Background
While Streptococcus pyogenes is known to cause acute rheumatic fever (ARF) and rheumatic heart disease (RHD), this relationship has not been systematically evaluated using objective frameworks. As S. pyogenes vaccines advance through clinical trials, regulatory approval for ARF-specific indications will require robust evidence of causality.
Methods
We conducted a structured narrative review using the Bradford Hill criteria to evaluate historical evidence linking S. pyogenes to ARF/RHD. Evidence was graded using Oxford Centre for Evidence-Based Medicine (OCEBM) Levels 1 (strongest) through 5 (weakest).
Results
Strongest evidence emerged under Strength of Association (Level 2) and Experiment/Consistency (Level 1), with meta-analyses showing increased risk of ARF following S. pyogenes infection (RR 1.74, 95% CI 1.13-2.69) and decreased odds after antibiotics (OR 0.36, 0.26-0.50). Coherence/Specificity (Level 3) provided moderate support, showing no alternative ARF etiology. Several studies demonstrated seasonal correlations in incidence, and evidence quantifying the Temporal progression from S. pyogenes to ARF was moderate (Level 3). Biological Gradient/Plausibility offered weaker support (Level 4) due to reliance on expert opinion and undefined immunological mechanisms.
Several limitations were evident in our review, including: reliance on historical military cohorts distinct from today’s endemic populations; inconsistent diagnostic criteria; minimal evidence linking S. pyogenes infection to RHD; and limited data on skin infection linked to ARF.
Discussion
While historical evidence establishes S. pyogenes as ARF's causative antecedent, important gaps remain. Future vaccine trials should prioritize contemporary endemic populations, incorporate standardized diagnostic criteria for ARF/RHD, and consider both pharyngeal and skin infection pathways to ARF/RHD.