Table 3.

Research Priorities in the Pathogenesis, Impact, and Prevention of Severe BPG Reactions

Issue	Research priority	Comment
1. Defining the extent and nature of the problem	A. An international registry of severe BPG reactions	Existing literature consists mainly of anecdotal reports and retrospective studies with a high likelihood of bias, low quality of evidence, and lack of understanding of the role of potential comorbidities 6 , 10 , 16 , 37 Can define: Incidence with appropriate denominators (per injection, per patient‐year) Severity Predisposing features (eg, severity of underlying heart disease) Clinical features, particularly to discern anaphylaxis from other reactions
	B. Prospective cohort studies	Can collect higher‐quality epidemiological data and also more detailed information routinely (eg, baseline echocardiograms, blood pressure monitoring during injections) Could be used to monitor impact of implementing new guidelines and recommendations. If done in a population‐based way and in multiple countries, could document impact of new guidelines in just a few years Potential to piggyback on existing initiatives such as the REMEDY study 2
2. Understanding perceptions of BPG, policy implications, and human impact of severe reactions and of policy changes	A. Qualitative and quantitative studies of perceptions and impact	In some countries or jurisdictions, bans have been placed on BPG administration because of concerns around safety, and in others there has been a lack of confidence among patients, leading to low adherence rates Define extent and nature of concerns among patients, clinicians, decision‐makers, and wider community, and compare with scientific evidence Document individual, family, and community impact of severe reactions and implementation of policy responses
	B. Policy research	Document range of policy responses to perceived or real risks of BPG Document impact of policy responses on confidence in BPG and on outcomes (eg, rheumatic fever recurrences, mortality) Inform recommendations around reinstituting BPG, particularly how to build, sustain, and regain trust, especially in underserved and under‐resourced communities
3. Ensure quality and supply of BPG and oral penicillin	A. Build on existing studies with systematic data collection to document active ingredient and impurity levels in supplies and evidence of stockouts	Requires international coordination and leadership
4. Determine clinical risk and mitigating factors	A. Detailed clinical studies including clinical trials of mitigating medications or clinical protocols	Could be embedded in prospective studies, such as in 1B
	B. Implementation science to evaluate new recommendations put into practice at scale, especially in resource‐limited settings	Requires increased training of implementation scientists locally, to provide credible and culturally relevant approaches

BPG indicates benzathine penicillin G; and REMEDY, Global Rheumatic Heart Disease Registry.