suggests a strong potential role for GAS skin infections (eg, impetigo) in the pathogenesis of ARF,^{22 23} either alone, or in combination with, GAS pharyngitis.^24–26 The impetigo burden is high among populations that suffer high rates of ARF in remote Australia, while confirmed GAS pharyngitis is rare.²⁷ Second, recent data from New Zealand has shown that the risk of ARF following impetigo parallels that following GAS throat infection.^{21 26} While there is appreciable growing evidence that GAS impetigo can be a precedent for ARF, whether treatment of impetigo will prevent ARF in the same way that treatment of pharyngitis may prevent ARF is as yet unstudied.^{22 23 28} Further research is needed to address this given the heavy global burden of impetigo, with >162 million children affected at any one time.²⁹

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

1. Establish sentinel surveillance sites to document trends and characteristics (eg, demographics) of GAS superficial infections overtime, including potential sequelae of ARF and RHD, particularly in LMIC.

2. Conduct transmission studies to elucidate how GAS moves within and between vulnerable communities at risk of ARF/RHD—including between children and adults—and the role that transmission has on population risk for new cases of ARF and progression to RHD.

3. Elucidate the role of non-traditional superficial GAS infections in risk for and pathogenesis of ARF and RHD, including whether treatment of the following interrupts the progression to ARF/RHD:

   • GAS skin infections (impetigo),

   • GAS throat carriage,

   • Non-A β-haemolytic Streptococcus (eg, group C, G) superficial infections and oropharyngeal carriage.

4. Evaluate the impact of antibiotic treatment of GAS impetigo on risk of developing ARF.

5. Establish GAS strain typing to improve understanding of impact of strain diversity and role of specific strains in ARF pathogenesis.

Key research topic 2: Improve diagnosis and treatment of superficial streptococcal infections in RHD endemic settings

Make better use of existing tools and strategies to improve community-level diagnosis of superficial GAS infections

Develop effective strategies to increase health-seeking behaviour for superficial GAS infections

Knowledge and awareness of the sore throat-ARF-RHD linkage is key to appropriate health-seeking behaviour for the often mild and self-limiting superficial GAS infections. However, globally, there remains a major public knowledge gap for a disease with major societal impact.^30–33 A recent systematic review summarised Africa’s enormous community and healthcare worker knowledge gap.³⁴ Additionally, sociocultural factors contribute to the high incidence of ARF/RHD, underscoring the need for engaging families and communities as important stakeholders.³⁵ Few large-scale studies have been conducted in the past 50 years in RHD endemic regions to evaluate the effectiveness of increasing awareness of pharyngitis/ARF/RHD and the consequent reduction of the prevalence of RHD. Long-term interventions have been performed in Cuba,³⁶ as well as Martinique and Guadeloupe³⁷ involving community-engagement with healthcare providers and teachers to improve health literacy, as well as support the diagnosis and treatment of suspected GAS infections. In both cases, there was a significant decrease in the onset of ARF cases. The landscape of effective health promotion campaigns has evolved due to advances in technology and internet usage, particularly following the influence of the COVID-19 pandemic broadening the capabilities of communities to spread knowledge.³⁸ Locally codesigned health promotion materials that can be adapted and adopted by other communities for scale-up are needed. The benefit of this has been recently demonstrated in New Zealand^{39 40} and Australia.⁴¹

The PPWG identified the following research and implementation opportunities to promote effective and profitable population education:

1. Use multidisciplinary community-engaged research to develop innovative and sustainable community education and action methods;

2. Employ rigorous implementation and dissemination approaches to evaluate the impact and sustainability of educational programming to reduce the community GAS burden.

Develop innovative approaches to healthcare provider education and competency

Success stories exist of programmes encompassing provider education as part of the intervention bundle in reducing the prevalence of RHD.^{36 42 43} One challenge to provider education, however, is the natural waning of the acquired knowledge over time. We identify the following research and implementation opportunities to promote effective and sustainable healthcare provider education and competency.

1. Employ user-centered design to develop and test innovative educational methods (e.g., e-learning, mobile health decision tools, non-traditional providers such as teachers to scale education and use of guideline-directed care for superficial GAS infections in RHD-endemic settings.

2. Ensure rigorous implementation and dissemination research for developed approaches to evaluate the impact and sustainability of educational programming to improve guideline-based care for superficial GAS infections.

Improve tools for community-level diagnosis of superficial GAS infections

Distinguishing pharyngitis due to GAS from viral pharyngitis is challenging, given the significant overlap of clinical signs and symptoms.⁴⁴ The gold standard of bacterial culture is not practical in many countries because of the resources and expertise required and the long turnaround time. Despite being highly specific in HIC, the application of rapid antigen diagnostic tests (RADTs)^{45 46} has been limited in LMIC by the associated costs, and tests have variable with uncertain performance in RHD-endemic settings.^47–50 Importantly, selected RADTs must have the appropriate sensitivity and specificity to support antimicrobial stewardship efforts.⁵¹ Scale-up of molecular point-of-care tests for COVID-19, HIV and TB has occurred in recent years. These platforms are now more widely available in LMIC and should be considered for primary prevention programmes as the optimal pathway forward given the lower performance characteristics of current RADTs.⁵² We identify the following research and implementation opportunities to promote pragmatic community-level diagnosis of superficial GAS infections:

1. Develop clinical decision rules with sufficient sensitivity and specificity that may be locally validated and implemented in low-resourced settings, including those with different climates, healthcare systems and urban–rural settings.

2. Develop and implement new methods for GAS diagnostic testing that are sensitive, available, quality-controlled and affordable for use in low-resource settings including: point-of-care PCR tests; tests that do not require a properly collected throat swab (eg, saliva test); molecular multipathogen diagnostic tests such as a ‘pharyngitis panel’ that includes viral pathogens of targets for research purposes.

3. Explore emerging artificial intelligence technology such as light assays and machine/deep learning as an approach to detect bacterial infection from throat images using simple smart phone applications.

Key research topic 3: Develop scalable and sustainable models for delivery of primary prevention

Delivery of primary prevention in RHD-endemic settings has proven challenging. Central to this challenge are some of the other outlined key areas, such as improving tools for case detection, improving healthcare-seeking behaviours and ensuring healthcare providers are implementing guideline-based strategies. There are also considerations for cost, which are addressed under key research topic 5 of this manuscript. A more recent population-based study, initiated by the New Zealand Rheumatic Fever Prevention Programme (RFPP), found that concentrated delivery of primary prophylaxis led to a subsequent reduction in ARF cases.⁵³ Similarly, other New Zealand-based studies have evaluated the efficacy of primary prophylaxis using a school-based sore throat clinic approach, which too resulted in a decline in both ARF and GAS incidence.^{54 55} Population-based primary prophyaxis may be a viable option for HIC settings with concentrated vulnerable populations; however, in low-resource settings with higher burden, this approach may not be feasible.⁵³ Scalable and efficacious solutions are needed to better integrate, promote and deliver primary prevention in diverse setting, which in turn would support improved access to care within the formal healthcare sector and through alternative community-engaged approaches. Further, there has been little research on improving international and local supply chains for essential medications and diagnostic tools, which continues to be an important barrier for delivery of primary prevention.^56–58

The PPWG identified the following research priorities for development of scalable and sustainable models for delivery of primary prevention:

1. Develop, test and compare novel approaches to integrate primary prevention into existing physical settings and organisational structures (ie, school-based, community-based, healthcare system-based using new diagnostics).

2. Innovate and test strategies for improving international and local supply chain flexibility to ensure critical supplies and essential medicines reach patients.

3. Use rigorous implementation and dissemination methodology to study the impact of integrated primary prevention programmes including community sensitisation, healthcare worker education and implementation of tools to improve local diagnostic capacity.

Key research topic 4: Understand the potential downstream effects of the scale-up of primary prevention

Despite the efficacy of antibiotic treatment of GAS pharyngitis to prevent ARF sequelae, contemporary pharyngitis management guidelines focus on distinguishing GAS pharyngitis from viral or other aetiologies of clinical pharyngitis,³⁸ given potential unintended consequences of inappropriate antibiotic use for pharyngitis and other upper respiratory tract infections including increased antimicrobial resistance.⁵⁹ Key concerns regarding the use of antibiotics for empiric treatment of sore throat without confirmation of GAS are: (1) the cost to the payer when GAS is not the aetiology, (2) potential antibiotic side effects (eg, pain of IM injections, gastrointestinal side effects, allergic reactions) (3) risk of promotion of antimicrobial resistance from inappropriate or unnecessary antibiotic use and (4) potential microbiome disruption.⁶⁰

To date, no clinical GAS isolates demonstrating resistance to penicillin (PCN) or other beta-lactams—first line antibiotics for GAS infections—have been identified. However, strains of GAS with penicillin-binding protein 2x (PBP2x) mutations, which decrease the susceptibility to beta-lactam antibiotics, have been detected in multiple countries and may be geographically widespread requiring further monitoring.^{61 62} Macrolide and clindamycin resistance levels vary by geographic area and time; resistance can be >10% in a community,^{63 64} and local levels of both constitutive and inducible clindamycin resistance may be a concern. Therefore, efforts can be made to study local antibiotic resistance profiles, to inform the prescribing of macrolides or clindamycin.^{44 64} However, such culture-based diagnostics may not be readily available in many RHD endemic countries, and PCN remains the preferred antibiotic wherever possible

The PPWG identified the following research opportunities and needs for capacity building:

1. Develop feasible and affordable approaches for monitoring local antibiotic resistance patterns, particularly for macrolides, trimethoprim-sulfamethoxazole, and clindamycin.

2. Establish capacity for surveillance and monitoring of emerging GAS beta-lactam resistance, including detection of GAS PBP2x gene mutations, in key sentinel sites.

3. Establish studies to monitor antimicrobial consumption and the effect on bystander pathogen (eg, Streptococcus pneumoniae, Staphylococcus aureus) resistance, gut microbiota, among others.

4. Determine the impact of primary prevention strategies in combination with contemporary diagnostic testing on antimicrobial consumption and compare them to other potential RHD control strategies.

5. Establish systems to monitor potential positive downstream effects, such as improvement of other hygiene-related illnesses, which may translate into reductions in morbidity and mortality among children less than 5 years of age.

Key research topic 5: Develop and conduct economic evaluation of primary prevention strategies in RHD endemic settings

There are few economic evaluations of primary prevention strategies in RHD endemic settings. A high-quality, model-based evaluation of investment in GAS pharyngitis treatment within the African Union from 2021 to 2030 estimated that the primary prevention approach alone would not lead to a positive return-on-investment.⁶⁵ However, the return-on-investment ratio may be improved by considering cheaper treatment strategies, including impetigo in the models, and including strategies with better specificity for GAS pharyngitis to reduce: unnecessary antibiotic consumption, increased antimicrobial resistance and increased associated costs to the patient. Nevertheless, the ability to prevent ARF cases by treating superficial GAS infections dictate the need to diagnose and treat these infections at an individual level. Therefore, improving the cost-effectiveness of GAS diagnosis and treatment strategies is still required. Accordingly, the PPWG identified the following as key implementation research priorities:

1. Convene a multidisciplinary working group to develop a standardised framework for economic evaluations of primary (and other stage) prevention strategies that is relevant to endemic settings.

2. Acquire cost of illness and quality of life data on superficial GAS infections and sequelae, such as

   • Direct costs for the diagnosis and treatment of pharyngitis and impetigo;

   • Indirect costs from formal and informal carer time, work loss or absenteeism, and disruption to education;

   • Quality-of-life impacts through instruments that can be translated to quality-adjusted life-years, such as the Paediatric Quality of Life Inventory or EuroQol Group instruments.

3. Determine the impact of primary prevention strategies in combination with contemporary diagnostic testing on excessive antimicrobial consumption, which leads to resistance in GAS and by-stander pathogens and disruption of the gut microbiota.

4. Perform high-quality health economic evaluation of primary prevention strategies, including:

   • The longer-term interaction between improved GAS pharyngitis and impetigo treatment rates preventing new cases of ARF and RHD and secondary and tertiary interventions preventing progression in develop cases of ARF and RHD;

   • Cost-effectiveness, budget-impact and return on investment, of alternative primary prevention strategies;

   • The benefits of increased primary care utilisation beyond the treatment of GAS infection and sequelae alone (ie, treatment of other infectious diseases).

5. Use implementation science strategies and community engagement efforts, which take into consideration social determinants of health, disease incidences and potential disparities present in vulnerable communities, to ensure sustainable and acceptable primary prevention strategies.

The need for community and government engaged research

The aforementioned research and implementation priorities entwine multi-sectoral stakeholders, dictating a need for diverse stakeholder engagement including: (A) local community engagement of children, families and community leaders to co-design culturally relevant health promotion campaigns; (B) government agencies engagement including healthcare, education, local government; (C) local, regional and international advocacy; (D) non-governmental organisation engagement and collaboration, among others. There is a need for implementation and dissemination research as these multiple stakeholders are involved in primary prevention approaches.

Conclusions

The increasing global coordination of efforts in the fight against ARF and RHD is promising. The ability to prevent ARF cases by treating superficial GAS infections dictate the need to diagnose and treat these infections at an individual level; therefore, improving and innovating strategies for GAS diagnosis and treatment cannot be neglected. Scalable and sustainable models for delivery of primary prevention are needed, as well as the conduct of economic evaluation of these primary prevention strategies. Community and government engagement especially in the implementation and dissemination research of various primary prevention strategies cannot be overstated. These opportunities are availed as a reference point for all stakeholders who aim to contribute to the increasing momentum towards the global control and prevention of RHD.

Data availability statement

A data availability statement is not applicable.

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