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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
  1. Joselyn Rwebembera1,
  2. Jeffrey W Cannon2,
  3. Amy Sanyahumbi3,
  4. Nona Sotoodehnia4,
  5. Kathryn Taubert5,6,
  6. Christopher Sabo Yilgwan7,
  7. Gene Bukhman8,9,
  8. Mary Masterson10,
  9. Fernando P Bruno10,
  10. Asha Bowen2,11,
  11. James B Dale12,
  12. Mark E Engel13,14,
  13. Andrea Beaton15,16,
  14. Chris Van Beneden17
  1. 1Division of Adult Cardiology, Uganda Heart Institute Ltd, Kampala, Uganda
  2. 2Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, Nedlands, Western Australia, Australia
  3. 3Division of Cardiology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
  4. 4Department of Medicine, University of Washington, Seattle, Washington, USA
  5. 5American Heart Association International, Basel, Switzerland
  6. 6Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
  7. 7Departments of Paediatrics and West African Center for Emerging Infectious Diseases, University of Jos/Jos University Teaching Hospital, Jos, Nigeria
  8. 8Center for Integration Science in Global Health Equity, Brigham and Women's Hospital, Boston, Massachusetts, USA
  9. 9Program in Global Noncommunicable Diseases and Social Change, Harvard Medical School, Boston, Massachusetts, USA
  10. 10National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA
  11. 11Department of Infectious Diseases, Perth Children's Hospital, Nedlands, Western Australia, Australia
  12. 12Department of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, USA
  13. 13AFROStrep Research Initiative, Cape Heart Institute, Department of Medicine, University of Cape Town, Rondebosch, South Africa
  14. 14South African Medical Research Council, Cape Town, South Africa
  15. 15Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  16. 16Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA
  17. 17CDC Foundation, Atlanta, Georgia, USA
  1. Correspondence to Dr Chris Van Beneden; cav7{at}cdc.gov

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.

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

Data availability statement

A data availability statement is not applicable.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjgh-2023-012356

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    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 RHD7 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 Zealand39 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.

    Ethics statements

    Patient consent for publication

    References

    1. ↵
      1. Roth GA,
      2. Mensah GA,
      3. Johnson CO, et al
      . Global burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study. J Am Coll Cardiol 2020;76:2982–3021. doi:10.1016/j.jacc.2020.11.010
      OpenUrlCrossRefPubMed
    2. ↵
      1. Rwebembera J,
      2. Beaton AZ,
      3. de Loizaga SR, et al
      . The global impact of rheumatic heart disease. Curr Cardiol Rep 2021;23:1–10. doi:10.1007/s11886-021-01592-2
      OpenUrl
    3. ↵
      1. Watkins DA,
      2. Beaton AZ,
      3. Carapetis JR, et al
      . Rheumatic heart disease worldwide: JACC Scientific Expert Panel. J Am Coll Cardiol 2018;72:1397–416. doi:10.1016/j.jacc.2018.06.063
      OpenUrlFREE Full Text
    4. ↵
      1. Seckeler MD,
      2. Hoke TR
      . The worldwide epidemiology of acute rheumatic fever and rheumatic heart disease. Clin Epidemiol 2011;3:67–84. doi:10.2147/CLEP.S12977
      OpenUrlCrossRefPubMed
    5. ↵
      1. Dougherty S,
      2. Carapetis J,
      3. Zuhlke L, et al
      . Acute rheumatic fever and rheumatic heart disease. Elsevier Health Sciences, 2020.
    6. ↵
      1. Rwebembera J,
      2. Nascimento BR,
      3. Minja NW, et al
      . Recent advances in the rheumatic fever and rheumatic heart disease continuum. Pathogens 2022;11:179. doi:10.3390/pathogens11020179
    7. ↵
      1. Organization WH
      . 71st World Health Assembly adopts resolution calling for greater action on rheumatic heart disease. Geneva, Switzerland: Seventy-First World Health Assembly World Health Organization, 2018.
    8. ↵
      1. White A
      . WHO resolution on rheumatic heart disease. Oxford University Press, 2018.
    9. ↵
      1. Mayosi B,
      2. Robertson K,
      3. Volmink J, et al
      . The Drakensberg declaration on the control of rheumatic fever and rheumatic heart disease in Africa. S Afr Med J 2006;96:246.
      OpenUrlPubMed
    10. ↵
      1. Mayosi BM,
      2. Gamra H,
      3. Dangou J-M, et al
      . Rheumatic heart disease in Africa: the Mosi-O-Tunya call to action. Lancet Glob Health 2014;2:e438–9. doi:10.1016/S2214-109X(14)70234-7
      OpenUrl
    11. ↵
      1. Watkins D,
      2. Zuhlke L,
      3. Engel M, et al
      . Seven key actions to eradicate rheumatic heart disease in Africa: the Addis Ababa communiqué. Cardiovasc J Afr 2016;27:184–7. doi:10.5830/CVJA-2015-090
      OpenUrlCrossRefPubMed
    12. ↵
      1. Remenyi B,
      2. Carapetis J,
      3. Wyber R, et al
      . Position statement of the World Heart Federation on the prevention and control of rheumatic heart disease. Nat Rev Cardiol 2013;10:284–92. doi:10.1038/nrcardio.2013.34
      OpenUrlCrossRefPubMed
    13. ↵
      1. Beaton A,
      2. Kamalembo FB,
      3. Dale J, et al
      . The American Heart Association’s call to action for reducing the global burden of rheumatic heart disease: a policy statement from the American Heart Association. Circulation 2020;142:e358–68. doi:10.1161/CIR.0000000000000922
      OpenUrl
    14. ↵
      1. Bisno AL
      . Group A streptococcal infections and acute rheumatic fever. N Engl J Med 1991;325:783–93. doi:10.1056/NEJM199109123251106
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      1. Robertson KA,
      2. Volmink JA,
      3. Mayosi BM
      . Antibiotics for the primary prevention of acute rheumatic fever: a meta-analysis. BMC Cardiovasc Disord 2005;5:1–9. doi:10.1186/1471-2261-5-11
      OpenUrlCrossRefPubMed
    16. ↵
      1. Gerber MA,
      2. Baltimore RS,
      3. Eaton CB, et al
      . Prevention of rheumatic fever and diagnosis and treatment of acute streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation 2009;119:1541–51. doi:10.1161/CIRCULATIONAHA.109.191959
      OpenUrlAbstract/FREE Full Text
    17. ↵
      1. Cordery R,
      2. Purba AK,
      3. Begum L, et al
      . Frequency of transmission, asymptomatic shedding, and airborne spread of Streptococcus pyogenes in schoolchildren exposed to scarlet fever: a prospective, longitudinal, multicohort, molecular epidemiological, contact-tracing study in England, UK. Lancet Microbe 2022;3:e366–75. doi:10.1016/S2666-5247(21)00332-3
      OpenUrl
    18. ↵
      1. Oliver J,
      2. Malliya Wadu E,
      3. Pierse N, et al
      . Group A Streptococcus pharyngitis and pharyngeal carriage: a meta-analysis. PLoS Negl Trop Dis 2018;12:e0006335. doi:10.1371/journal.pntd.0006335
    19. ↵
      1. Chandnani HK,
      2. Jain R,
      3. Patamasucon P
      . Group C Streptococcus causing rheumatic heart disease in a child. J Emerg Med 2015;49:12–4. doi:10.1016/j.jemermed.2014.12.057
      OpenUrl
    20. ↵
      1. Haidan A,
      2. Talay SR,
      3. Rohde M, et al
      . Pharyngeal carriage of group C and group G streptococci and acute rheumatic fever in an Aboriginal population. The Lancet 2000;356:1167–9. doi:10.1016/S0140-6736(00)02765-3
      OpenUrl
    21. ↵
      1. Pinho MD,
      2. Melo-Cristino J,
      3. Ramirez M
      . Clonal relationships between invasive and noninvasive Lancefield group C and G streptococci and emm-specific differences in invasiveness. J Clin Microbiol 2006;44:841–6. doi:10.1128/JCM.44.3.841-846.2006
      OpenUrlAbstract/FREE Full Text
    22. ↵
      1. Parks T,
      2. Smeesters PR,
      3. Steer AC
      . Streptococcal skin infection and rheumatic heart disease. Curr Opin Infect Dis 2012;25:145–53. doi:10.1097/QCO.0b013e3283511d27
      OpenUrlCrossRefPubMed
    23. ↵
      1. Thomas S,
      2. Bennett J,
      3. Jack S
      . Descriptive analysis of group A Streptococcus in skin swabs and acute rheumatic fever. Lancet Reg Health West Pac 2021;8:100101. doi:10.1016/j.lanwpc.2021.100101
      OpenUrl
    24. ↵
      1. Oliver J,
      2. Bennett J,
      3. Thomas S, et al
      . Preceding group A Streptococcus skin and throat infections are individually associated with acute rheumatic fever: evidence from New Zealand. BMJ Glob Health 2021;6:e007038. doi:10.1136/bmjgh-2021-007038
    25. ↵
      1. O’Sullivan L,
      2. Moreland NJ,
      3. Webb RH, et al
      . Acute rheumatic fever after group A Streptococcus pyoderma and group G Streptococcus pharyngitis. Pediatr Infect Dis J 2017;36:692–4. doi:10.1097/INF.0000000000001558
      OpenUrlPubMed
    26. ↵
      1. Thornley S,
      2. Marshall R,
      3. Jarrett P, et al
      . Scabies is strongly associated with acute rheumatic fever in a cohort study of Auckland children. J Paediatr Child Health 2018;54:625–32. doi:10.1111/jpc.13851
      OpenUrlPubMed
    27. ↵
      1. McDonald MI,
      2. Towers RJ,
      3. Andrews RM, et al
      . Low rates of streptococcal pharyngitis and high rates of pyoderma in Australian Aboriginal communities where acute rheumatic fever is hyperendemic. Clin Infect Dis 2006;43:683–9. doi:10.1086/506938
      OpenUrlCrossRefPubMedWeb of Science
    28. ↵
      1. Wyber R,
      2. Bowen AC,
      3. Ralph AP, et al
      . Primary prevention of acute rheumatic fever. Aust J Gen Pract 2021;50:265–9. doi:10.31128/AJGP-02-21-5852
      OpenUrl
    29. ↵
      1. Bowen AC,
      2. Mahé A,
      3. Hay RJ, et al
      . The global epidemiology of impetigo: a systematic review of the population prevalence of impetigo and pyoderma. PLoS One 2015;10:e0136789. doi:10.1371/journal.pone.0136789
    30. ↵
      1. Hailu A,
      2. Tsega T,
      3. Gebregziabher T, et al
      . Community awareness of sore throat and rheumatic heart disease in northern Ethiopia. SSRN Journal 2019. doi:10.2139/ssrn.3369791
    31. ↵
      1. Bergmark R,
      2. Bergmark B,
      3. Blander J, et al
      . Burden of disease and barriers to the diagnosis and treatment of group A beta-hemolytic streptococcal pharyngitis for the prevention of rheumatic heart disease in Dar es Salaam, Tanzania. Pediatr Infect Dis J 2010;29:1135–7. doi:10.1097/inf.0b013e3181edf475
      OpenUrlCrossRefPubMed
    32. ↵
      1. Mougrabi MM,
      2. Aljuaid RS,
      3. Alrabie AD, et al
      . Awareness of rheumatic fever and rheumatic heart disease among the population in Taif, Saudi Arabia 2020. J Family Med Prim Care 2021;10:3056–63. doi:10.4103/jfmpc.jfmpc_2550_20
      OpenUrl
    33. ↵
      1. Nalubwama H,
      2. Ndagire E,
      3. Sarnacki R, et al
      . Community perspectives on primary prevention of rheumatic heart disease in Uganda. Glob Heart 2022;17:5. doi:10.5334/gh.1094
    34. ↵
      1. Thuso T
      . Awareness of rheumatic heart disease in Africa: a systematic review [Thesis]. Faculty of Health Sciences, Dept Medicine, Univ Cape Town, 2017.
    35. ↵
      1. Karthikeyan G,
      2. Mayosi BM
      . Is primary prevention of rheumatic fever the missing link in the control of rheumatic heart disease in Africa? Circulation 2009;120:709–13. doi:10.1161/CIRCULATIONAHA.108.836510
      OpenUrlAbstract/FREE Full Text
    36. ↵
      1. Nordet P,
      2. Lopez R,
      3. Dueñas A, et al
      . Prevention and control of rheumatic fever and rheumatic heart disease: the Cuban experience (1986-1996-2002). Cardiovasc J Afr 2008;19:135–40.
      OpenUrlPubMedWeb of Science
    37. ↵
      1. Bach JF,
      2. Chalons S,
      3. Forier E, et al
      . 10-year educational programme aimed at rheumatic fever in two French Caribbean Islands. Lancet 1996;347:644–8. doi:10.1016/s0140-6736(96)91202-7
      OpenUrlCrossRefPubMedWeb of Science
    38. ↵
      1. Initiative e
      . A report on the use of social media to prevent behavioral risk factors associated with chronic disease; 2009.
    39. ↵
      1. Anderson A,
      2. Spray J
      . Beyond awareness: towards a critically conscious health promotion for rheumatic fever in Aotearoa, New Zealand. Soc Sci Med 2020;247:112798. doi:10.1016/j.socscimed.2020.112798
      OpenUrlPubMed
    40. ↵
      1. Tu’akoi S,
      2. Ofanoa M,
      3. Ofanoa S, et al
      . Co-designing an intervention to prevent rheumatic fever in Pacific people in South Auckland: a study protocol. Int J Equity Health 2022;21:101. doi:10.1186/s12939-022-01701-9
    41. ↵
      1. McRae T,
      2. Leaversuch F,
      3. Sibosado S, et al
      . Culturally supported health promotion to See, Treat, Prevent (SToP) skin infections in Aboriginal children living in the Kimberley region of Western Australia: a qualitative analysis. Lancet Reg Health West Pac 2023;35:100757. doi:10.1016/j.lanwpc.2023.100757
    42. ↵
      1. Arguedas A,
      2. Mohs E
      . Prevention of rheumatic fever in Costa Rica. J Pediatr 1992;121:569–72. doi:10.1016/s0022-3476(05)81146-1
      OpenUrlCrossRefPubMedWeb of Science
    43. ↵
      1. Nordet P
      . WHO programme for the prevention of rheumatic fever/rheumatic heart disease in 16 developing countries: report from phase I (1986-90). Bull World Health Organ 1992;70:213–9. Available: https://apps.who.int/iris/handle/10665/261481
      OpenUrlPubMedWeb of Science
    44. ↵
      1. Shulman ST,
      2. Bisno AL,
      3. Clegg HW, et al
      . Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the infectious diseases society of America. Clin Infect Dis 2012;55:1279–82. doi:10.1093/cid/cis847
      OpenUrlCrossRefPubMed
    45. ↵
      1. Ralph AP,
      2. Holt DC,
      3. Islam S, et al
      . Potential for molecular testing for group A Streptococcus to improve diagnosis and management in a high-risk population: a prospective study. Open Forum Infect Dis 2019;6:ofz097. doi:10.1093/ofid/ofz097
    46. ↵
      1. Taylor A,
      2. Morpeth S,
      3. Webb R, et al
      . The utility of rapid group A Streptococcus molecular testing compared with throat culture for the diagnosis of group A streptococcal pharyngitis in a high-incidence rheumatic fever population. J Clin Microbiol 2021;59:e00978-21. doi:10.1128/JCM.00978-21
    47. ↵
      1. Gerber MA,
      2. Shulman ST
      . Rapid diagnosis of pharyngitis caused by group A streptococci. Clin Microbiol Rev 2004;17:571–80, doi:10.1128/CMR.17.3.571-580.2004
      OpenUrlAbstract/FREE Full Text
    48. ↵
      1. Upton A,
      2. Bissessor L,
      3. Farrell E, et al
      . Comparison of Illumigene group A Streptococcus assay with culture of throat swabs from children with sore throats in the New Zealand School-based Rheumatic Fever Prevention Program. J Clin Microbiol 2016;54:153–6. doi:10.1128/JCM.02440-15
      OpenUrlAbstract/FREE Full Text
    49. ↵
      1. Upton A,
      2. Lowe C,
      3. Stewart J, et al
      . In vitro comparison of four rapid antigen tests for group A Streptococcus detection. N Z Med J 2014;127:77–83.
      OpenUrl
    50. ↵
      1. Tanz RR,
      2. Gerber MA,
      3. Kabat W, et al
      . Performance of a rapid antigen-detection test and throat culture in community pediatric offices: implications for management of pharyngitis. Pediatrics 2009;123:437–44. doi:10.1542/peds.2008-0488
      OpenUrlCrossRefPubMedWeb of Science
    51. ↵
      1. Tanz RR,
      2. Ranniger EJ,
      3. Rippe JL, et al
      . Highly sensitive molecular assay for group A streptococci over-identifies carriers and may impact outpatient antimicrobial stewardship. Pediatr Infect Dis J 2019;38:769–74. doi:10.1097/INF.0000000000002293
      OpenUrlCrossRef
    52. ↵
      1. Barth DD,
      2. Cinanni G,
      3. Carapetis JR, et al
      . Roadmap to incorporating group A Streptococcus molecular point-of-care testing for remote Australia: a key activity to eliminate rheumatic heart disease. Med J Aust 2022;217:279–82. doi:10.5694/mja2.51692
      OpenUrl
    53. ↵
      1. Jack SJ,
      2. Williamson DA,
      3. Galloway Y, et al
      . Primary prevention of rheumatic fever in the 21st century: evaluation of a national programme. Int J Epidemiol 2018;47:1585–93. doi:10.1093/ije/dyy150
      OpenUrlPubMed
    54. ↵
      1. Walsh L,
      2. Innes-Smith S,
      3. Wright J, et al
      . School-based streptococcal a sore-throat treatment programs and acute rheumatic fever amongst indigenous Māori: a retrospective cohort study. Pediatr Infect Dis J 2020;39:995–1001. doi:10.1097/INF.0000000000002770
      OpenUrl
    55. ↵
      1. Lennon D,
      2. Anderson P,
      3. Kerdemilidis M, et al
      . First presentation acute rheumatic fever is preventable in a community setting: a school-based intervention. Pediatr Infect Dis J 2017;36:1113–8. doi:10.1097/INF.0000000000001581
      OpenUrlPubMed
    56. ↵
      1. Wyber R,
      2. Taubert K,
      3. Marko S, et al
      . Benzathine penicillin G for the management of RHD: concerns about quality and access, and opportunities for intervention and improvement. Glob Heart 2013;8:227–34. doi:10.1016/j.gheart.2013.08.011
      OpenUrl
    57. ↵
      1. Hedman L
      . Global approaches to addressing shortages of essential medicines in health systems, 30. WHO Drug Information, 2016: 180.
    58. ↵
      1. Yellapu V,
      2. Malik QZ,
      3. Perez Figueroa I, et al
      . Global burden of rheumatic heart disease and the shortage of penicillin. Circulation 2019;140:A15479. Available: https://www.ahajournals.org/doi/10.1161/circ.140.suppl_1.15479
    59. ↵
      1. Morita JY,
      2. Kahn E,
      3. Thompson T, et al
      . Impact of azithromycin on oropharyngeal carriage of group A Streptococcus and nasopharyngeal carriage of macrolide-resistant Streptococcus pneumoniae. Pediatr Infect Dis J 2000;19:41–6. doi:10.1097/00006454-200001000-00009
      OpenUrlCrossRefPubMedWeb of Science
    60. ↵
      1. Ramirez J,
      2. Guarner F,
      3. Bustos Fernandez L, et al
      . Antibiotics as major disruptors of gut microbiota. Front Cell Infect Microbiol 2020;10:572912. doi:10.3389/fcimb.2020.572912
    61. ↵
      1. Vannice KS,
      2. Ricaldi J,
      3. Nanduri S, et al
      . Streptococcus pyogenes Pbp2X mutation confers reduced susceptibility to Β-lactam antibiotics. Clin Infect Dis 2020;71:201–4. doi:10.1093/cid/ciz1000
      OpenUrlPubMed
    62. ↵
      1. Musser JM,
      2. Beres SB,
      3. Zhu L, et al
      . Reduced susceptibility of Streptococcus pyogenes to Β-lactam antibiotics associated with mutations in the gene is geographically widespread; 2020.
    63. ↵
      1. Fay K,
      2. Onukwube J,
      3. Chochua S, et al
      . Patterns of antibiotic nonsusceptibility among invasive group A Streptococcus infections—United States, 2006–2017. Clin Infect Dis 2021;73:1957–64. doi:10.1093/cid/ciab575
      OpenUrl
    64. ↵
      1. Mosites E,
      2. Kaplan EL,
      3. Li YL, et al
      . The group A Streptococcus. In: Boulton ML, Wallace RB, eds. Maxcy-Rosenau-Last Public Health & Preventive Medicine. 16th. edn. New York, NY: McGraw Hill, 2022.
    65. ↵
      1. Coates MM,
      2. Sliwa K,
      3. Watkins DA, et al
      . An investment case for the prevention and management of rheumatic heart disease in the African Union 2021-30: a modelling study. Lancet Glob Health 2021;9:e957–66. doi:10.1016/S2214-109X(21)00199-6
      OpenUrl

    Footnotes

    • Handling editor Seye Abimbola

    • Twitter @ktaubert, @realdoctorbruno

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

    • Funding This research did not receive any specific grant from funding agencies 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, National Institutes of Health, United States Government, or the affiliated institutions.

    • Competing interests ABeaton, AS, CSY and NS received funding support from the National Institutes of Health. ABeaton, AS and MEE received funding support from American Heart Association. ABeaton received funding support from Leducq Foundation, Edwards Lifesciences—Every Heartbeat Matters, The Philips Foundation and Thrasher Pediatric Research Fund. CSY received consultation fees from the WHO. JD received consulting fees from Variation Biotechnology. MEE received funding support from South African Research Council. ABowen receives funding support from the National Health and Medical Research Council of Australia.

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