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Acute rheumatic fever (ARF) is an autoimmune disorder resulting from Group A Streptococcus (GAS) pharyngitis or impetigo in children and adolescents, which may evolve to rheumatic heart disease (RHD) with persistent cardiac valve damage. RHD causes substantial mortality and morbidity globally, predominantly among socioeconomically disadvantaged populations, with an interplay of social determinants of health and genetic factors determining overall risk. ARF diagnosis is based on a constellation of clinical and laboratory features as defined by the 2015 Jones Criteria, although advances in molecular point-of-care testing and the ongoing search for ARF biomarkers offer the potential to revolutionise diagnostics. There are persistent gaps in ARF pathophysiology with little progress in therapeutics over the last several years. The greater focus towards primordial, primary, and secondary prevention such as advances in GAS vaccine development, innovations in digital health technology, improved antibiotic formulations for secondary prevention, and decentralised programmatic implementation to improve health-care delivery offer feasible solutions towards reducing future ARF burden globally.

We describe trends in acute rheumatic fever (ARF), rheumatic heart disease (RHD), and RHD deaths among population groups in New Zealand. We analyzed initial primary ARF and RHD hospitalizations during 2000-2018 and RHD mortality rates during 2000-2016. We found elevated rates of initial ARF hospitalizations for persons of Māori (adjusted rate ratio [aRR] 11.8, 95% CI 10.0-14.0) and Pacific Islander (aRR 23.6, 95% CI 19.9-27.9) ethnicity compared with persons of European/other ethnicity. We also noted higher rates of initial RHD hospitalization for Māori (aRR 3.2, 95% CI 2.9-3.5) and Pacific Islander (aRR 4.6, 95% CI 4.2-5.1) groups and RHD deaths among these groups (Māori aRR 12.3, 95% CI 10.3-14.6, and Pacific Islanders aRR 11.2, 95% CI 9.1-13.8). Rates also were higher in socioeconomically disadvantaged neighborhoods. To curb high rates of ARF and RHD, New Zealand must address increasing social and ethnic inequalities.

Acute rheumatic fever (ARF) is an autoimmune disease caused by group A streptococcal infection. Recurrent episodes of ARF can lead to rheumatic heart disease (RHD), which is the leading cause of cardiovascular mortality in children worldwide, especially in low- and middle-income countries. Investigations into the etiology of ARF and RHD constitute a crucial milestone in the advancement of both preventive measures and therapeutic interventions. The purpose of this mini review is to delineate the etiology and pathophysiological mechanisms underlying ARF and RHD. Selective searches were conducted in PubMed to retrieve literature published between 1968 and 2024, employing key terms such as “acute rheumatic fever”, “rheumatic heart disease”, “group A Streptococcus ”, “streptococcal pharyngitis”, “pathogenesis”, and “pathophysiology”. The pathogenesis of infections caused by group A streptococci, and their effects on ARF and RHD, have been thoroughly examined. A central hypothesis is that autoimmune responses are triggered by molecular mimicry, but alternate pathogenic mechanisms are continuously being explored. There is an urgent need for high-quality research that can inform efforts aimed at decreasing the occurrence of ARF and halting the advancement of RHD, which requires researchers to understand its causes and to develop appropriate preventive and therapeutic programs.

Acute Rheumatic Fever and Rheumatic Heart Disease (ARF/RHD) affect over 45 million people globally. ARF/RHD are autoimmune complications following group A streptococcal infections. Current diagnosis of ARF requires thorough medical examination, echocardiography and laboratory tests that are unavailable in most primary care settings where patients with ARF typically first present. This pilot study was conducted to determine whether machine learning-based predictive models could be used to stratify host tissue protein reactive antibodies associated with ARF, that could be incorporated into a lateral flow point-of-care (POC) platform for ARF screening. We investigated serum antibody levels against four host tissue proteins (cardiac myosin, laminin, keratin, and tropomyosin) known to increase in ARF. Serum samples were obtained from: (i) a rat autoimmune valvulitis model (RAV) of RHD (30 streptococcal M protein-injected rats versus 30 controls); and (ii) human samples (25 newly diagnosed ARF patients versus 50 healthy controls). Four machine learning algorithms (logistic regression, decision tree, random forest, and AdaBoost) predicted ARF status using antibody levels detected by enzyme-linked immunosorbent assay (ELISA). Rats injected with streptococcal M protein developed cardiac pathology and demonstrated three-fold higher optical density values for all four host tissue protein reactive antibodies compared to controls. ARF patients showed significantly elevated antibody levels against all host tissue proteins tested ( p  < 0.01). Random forest achieved optimal performance for rat data (sensitivity 100%, specificity 92.5%, AUROC = 0.97), while AdaBoost excelled for human samples using binary biomarkers (sensitivity 85.0%, specificity 82.8%, AUROC = 0.87). We demonstrate the screening potential of known host tissue protein reactive antibodies and propose lateral flow assay POC technology as a possible advancement toward improved early screening for ARF in resource-constrained environments.

We report a cluster of acute rheumatic fever (ARF) cases and the public health response in a high‐burden Australian setting. The public health unit was notified of an increase in ARF cases in a remote Australian Aboriginal community. A multi‐disciplinary group coordinated the response. Household contacts were screened for ARF or group A Streptococcus (GAS) infection by questionnaire and swab collection, offered an echocardiogram if aged 5–20 years, and intramuscular benzathine benzylpenicillin if aged over one year or if less than one year with impetigo. Fifteen definite and seven probable ARF cases were diagnosed in the community in July–December 2014 (all‐age incidence of definite ARF: 1,473/100,000). The public health response identified two additional cases of ARF. A total of 81 contacts were screened; GAS was detected in 3/76 (4%) throat swabs and 11/24 (46%) skin swabs. Molecular typing revealed high GAS strain diversity. The incidence of ARF during this cluster was very high. Carriage and infection with GAS was observed, but no outbreak strain identified. A national public health guideline has since been developed that includes advice on the investigation of an ARF outbreak/cluster. Sustained efforts with strong community engagement are required to tackle high ARF rates.

Rheumatic fever (RF) and rheumatic heart disease (RHD) continue to be a major health hazard in most developing countries as well as sporadically in developed economies. Despite reservations about the utility, echocardiographic and Doppler (E&D) studies have identified a massive burden of RHD suggesting the inadequacy of the Jones′ criteria updated by the American Heart Association in 1992. Subclinical carditis has been recognized by E&D in patients with acute RF without clinical carditis as well as by follow up of RHD patients presenting as isolated chorea or those without clinical evidence of carditis. Over the years, the medical management of RF has not changed. Paediatric and juvenile mitral stenosis (MS), upto the age of 12 and 20 yr respectively, severe enough to require operative treatement was documented. These negate the belief that patients of RHD become symptomatic ≥20 years after RF as well as the fact that congestive cardiac failure in childhood indicates active carditis and RF. Non-surgical balloon mitral valvotomy for MS has been initiated. Mitral and/or aortic valve replacement during active RF in patients not responding to medical treatment has been found to be life saving as well as confirming that congestive heart failure in acute RF is due to an acute haemodynamic overload. Pathogenesis as well as susceptibility to RF continue to be elusive. Prevention of RF morbidity depends on secondary prophylaxis which cannot reduce the burden of diseases. Primary prophylaxis is not feasible in the absence of a suitable vaccine. Attempts to design an antistreptococcal vaccine utilizing the M-protein has not succeeded in the last 40 years. Besides pathogenesis many other questions remain unanswered.

Rheumatic heart disease (RHD) is a complication of group A streptococcal infection that results from a complex interaction between the genetic make-up of the host, the infection itself and several other environmental factors, largely reflecting poverty. RHD is estimated to affect 33.4 million people and results in 10.5 million disability-adjusted life-years lost globally. The disease has long been considered heritable but still little is known about the host genetic factors that increase or reduce the risk of developing RHD. In the 1980s and 1990s, several reports linked the disease to the human leukocyte antigen (HLA) locus on chromosome 6, followed in the 2000s by reports implicating additional candidate regions elsewhere in the genome. Subsequently, the search for susceptibility loci has been reinvigorated by the use of genome-wide association studies (GWAS) through which millions of variants can be tested for association in thousands of individuals. Early findings implicate not only HLA, particularly the HLA-DQA1 to HLA-DQB1 region, but also the immunoglobulin heavy chain locus, including the IGHV4-61 gene segment, on chromosome 14. In this Review, we assess the emerging role of GWAS in assessing RHD, outlining both the advantages and disadvantages of this approach. We also highlight the potential use of large-scale, publicly available data and the value of international collaboration to facilitate comprehensive studies that produce findings that have implications for clinical practice.Rheumatic heart disease is a complication of group A streptococcal infection and rheumatic fever. In this Review, Muhamed and colleagues assess the emerging role of genome-wide association studies in detecting loci associated with genetic susceptibility to rheumatic heart disease.

Rheumatic heart disease (RHD) poses a major disease burden among disadvantaged populations globally. It results from acute rheumatic fever (ARF), a complication of Group A Streptococcal (GAS) infection. These conditions are acknowledged as diseases of poverty, however the role of specific social and environmental factors in GAS infection and progression to ARF/RHD is not well understood. The aim of this systematic review was to determine the association between social determinants of health and GAS infection, ARF and RHD, and the effect of interventions targeting these. We conducted a systematic literature review using PubMed, the Cochrane Library and Embase. Observational and experimental studies that measured: crowding, dwelling characteristics, education, employment, income, nutrition, or socioeconomic status and the relationship with GAS infection, ARF or RHD were included. Findings for each factor were assessed against the Bradford Hill criteria for evidence of causation. Study quality was assessed using a standardised tool. 1,164 publications were identified. 90 met inclusion criteria, comprising 91 individual studies. 49 (50.5%) were poor quality in relation to the specific study question. The proportion of studies reporting significant associations between socioeconomic determinants and risk of GAS infection was 57.1%, and with ARF/RHD was 50%. Crowding was the most assessed factor (14 studies with GAS infection, 36 studies with ARF/RHD) followed by socioeconomic status (6 and 36 respectively). The majority of studies assessing crowding, dwelling characteristics, education and employment status of parents or cases, and nutrition, reported a positive association with risk of GAS infection, ARF or RHD. Crowding and socioeconomic status satisfactorily met the criteria of a causal association. There was substantial heterogeneity across all key study aspects. The extensive literature examining the role of social determinants in GAS infection, ARF and RHD risk lacks quality. Most were observational, not interventional. Crowding as a cause of GAS infection and ARF/RHD presents a practical target for prevention actions.

Acute rheumatic fever (ARF) and its sequelae, Rheumatic heart disease (RHD), contribute significantly to the cardiovascular morbidity and mortality in developing countries. Generally considered a disease of poverty and poor socio-economic conditions, RHD affects the population at the most productive phase of their life. The diagnostic criteria for ARF have been constantly updated to improve the sensitivity. The diagnosis of ARF was entirely clinical however, recently echocardiographic evidence has been added as a major criterion. The disease seems to be on the decline in India, but recent studies using echocardiography have shown high prevalence of RHD among school children. The focus of management has been on prompt recognition and treatment of streptococcal pharyngitis and preventing recurrences of ARF with long-term antibiotic prophylaxis. However, emphasis should be placed on the appropriate management of patients with established RHD, in order to limit the RHD related mortality.

The pathogenesis of acute rheumatic fever (ARF) is poorly understood, limiting the development of immune-modulating therapies to treat disease and prevent progressive heart damage. Here, participants with definite ARF were compared to other severe acute paediatric conditions and matched healthy controls by profiling circulating immune molecules and cells to inform disease mechanisms and potential druggable pathways. ARF shared immunological similarities with other inflammatory conditions, including elevated serum IL-6 and an increased frequency of circulating CD4 + T cells. However, elevation of the chemokine CCL5 and immunoglobulin IgG3, along with reduced expression of the chemokine receptor CXCR3 in the T cell compartment distinguished ARF from all other groups. Immunofluorescence imaging of rheumatic valve tissue confirmed a role for CXCR3-mediated T cell tissue homing during inflammatory disease. Together with a reduced frequency of circulating regulatory T cells, these data underscore a perturbed T cell compartment and provide a rationale for exploring currently available immune-modulating therapies to treat ARF. Acute rheumatic fever (ARF) is a serious sequela of Strep A infection, for which a diagnostic biomarker is still lacking. Here, the authors demonstrate that CXCR3 directs T cells to heart valves in patients with ARF, linking inflammation to tissue damage.