Acute rheumatic fever (ARF) is an acute, immune-mediated process that occurs following an untreated Group A Streptococcus (GAS) infection that can result in complications, such as valvular heart disease, myocarditis and arrhythmias. ARF is now rare in the United States which can make it difficult recognize. The standard for diagnosing ARF remains therevised Jones criteria, including serologic evidence of GAS infection. Given it is encountered so infrequently in the United States, clinicians may face uncertainty when interpreting serologic studies and pursuing cardiac imaging in suspected cases. Case report We describe a case of a young white man previously diagnosed with recurrent pericarditis who presented to Tufts Medical Center with chest pain and dyspnea. Around the time of presentation, the patient had tested positive for SARS-CoV-2 with concurrent pharyngitis with white tonsillar exudates. Initial workup was notable for elevated troponin T felt to be out of proportion to pericarditis and changes consistent with myocarditis on cardiac MRI. There were no valvular abnormalities detected on echocardiogram or cardiac MRI. It was later revealed that the patient had been experiencing migratory arthralgias, prompting the measurement of antistreptolysin O (ASO) and antideoxyribonuclease B (ADB), which were both elevated. In combination with serologic evidence of a prior GAS infection, a diagnosis of acute rheumatic fever was made as he satisfied one major (myocarditis) and two minor revised Jones criteria (polyarthralgia and elevated CRP). Though COVID-19 myocarditis was considered as the etiology of his presentation, the recurrent nature of his myopericarditis, multiple prior GAS pharyngitis infections, and elevation in GAS serologic markers favor the diagnosis of ARF. Our case report demonstrates the importance of considering ARF, despite its rarity in the United States. As subacute myocarditis can go undiagnosed by echocardiography, we demonstrate that cardiac MRI is an important tool in establishing a diagnosis of myocarditis that is otherwise inconclusive. The serologic markers ASO and ADB should be used in combination to confirm a preceding GAS infection, given their variability from individual to individual.

Group A Streptococcus (GAS) causes millions of infections annually, including a recent global surge in invasive disease. To survive in the human host, GAS must rapidly reprogram virulence gene expression in response to host-derived stresses. This study characterizes two conserved transcriptional regulators, SpxA1 and SpxA2, that govern this response through interaction with RNA polymerase to indirectly influence the DNA-binding activity of downstream transcription factors. We show that SpxA2, activated by a cell envelope stress-sensing system responding to human antimicrobial peptides, reshapes the binding of the master virulence regulator CovR in a promoter-specific manner, coupling cell envelope stress sensing to virulence gene regulation. The stoichiometric balance between SpxA1 and SpxA2 functions as a regulatory rheostat calibrating overall virulence gene regulatory tone, providing a framework for understanding how RNA polymerase-interacting regulators coordinate stress responses and virulence gene control across Gram-positive bacterial pathogens.

The human-specific bacterial pathogen Group A Streptococcus (GAS) is a significant cause of morbidity and mortality due to its ability to cause severe invasive infection. Although macrophages are important for controlling GAS infection, we and others have demonstrated that GAS can persist in macrophages by perforating the phagolysosome using the pore-forming toxin streptolysin O (SLO). In this study, we examined how phagosomal perforation releases lysosomal and bacterial proteins into the cytosol and alters cytosolic protein content in the macrophage. Using IL-1β as a measure of intracellular pathogen detection, we confirmed that cytosolic preparations from macrophages infected with either wild-type (WT) or SLO-deficient (ΔSLO) bacteria contained new proteins that are absent in uninfected cytosol controls. Proteomic analysis revealed distinct cytosolic protein profiles in both WT- and ΔSLO-infected macrophages. M1 protein was detected only in the cytosol of WT-infected macrophages and corresponded with the IL-1β response, indicating SLO-mediated release of M1 protein from the phagosome, and providing a mechanism for cytosolic recognition of this virulence factor. Unexpectedly, cytosolic extracts of both WT- and ΔSLO-infected macrophages contained histone proteins H1-H4, suggesting that nucleosomal complexes are released into the cytosol during GAS infection. Our work reveals both a mechanism for the activation of the inflammatory response on a cellular level, and the surprising consequences of phagosomal perforation in GAS infections. These responses may collectively contribute to the pathologies observed during severe invasive GAS infection, and can help inform therapies aimed at improving macrophage function and patient outcomes.

Group A Streptococcus (GAS) remains universally susceptible to penicillin; however, resistance to macrolides and clindamycin varies geographically and may affect management, particularly in patients with penicillin allergy. Recent increases in GAS incidence reported in the United Kingdom highlight the need for continued local epidemiological and antimicrobial resistance surveillance. We conducted a retrospective laboratory-based surveillance study at a UK district general hospital between January 2017 and December 2023. All laboratory-confirmed GAS isolates were included. Isolates were classified as invasive or non-invasive based on specimen source. Antimicrobial susceptibility testing was performed using European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodology, and emm typing was undertaken for available invasive isolates. Data were analysed descriptively to assess temporal trends across pre-pandemic, pandemic and post-pandemic periods. A total of 2,893 GAS isolates were identified, including 45 invasive isolates (1.6%). GAS activity demonstrated marked temporal variation during the seven-year surveillance period, with substantial suppression during 2020-2021 followed by a marked increase in 2022-2023, exceeding pre-pandemic levels. Throat swab specimens accounted for the largest proportion of isolates (59.0%), followed by wound specimens (22.8%) and genital specimens (12.4%). Penicillin susceptibility remained universal throughout the study period. Erythromycin and clindamycin susceptibility demonstrated temporal variation, with the lowest susceptibility observed in 2021 before recovery in subsequent years. Tetracycline susceptibility remained relatively stable. Among typed invasive isolates (29/45), emm1 was the predominant emm type (48.3%). GAS activity demonstrated marked temporal variation, with a substantial increase following the COVID-19 pandemic. Despite this, antimicrobial susceptibility patterns remained largely stable, with universal penicillin susceptibility. Variability in macrolide and clindamycin susceptibility highlights the importance of ongoing surveillance to inform empirical therapy, particularly in penicillin-allergic patients. The predominance of emm1 among invasive isolates aligns with national trends and supports continued molecular surveillance.

Chicago Department of Public Health identified 3 pediatric patients hospitalized with group A Streptococcus (GAS) disease during October 26-November 3, 2023, in a large congregate family migrant shelter in Chicago, Illinois, USA. One patient had invasive GAS infection; 2 had peritonsillar abscesses requiring drainage. Despite infection control measures, GAS pharyngitis cases continued through November 13. Chicago Department of Public Health coordinated clinical partners to perform rapid antigen detection testing and throat cultures for residents and staff with pharyngitis symptoms. During November 20, 2023-January 3, 2024, a total of 428 symptomatic persons were evaluated; 166 tested positive for GAS. Among persons with GAS pharyngitis, median age was 12 years (range 0-45 years); 54.2% were women and girls. Common symptoms included sore throat (87.3%) and fever (63.3%). One pediatric resident death caused by invasive GAS was confirmed postmortem. This response highlights outbreak challenges in large congregate shelters housing children.

Added value of point-of-care testing for Group A Streptococcus in community pharmacy sore throat pathways: Analysis of the Wales Sore Throat Test and Treat service.

Host antimicrobial peptide LL-37 inhibits CovS kinase activity and antagonizes CovR-Mediated activation in group A Streptococcus.

A multi-drug resistant emm92-type strain of group A Streptococcus (GAS) has emerged as an important causative agent of invasive infections-particularly affecting people who inject drugs-in the United States. To curtail this developing threat, we aimed to identify and repurpose FDA-investigated compounds as antimicrobials. To identify growth-inhibiting compounds, a machine learning-based model was trained on the emm92-iGAS growth response to 2560 bioactive compounds. The model was used to screen a 6111 FDA-evaluated drug library in silico. Of the 9 validated compounds, GW3965 experimentally exhibited a 99% reduction in iGAS survival at an MIC of 6.25 µM. Treatment with GW3965 aided complete wound closure in a human skin equivalent model, and decreased lesion size and reduced bacterial burden in a mouse model of skin and soft tissue infection. Application of a machine learning model expedited the discovery of GW3965 as a therapeutic for iGAS skin and soft tissue infections.

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are defined by the abrupt onset of tics and/or obsessive–compulsive symptoms temporally linked to group A Streptococcus (GAS). Post-pandemic reports note a rebound of pediatric invasive GAS (iGAS), providing an epidemiologic backdrop for more frequent neuropsychiatric presentations. This narrative review (2020–2025; PubMed/MEDLINE, ScienceDirect, Wiley Online Library, MDPI, plus snowballing) synthesizes evidence on the PANDAS/PANS–GAS relationship, clinical spectrum, differential diagnosis with Sydenham chorea (SC), immunopathogenesis, and treatment. Beyond classic OCD and motor tics, the phenotype includes speech disfluency, ocular tics, and acute eating restriction with functional and nutritional risk. Immunologic data support molecular mimicry, Th17/IL-17–driven neuroinflammation, blood‒brain barrier dysfunction, and antineuronal or folate receptor-α antibodies; however, no single validated biomarker exists, and antistreptolysin O (ASO), anti-DNase B document exposure only. Management is individualized and multimodal: antibiotic eradication (with prophylaxis in selected, frequently relapsing cases), immunomodulation (steroids, intravenous immunoglobulin (IVIG), therapeutic plasma exchange) for severe/refractory courses, and Cognitive Behavioral Therapy/Selective Serotonin Reuptake Inhibitors (CBT/SSRIs) for core psychiatric symptoms. Contemporary data strengthen a post-streptococcal, immune-mediated framework while underscoring heterogeneous case definitions and the paucity of high-quality trials; prospective biomarker and treatment validation remain priorities.

Group A Streptococcus (GAS) is an increasingly important respiratory pathogen, causing illnesses ranging from life-threatening infections to pharyngitis and asymptomatic carriage. The factors influencing GAS transmission remain poorly defined, and, in the absence of a GAS vaccine, identifying determinants that may guide outbreak-control strategies is essential. In this observational cross-sectional study, substantial asymptomatic carriage was observed among children and adults in daycare centers experiencing GAS outbreaks: 22% by throat culture and 41% by nucleic acid amplification testing (NAAT). Co-detection of respiratory viruses was also common, and in one outbreak, enterovirus detection was more frequent among GAS-positive individuals. These findings provide preliminary insight into the complex dynamics of GAS transmission and highlight asymptomatic carriage and viral co-infections as potential intervention targets. However, the increased sensitivity of GAS NAATs compared with culture may complicate outbreak management by potentially driving unnecessary antimicrobial use.

Scarlet fever, caused by group A streptococcus (GAS), has resurged globally since the early 2010s. Although schools and pre-schools are well acknowledged as the high-risk settings for scarlet fever outbreaks, little is known about the effect of school terms on scarlet fever epidemics among pre-school-aged and school-aged children. In this study, we aimed to understand the role of school terms in scarlet fever epidemics by leveraging a population-based surveillance across 15 years in China. We included weekly scarlet fever cases from 2005 to 2019 in Liaoning Province (one of the provinces with highest incidence of scarlet fever) among children aged ≤ 12 years who were subsequently categorised into three groups: school-attending, pre-school-attending, and non-pre-school-attending. We used wavelet spectrum analysis to identify periodicity patterns of scarlet fever epidemics. We applied negative binomial regression models to estimate the relative risk (RR) of scarlet fever associated with school terms and population categories, adjusting for background risk of infection, meteorological factors, and temporal trends. A total of 64,950 scarlet fever cases were identified, with non-pre-school-attending children, pre-school-attending children and school-attending children accounting for 16%, 44%, and 40%, respectively. Scarlet fever exhibited a significant semi-annual pattern, usually peaking in May to June (during the spring semester) and November to December (during the autumn semester), with substantial declines during school breaks. Wavelet analysis identified this strong semi-annual signal, plus an additional 3.3-year (171-week) periodicity signal. Compared to non-pre-school-attending children during school breaks, school term was associated with a 2-fold higher risk of scarlet fever in pre-school-attending children (relative risk [RR] 2.14, 95% confidence interval [CI] 1.94-2.36) and school-attending children (RR 2.07, 95% CI 1.88-2.27), whereas a reduced risk was observed in non-pre-school-attending children (RR 0.84, 95% CI 0.77-0.91). During school breaks, pre-school-attending children remained at higher risk than non-pre-school-attending children (RR 1.80, 95% CI 1.63-1.99), while school-attending children showed no significantly increased risk (RR 0.97, 95% CI 0.88-1.08). Further stratification by school semester indicated that the association between school term and scarlet fever risk for pre-school-attending children and school-attending children was stronger in the autumn semester than in the spring semester. School terms have differential effects on scarlet fever risk across population categories. School-attending children have a higher risk for scarlet fever during school terms while pre-school-attending children have a higher risk for scarlet fever all year round than non-pre-school-attending children. By contrast, the risk decreases among non-pre-school-attending children during school terms. These findings support the development of targeted public health interventions to mitigate scarlet fever outbreaks in high-incidence regions.

Background Acute otitis media (AOM) is the 2nd most frequent ENT diagnosis in early childhood. Objective The aim of the study was to evaluate the clinical, anamnestic and micro-social predictors of AOM in children and its association with heat-shock protein gene (HSP70-2, rs1061581) polymorphism. Material and Methods A total of 95 children with AOM (7–18 years old) participated in the study. HSP70-2 (rs1061581) gene genotyping was performed by qPCR method. Risk factors were analyzed. Results The A-allele of the HSP70-2 gene is a predictor of a more severe AOM course in children and increases its risk and purulent ear discharge almost 2.5 times (p < 0.05), otorrhea – twofold. In preadolescence chronic hypertrophic or vasomotor rhinitis, adenoid vegetations of II-III degrees and non-obstructive diseases of the lower respiratory tract cause an AOM increase risk 3–6 times (p < 0.05). In adolescence, the probability of AOM increases with chronic persistence of hemolytic streptococcus in the oropharynx and broncho-obstructive diseases almost 10 times (p < 0.05). Early daycare attendance before the age of 3 elevates AOM likelihood more than 3 times (p = 0.001). Conclusion and significance Clinical and social predictors affect the severity of AOM in children depending on age. A-allele (rs1061581) associates with a more severe AOM course in children.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is characterized by prepubertal abrupt onset of obsessive-compulsive disorder (OCD). The sine qua non is group A streptococcus (GAS) infection, which is hypothesized to elicit an IgG-class anti-GAS antibody response that cross-reacts with antigens in the basal ganglia. However, the association between GAS antibody (GAS-IgG) levels and PANDAS has been inconsistent, and qualitative differences in GAS-IgG profiles have not been carefully evaluated in well-phenotyped cohorts. Moreover, independent studies have yet to converge on anti-neural autoantibodies that are specific to PANDAS.Here, we used phage display immunoprecipitation sequencing (PhIP-Seq) to perform ultra-deep anti-pathogen antibody repertoire profiling of serum from definitive pediatric PANDAS patients (N = 34) collected as part of a prior double-blind, placebo-controlled clinical trial of intravenous immunoglobulin (IVIg). PANDAS cases were compared to pediatric controls without a history of neuropsychiatric illness (N = 31). To assess for objective evidence of neuroglial injury, serum neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) levels were compared to healthy pediatric controls. Within PANDAS, NfL and GFAP levels were compared between pre- and post-treatment sera. To evaluate for central autoantibodies, a subset of baseline cerebrospinal fluid (CSF) samples (N = 25) was profiled by full-length human protein microarray.Though GAS reactivity by PhIP-Seq was well correlated with clinical anti-DNaseB and anti-streptolysin O titers, there were no quantitative or qualitative differences in GAS-IgG profiles between PANDAS and controls. Furthermore, NfL and GFAP levels did not differ between cases and controls. Within PANDAS, changes in NfL or GFAP levels at six weeks did not differ between placebo and IVIg groups. However, CSF autoantibody profiling by protein microarray revealed infrequent but notable candidate autoantibodies. In one patient, we identified autoantibodies against Argonaute family proteins (AGO-IgG), a marker of autoimmune sensory neuropathy. Longitudinal measurement of AGO-IgG in sera revealed that titers were unchanged after placebo, but decreased after IVIg, coinciding with symptomatic improvement, including a decrease in that patient’s CY-BOCS score.Overall, these results do not support an etiologic role for GAS-IgG in PANDAS. However, some individuals diagnosed with PANDAS may harbor anti-neural autoantibodies.

Non-pharmaceutical interventions (NPIs) imposed during the COVID-19 pandemic were known to create an immunity debt. This study aimed to quantify the immunity debt for respiratory syncytial virus (RSV), adenovirus, group A Streptococcus (GAS), and influenza in Japan between 2014 and 2024. We conducted a retrospective observational study using national surveillance data and electronic health records in 23 clinics. We conducted an interrupted time series analysis using a quasi-Poisson regression model to estimate the counterfactual incidence that would have occurred in the absence of NPIs. The number of RSV cases declined by 84% in the 2020–2021 season and increased by 39% in the 2021–2022 season, primarily due to an increase in cases among 2-year-old children (94%). Adenovirus, GAS, and influenza were suppressed during the 2020–2022 season by 58–99%. Adenovirus cases increased by 195% in 2023, with a 458% increase among children aged 5–9 years. GAS increased by 36% in 2024, with a 96% increase among 10- to 14-year-olds. Influenza increased by 158% in 2023, with a 299% increase among 10- to 14-year-olds. Surveillance data and 23 clinics’ data showed similar trends. The study suggests that the intensity and timing of the immunity debt differed by pathogen.

Multiple sclerosis and autoimmunity: learnings from post-streptococcal autoimmunity.

Group A Streptococcus (GAS) infections are common in children, ranging from mild to life-threatening invasive disease. Large-scale descriptions of changes in pediatric invasive GAS infections in the United States, particularly during the COVID-19 pandemic, are limited. We used CDC's Active Bacterial Core surveillance (ABCs), a multistate, population- and laboratory-based surveillance system, to assess changes in pediatric (<18 years old) invasive GAS incidence, clinical presentation, and bacterial strain characteristics from 2004-2023. Interrupted time series analysis was used to compare observed versus expected GAS incidence during 2020-2023, informed by trends before the COVID-19 pandemic (2004-2019). During 2004-2023, 2,856 invasive GAS cases were identified. Incidence remained stable from 2004-2019 (mean incidence 1.9 per 100,000), decreased in 2020 (1.0) and 2021 (0.6), and rebounded in 2022 (1.5) and 2023 (4.4). ICU admission increased from 2011 to 2023; case fatality remained stable. Penicillin resistance was not detected. Clindamycin non-susceptibility doubled from 2011 (3.8%) to 2022 (7.5%), before slightly decreasing in 2023 (6.4%). Infections due to emm1, the most frequently identified emm type in children with severe disease, almost disappeared in 2021 but surged in late 2022. After remaining stable for more than a decade, pediatric invasive GAS incidence declined during the COVID-19 pandemic and rebounded in 2022, more than doubling 2004-2019 incidence in 2023. While case fatality remained low, ICU admissions increased over time, highlighting the need for effective preventive measures such as vaccines. Increasing clindamycin non-susceptibility bears continued monitoring.

In Canada, Group A streptococcal (GAS) pneumonia is a severe invasive GAS (iGAS) condition reportable to public health for consideration of chemoprophylaxis for close contacts. It is often complicated by parapneumonic effusion. Sterile site culture from pleural fluid is the diagnostic gold standard but is insensitive, particularly given that many patients will have received antibiotics prior to sample collection. Xpert Xpress Strep A (Cepheid, Sunnyvale, CA) is a quantitative real-time (qPCR) assay targeting the speB gene designed to rapidly detect Streptococcus pyogenes from throat swabs. We evaluated its performance compared to bacterial culture for pediatric pleural fluids. A convenience sample of 36 specimens (21 positive, 15 negative) obtained January 2023 to April 2025 was included. Results were compared to a composite reference standard consisting of positive culture and a laboratory-developed (LD) qPCR targeting the spy1258 gene. Limit of detection (LoD) for LD qPCR was determined by testing a dilution series of negative pleural fluids spiked with a predefined concentration (copies/mL) of S. pyogenes ATCC 19615 and using 95% hit rate analysis for Xpert. All 21 positive samples tested (100%) were detected by Xpert and the composite reference standard, while only 8/21 (38%) were culture positive. Xpert demonstrated 100% positive percent agreement, negative percent agreement, and overall categorical agreement (ĸ = 1) with the composite reference standard and individual LD qPCR. There was 64% categorical agreement between Xpert and culture alone (ĸ = 0.3). Xpert was more sensitive for detecting S. pyogenes than culture from pleural fluid. Faster turnaround time shortened the window to optimal therapy, supporting its diagnostic utility.IMPORTANCEGroup A streptococcal (GAS) pneumonia, a predominant pathogen in pediatric complicated pneumonia and a severe form of invasive GAS infection, requires prompt diagnosis, both for clinical patient management and identification of close contacts for public health evaluation. Pleural effusion is a common complication. Recovery of GAS from a sterile site like pleural fluid is a key criterion to categorize disease as invasive. However, microbiological yield is often low and may be improved by applying molecular diagnostic techniques. In our study, we demonstrate the utility of Xpert Xpress Strep A for Cepheid GeneXpert for rapid detection of GAS in pediatric pleural fluids. We demonstrated excellent sensitivity with Xpert detecting all 21/21 (100%) positive specimens, compared to culture alone, which was only positive for 8/21 (38%).

From 2022 onwards, several countries, including the Netherlands, reported a marked increase in invasive group A streptococcal (iGAS) infections. Therefore, we aimed to describe the clinical presentation, disease course, treatment and outcomes of group A streptococcus (GAS) meningitis, a rare but severe manifestation of GAS infection in pediatric patients. Children with GAS meningitis were selected from the COPP-iGAS study, a national observational cohort study in children 0-17 years of age with in-hospital diagnosis of iGAS between 2015 and June 2024, conducted across 20 hospitals in the Netherlands, including all 7 academic centers with a pediatric intensive care unit. Twenty-seven children were included, of whom 41% (11/27) were younger than 5 years of age. Most patients presented during the first quarter of the year (n = 13/27, 48%). Admission to an intensive care unit occurred in 15/27 (56%) patients and 4/27 (15%) patients died. Detailed clinical data were available for 13/27 patients. Clinical course data could be evaluated for 12 of these patients. Among those 12 patients, almost two-thirds had a complicated disease course, mainly involving cardiorespiratory failure (4/12, 33%). All 12 patients received prolonged antibiotic therapy [median 43 days (IQR 14-61)], predominantly intravenously [median 42 days (IQR 14-50)]. Adjunctive therapy included corticosteroids (6/12, 50%), antiviral agents (3/12, 25%) and anticoagulants (3/12, 25%). Our findings highlight that pediatric GAS meningitis is a severe condition characterized by high intensive care admission rates and substantial mortality. In the subgroup with detailed clinical data, complications were frequent and prolonged antibiotic treatment was common. Increased clinical awareness is warranted.

Streptococcus pyogenes, or Group A Streptococcus (GAS), is a human pathogen responsible for a range of diseases, from mild infections to severe illnesses. Despite its significance in modern clinical settings, little is known about the pathogen’s evolutionary history or its presence in ancient human populations. Here, we present genomic evidence of S. pyogenes in the pre-Columbian Americas. We analysed a tooth from a naturally mummified individual dating to the Late Intermediate Period (1283–1383 cal AD), housed in the National Museum of Archeology (MUNARQ) in La Paz, Bolivia. Mitochondrial DNA analysis confirmed the host’s Native American ancestry. Shotgun metagenomic sequencing and de-novo assembly enabled the near-complete reconstruction of an ancient S. pyogenes genome displaying close similarity to contemporary strains linked to pharyngitis. The genome contains core virulence genes, but prophages lack streptococcal pyrogenic exotoxins. Phylogenetic analyses place the strain at the base of modern S. pyogenes diversity, and Bayesian analyses indicate that most extant lineages diversified globally within the past ~5,500 years. Our results push back the confirmed presence of S. pyogenes in the Americas by several centuries and suggest that the pathogen circulated among Indigenous populations prior to the European contact.

Detection and treatment of streptococcal pharyngitis in children reduces acute rheumatic fever by 70-80%. However, investment in primary prevention is limited in rheumatic heart disease (RHD) endemic countries due to lack of diagnostic capacity. We conducted a pragmatic public health trial (Rheumatic Heart Disease Community Streptococcal Treatment Program (RESET)) to determine the effect of an integrated group A streptococcal (GAS) education and treatment programme on the echocardiographic burden of RHD among children aged 5-15 years in Uganda. We implemented our interventions within the primary healthcare system of Tororo district, Eastern Uganda, over 2 years. The primary outcome was a reduction in RHD prevalence. Secondary outcomes included improved provider and community knowledge and increased health-seeking behaviour for sore throat. Interventions targeted three key barriers to primary prevention: limited provider expertise in diagnosing and treating GAS pharyngitis, poor uptake of guideline-based treatment and low public awareness of the link between sore throat and RHD. There was no significant change in RHD prevalence from baseline (0.66%, 95% CI 0.58% to 0.73%) to 2 years post-implementation (0.61%, 95% CI 0.51% to 0.71%). Primary training was completed by 101 healthcare workers with knowledge scores improving from 55% pre-training to 75% post-training. Secondary training reached 470 providers across 81 facilities. Facility assessments found only one-third met nearly all readiness metrics. Over 2000 community education events reached an estimated 380 000 people. Recognition of sore throat as a serious issue improved with 89% post-campaign identifying its link to heart disease. Health centre logs showed no increase in sore throat presentations over 22 months. As the first large-scale integrated primary prevention programme for RHD in sub-Saharan Africa, RESET demonstrated both feasibility of scaling up patient and provider education and implementation challenges in translating education into action. Ongoing research aims to identify care-seeking barriers and co-design a sore throat treatment model tailored to the community's cultural and contextual needs. NCT05276999.