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The spectrum of diseases caused by Streptococcus pyogenes (Strep A) ranges from superficial to serious life-threatening invasive infections. We conducted a scoping review of published articles between 1980 and 2021 to synthesize evidence of state transitions across the Strep A disease spectrum. We identified 175 articles reporting 262 distinct observations of Strep A disease state transitions. Among the included articles, the transition from an invasive or toxin-mediated disease state to another disease state (i.e., to recurrent ARF, RHD or death) was described 115 times (43.9% of all included transition pairs) while the transition to and from locally invasive category was the lowest (n = 7; 0.02%). Transitions from well to any other state was most frequently reported (49%) whereas a relatively higher number of studies (n = 71) reported transition from invasive disease to death. Transitions from any disease state to locally invasive, Strep A pharyngitis to invasive disease, and chronic kidney disease to death were lacking. Transitions related to severe invasive diseases were more frequently reported than superficial ones. Most evidence originated from high-income countries and there is a critical need for new studies in low- and middle-income countries to infer the state transitions across the Strep A disease spectrum in these high-burden settings., (© 2024. The Author(s).)

Over-the-counter (OTC) and direct-to-consumer (DTC) tests have been gaining popularity due to their potential to provide accurate and quick diagnostic results without any test order from healthcare professionals, while providing patients the opportunity to actively engage in their own health management. Group A streptococcus is a common transmissible pathogen that leads to acute pharyngitis. Accurate and timely diagnosis of Group A streptococcus pharyngitis is critical to urge patients to seek professional healthcare, to support antibiotic stewardship, to reduce disease transmission, and to prevent rare but potentially life-threatening complications such as acute rheumatic fever, rheumatic heart disease, and poststreptococcal glomerulonephritis. This review provides an overview for OTC and DTC testing in general, discusses the clinical utilization of Group A streptococcus testing, analyzes the limitations and challenges of current Group A streptococcus testing methodologies if developed into OTC or DTC tests. Finally, this review provides an outlook for future developments that would further improve healthcare outcomes., (Copyright © 2022 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

It is a sad reality that although eminently preventable, and despite possessing such knowledge for >70 years, rheumatic heart disease (RHD) remains the most common cause of cardiovascular morbidity and early mortality in young people worldwide. A disease of the poor, RHD is one of the most neglected diseases. Several challenges are unique to the acute rheumatic fever/RHD continuum and contribute to its persistence, including its sequestration among the poorest, its protracted natural history, the erratic availability of penicillin, and the lack of a concerted effort in endemic regions. However, there is cause for optimism following a resurgence in scientific interest over the last 15 years. This review presents the latest advancements in epidemiology, diagnosis, and management. It also discusses pressing research questions on disease pathophysiology, the barriers to implementation of effective management strategies, and pragmatic policy solutions required for translation of current knowledge into meaningful action., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Group A streptococcal (GAS) infection is associated with a spectrum of autoimmune diseases including acute rheumatic fever/rheumatic heart disease (ARF/RHD) and neurobehavioral abnormalities. Antibodies against GAS M proteins cross-react with host tissue proteins in the heart and brain leading to the symptomatology observed in ARF/RHD. As throat carriage of Streptococcus dysgalactiae subspecies equisimilis (SDSE) has been reported to be relatively high in some ARF/RHD endemic regions compared with GAS, and both SDSE and GAS express coiled-coil surface protein called M protein, we hypothesized that streptococci other than GAS can also associated with ARF/RHD and neurobehavioral abnormalities. Neurobehavioral assessments and electrocardiography were performed on Lewis rats before and after exposure to recombinant GAS and SDSE M proteins. Histological assessments were performed to confirm inflammatory changes in cardiac and neuronal tissues. ELISA and Western blot analysis were performed to determine the cross-reactivity of antibodies with host connective, cardiac and neuronal tissue proteins. Lewis rats injected with M proteins either from GAS or SDSE developed significant cardiac functional and neurobehavioral abnormalities in comparison to control rats injected with phosphate-buffered saline. Antibodies against GAS and SDSE M proteins cross-reacted with cardiac, connective and neuronal proteins. Serum from rats injected with streptococcal antigens showed higher immunoglobulin G binding to the striatum and cortex of the brain. Cardiac and neurobehavioral abnormalities observed in our experimental model were comparable to the cardinal symptoms observed in patients with ARF/RHD. Here for the first time, we demonstrate in an experimental model that M proteins from different streptococcal species could initiate and drive the autoimmune-mediated cardiac tissue damage and neurobehavioral abnormalities., (© 2022 The Authors. Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Background: Group A Streptococcus (GAS) causes superficial pharyngitis and skin infections as well as serious autoimmune sequelae such as acute rheumatic fever (ARF) and subsequent rheumatic heart disease. ARF pathogenesis remains poorly understood. Immune priming by repeated GAS infections is thought to trigger ARF, and there is growing evidence for the role of skin infections in this process., Methods: We utilized our recently developed 8-plex immunoassay, comprising antigens used in clinical serology for diagnosis of ARF (SLO, DNase B, SpnA), and 5 conserved putative GAS vaccine antigens (Spy0843, SCPA, SpyCEP, SpyAD, Group A carbohydrate), to characterize antibody responses in sera from New Zealand children with a range of clinically diagnosed GAS disease: ARF (n = 79), GAS-positive pharyngitis (n = 94), GAS-positive skin infection (n = 51), and matched healthy controls (n = 90)., Results: The magnitude and breadth of antibodies in ARF was very high, giving rise to a distinct serological profile. An average of 6.5 antigen-specific reactivities per individual was observed in ARF, compared to 4.2 in skin infections and 3.3 in pharyngitis., Conclusions: ARF patients have a unique serological profile, which may be the result of repeated precursor pharyngitis and skin infections that progressively boost antibody breadth and magnitude., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)

Acute post-streptococcal glomerulonephritis (APSGN) and acute rheumatic fever (ARF) are common immune-mediated complications after group A streptococcus (GAS) infection. The causative antigenic epitopes on GAS are different for APSGN and ARF, and their simultaneous occurrence is uncommon. A 12-year-old boy presented with fever and gross haematuria. He had subcutaneous nodules on the dorsum of both feet along with a new holosystolic murmur at the apex, and he developed hypertension and generalised oedema after admission. Investigation confirmed the diagnosis of ARF with APSGN. He received a corticosteroid to control inflammation of both the conditions. His clinical signs gradually improved but he still had rheumatic heart disease. As both diseases can occur in the same patient, treatment should be provided for both conditions. Abbreviations: APSGN: acute post-streptococcal glomerulonephritis; ARF: acute rheumatic fever; ASO: antistreptolysin O; Cr: serum creatinine; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; GAS: group A streptococcus; RBC: red blood cells; RPGN: rapidly progressive glomerulonephritis; S1: first heart sound; S2: second heart sound; TTE: transthoracic echocardiogram.

Background: Our study aimed to systematically identify RHD stakeholders and categories of stakeholders to consider when developing a scorecard that reflects a broad stakeholder input., Method: We used the Schiller et al.(2013) framework to identify RHD stakeholders and stakeholder categories in Tanzania and Uganda. The process involved identifying stakeholders by searching literature related to incidence, prevalence, morbidity, mortality, health services, or health outcomes of Group A streptococcus, acute rheumatic fever, or rheumatic heart disease in these countries. The strategy was completed for two electronic databases in 2016 and in 2020 to update the results. We also engaged known stakeholders to obtain practice-based insight. We then categorised and visually represented the identified stakeholders., Results: We identified 139 stakeholders in Uganda, with 68% being from 15 different countries across 31 locations. In comparison, local Ugandan stakeholders were dispersed in six locations across the country. In Tanzania, we identified 128 stakeholders, with 66% being locally based and dispersed in seven locations across the country and stakeholders from different countries were situated in 18 countries across 28 locations. We categorised all identified stakeholders into one or more of five categories 1) Civil Society and General Public, 2) Education Sector, 3) Research, Training and Capacity Building, 4) Healthcare service delivery, and 5) Health Policy and Administration., Conclusion: The stakeholder categories identified include multiple sectors and stakeholders from multiple countries, this reflects the complexities of RHD. This also highlights the need for collaboration and partnership as a critical action for preventing and controlling RHD., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Group A Streptococcus (GAS) is a major human pathogen responsible for superficial infections through to life-threatening invasive disease and the autoimmune sequelae acute rheumatic fever (ARF). Despite a significant global economic and health burden, there is no licensed vaccine available to prevent GAS disease. Several pre-clinical vaccines that target conserved GAS antigens are in development. Assays that measure antigen-specific antibodies are essential for vaccine research. The aim of this study was to develop a multiplex beadbased immunoassay that can detect and quantify antibody responses to multiple GAS antigen targets in small volume blood samples. This builds on our existing triplex assay comprised of antigens used in clinical serology for the diagnosis of ARF (SLO, DNase B and SpnA). Five additional conserved putative GAS vaccine antigens (Spy0843, SCPA, SpyCEP, SpyAD and the Group A carbohydrate), were coupled to spectrally unique beads to form an 8-plex antigen panel. After optimisation of the assay protocol, standard curves were generated, and assessments of assay specificity, precision and reproducibility were conducted. A broad range of antibody (IgG) titres were able to be quickly and accurately quantified from a single serum dilution. Assay utility was assessed using a panel of 62 clinical samples including serum from adults with GAS bacteraemia and children with ARF. Circulating IgG to all eight antigens was elevated in patients with GAS disease (n = 23) compared to age-matched controls (n = 39) (P < 0.05). The feasibility of using dried blood samples to quantify antigen-specific IgG was also demonstrated. In summary, a robust and reproducible 8-plex assay has been developed that simultaneously quantifies IgG antibodies to GAS vaccine and diagnostic antigens., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Rates of acute rheumatic fever, a sequelae of group A Streptococcal (GAS) infection, remain unacceptably high in Indigenous Māori and Pacific children in New Zealand. This prospective study aimed to describe GAS antibody titres in healthy children (5-14 years) by ethnicity, and to determine how paired titres vary with GAS culture positive and negative pharyngitis, and GAS skin infections., Methods: Analysis included 887 children (32% Māori, 36% Pacific, 33% European/Other) from Auckland, New Zealand. Cases comprise 772 children who had a sore throat or skin infection, which resulted in a swab taken for culture. Healthy controls were asymptomatic (N = 154) and matched by age, ethnicity and region. All participants had a serum sample, with a second sample collected from cases only. Sera were analysed for anti-streptolysin O (ASO) and anti-DNase-B (ADB) antibodies., Results: Healthy Māori and Pacific children had higher GAS antibody titres than healthy European/Other children. Children with GAS-positive sore throat had the highest mean ASO titres and children with GAS-positive skin infection had the highest mean ADB titres. When a two-fold increase or an upper limit of normal cut-off (ASO 450 IU/ml, ADB 400 U/ml) was applied to titres from children with GAS-positive sore throat, 62.1% were classified as having serologically confirmed GAS pharyngitis and 37.9% had GAS detected without serological response., Conclusions: Elevated ASO titres were associated with GAS pharyngitis and elevated ADB titres were associated with GAS skin infections in New Zealand children. Higher ASO/ADB titres in healthy Māori and Pacific children could indicate a greater prior exposure to GAS infections., (Copyright © 2021. Published by Elsevier Ltd.)

Rheumatic fever is a serious post-infectious sequela of group A Streptococcus (GAS). Prior GAS exposures were mapped in sera using a large panel of M-type specific peptides. Rheumatic fever patients had serological evidence of significantly more GAS exposures than matched controls suggesting immune priming by repeat infections contributes to pathogenesis., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Group A streptococcus (GAS) causes significant morbidity and mortality in New Zealand and is responsible for invasive disease and immune sequelae, including acute rheumatic fever (ARF). Early treatment of GAS pharyngitis reduces the risk of ARF. In settings with a high burden of GAS disease, a rapid GAS pharyngitis diagnostic test with a strong negative predictive value is needed to enable prompt and accurate treatment. This prospective study compares the Xpert Xpress Strep A molecular test (Cepheid) to throat culture and a second molecular method, the BioGX group A streptococcus-open system reagent (OSR) for BD Max for the diagnosis of GAS pharyngitis. Throat swabs were collected from the emergency department and wards of Middlemore Hospital, New Zealand. The BioGX group A streptococcus OSR for BD Max contributes to the composite gold standard of throat culture or both molecular methods positive. Basic demographic, clinical, and laboratory data were collected. Two hundred five out of two hundred fourteen swabs were suitable for analysis. Of those, 28/205 (13.7%) were GAS culture positive, 45/205 (22%) Xpert Xpress Strep A positive, and 38/205 (18.5%) BioGX positive. Compared to culture, the sensitivity, specificity, and positive and negative predictive values of the Xpert Xpress Strep A molecular test were 100%, 90.4%, 62.2%, and 100%, respectively. Compared to the composite gold standard, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 100%, 95.8%, 84.4%, and 100%, respectively. Seventeen samples were Xpert Xpress positive but culture negative; 6 of these 17 swabs represent true positives with evidence of recent GAS infection. Ten samples were culture negative but both Xpert Xpress and BioGX positive. The Xpert Xpress Strep A molecular test is highly sensitive with a strong negative predictive value and rapid turnaround time. It can be safely introduced as a first-line test for throat swabs in a high-incidence ARF population.

Objectives: To explore the acceptability of a novel, outreached-based approach to improve primary and primordial prevention of Strep A skin sores, sore throats and acute rheumatic fever in remote Aboriginal communities., Methods: A comprehensive prevention program delivered by trained Aboriginal Community Workers was evaluated using approximately fortnightly household surveys about health and housing and clinical records., Results: Twenty-seven primary participants from three remote Aboriginal communities in the Northern Territory consented, providing 37.8 years of retrospective baseline data and 18.5 years of prospective data during the study period. Household members were considered to be secondary participants. Five Aboriginal Community Workers were trained and employed, delivering a range of supports to households affected by acute rheumatic fever including environmental health support and education. Clinical record audit and household self-report of Strep A infections were compared. No association between clinical- and self-report was identified., Conclusions: Ongoing participation suggests this outreach-based prevention program was acceptable and associated with improved reporting of household maintenance issues and awareness of prevention opportunities for Strep A infections. Implications for public health: Biomedical, clinic-based approaches to the management of Strep A infections in remote communities can be usefully augmented by outreach-based supports delivered by Aboriginal Community Workers responding to community needs., (© 2021 The Authors.)

Background: Acute rheumatic fever (ARF) is a serious sequela of Group A Streptococcus (GAS) infection associated with significant global mortality. Pathogenesis remains poorly understood, with the current prevailing hypothesis based on molecular mimicry and the notion that antibodies generated in response to GAS infection cross-react with cardiac proteins such as myosin. Contemporary investigations of the broader autoantibody response in ARF are needed to both inform pathogenesis models and identify new biomarkers for the disease., Methods: This study has utilised a multi-platform approach to profile circulating autoantibodies in ARF. Sera from patients with ARF, matched healthy controls and patients with uncomplicated GAS pharyngitis were initially analysed for autoreactivity using high content protein arrays (Protoarray, 9000 autoantigens), and further explored using a second protein array platform (HuProt Array, 16,000 autoantigens) and 2-D gel electrophoresis of heart tissue combined with mass spectrometry. Selected autoantigens were orthogonally validated using conventional immunoassays with sera from an ARF case-control study (n=79 cases and n=89 matched healthy controls) and a related study of GAS pharyngitis (n=39) conducted in New Zealand., Results: Global analysis of the protein array data showed an increase in total autoantigen reactivity in ARF patients compared with controls, as well as marked heterogeneity in the autoantibody profiles between ARF patients. Autoantigens previously implicated in ARF pathogenesis, such as myosin and collagens were detected, as were novel candidates. Disease pathway analysis revealed several autoantigens within pathways linked to arthritic and myocardial disease. Orthogonal validation of three novel autoantigens (PTPN2, DMD and ANXA6) showed significant elevation of serum antibodies in ARF (p < 0.05), and further highlighted heterogeneity with patients reactive to different combinations of the three antigens., Conclusions: The broad yet heterogenous elevation of autoantibodies observed suggests epitope spreading, and an expansion of the autoantibody repertoire, likely plays a key role in ARF pathogenesis and disease progression. Multiple autoantigens may be needed as diagnostic biomarkers to capture this heterogeneity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 McGregor, Tay, Carlton, Hanson-Manful, Raynes, Forsyth, Brewster, Middleditch, Bennett, Martin, Wilson, Atatoa Carr, Baker and Moreland.)

Acute rheumatic fever (ARF) is a serious post-infectious immune sequelae of Group A streptococcus (GAS). Pathogenesis remains poorly understood, including the events associated with collagen autoantibody generation. GAS express streptococcal collagen-like proteins (Scl) that contain a collagenous domain resembling human collagen. Here, the relationship between antibody reactivity to GAS Scl proteins and human collagen in ARF was investigated. Serum IgG specific for a representative Scl protein (Scl1.1) together with collagen-I and collagen-IV mimetic peptides were quantified in ARF patients (n = 36) and healthy matched controls (n = 36). Reactivity to Scl1.1 was significantly elevated in ARF compared to controls (P < 0.0001) and this was mapped to the collagen-like region of the protein, rather than the N-terminal non-collagenous region. Reactivity to collagen-1 and collagen-IV peptides was also significantly elevated in ARF cases (P < 0.001). However, there was no correlation between Scl1.1 and collagen peptide antibody binding, and hierarchical clustering of ARF cases by IgG reactivity showed two distinct clusters, with Scl1.1 antigens in one and collagen peptides in the other, demonstrating that collagen autoantibodies are not immunologically related to those targeting Scl1.1. Thus, anti-collagen antibodies in ARF appear to be generated as part of the autoreactivity process, independent of any mimicry with GAS collagen-like proteins., (© The Author(s) 2021. Published by Oxford University Press on behalf of FEMS. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We investigated outcomes for patients born after 1983 and hospitalized with initial acute rheumatic fever (ARF) in New Zealand during 1989-2012. We linked ARF progression outcome data (recurrent hospitalization for ARF, hospitalization for rheumatic heart disease [RHD], and death from circulatory causes) for 1989-2015. Retrospective analysis identified initial RHD patients <40 years of age who were hospitalized during 2010-2015 and previously hospitalized for ARF. Most (86.4%) of the 2,182 initial ARF patients did not experience disease progression by the end of 2015. Progression probability after 26.8 years of theoretical follow-up was 24.0%; probability of death, 1.0%. Progression was more rapid and ≈2 times more likely for indigenous Māori or Pacific Islander patients. Of 435 initial RHD patients, 82.2% had not been previously hospitalized for ARF. This young cohort demonstrated low mortality rates but considerable illness, especially among underserved populations. A national patient register could help monitor, prevent, and reduce ARF progression.

Rheumatic heart disease (RHD) is a large, preventable, global public health burden. In New Zealand (NZ), acute rheumatic fever (ARF) and RHD rates are highest for Māori and Pacific children. This structured review explores the evidence for primary prevention interventions to diagnose and effectively treat group A Streptococcus (GAS) pharyngitis and skin infections to reduce rates of ARF and RHD. Medline, EMBASE and Scopus databases were searched as well as other electronic publications. Included were 50 publications from 1980 onwards. This review has identified that there is little available evidence for effective primary prevention strategies to reduce ARF rates in NZ. However, two primary intervention strategies that should be considered by communities at high-risk of ARF are: the use of school-based clinics to identify and treat GAS pharyngitis and GAS skin infections; and intramuscular benzathine penicillin G with lignocaine analgesia in children who present with a GAS positive throat., (© 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Background: The neuropsychiatric disorders due to post-streptococcal autoimmune complications such as Sydenham's chorea (SC) are associated with acute rheumatic fever and rheumatic heart disease (ARF/RHD). An animal model that exhibits characteristics of both cardiac and neurobehavioral defects in ARF/RHD would be an important adjunct for future studies. Since age, gender, strain differences, and genotypes impact on the development of autoimmunity, we investigated the behavior of male and female Wistar and Lewis rat strains in two age cohorts (<6 weeks and >12 weeks) under normal husbandry conditions and following exposure to group A streptococcus (GAS)., Methods: Standard behavioral assessments were performed to determine the impairments in fine motor control (food manipulation test), gait and balance (beam walking test), and obsessive-compulsive behavior (grooming and marble burying tests). Furthermore, electrocardiography, histology, and behavioral assessments were performed on male and female Lewis rats injected with GAS antigens., Results: For control Lewis rats there were no significant age and gender dependent differences in marble burying, food manipulation, beam walking and grooming behaviors. In contrast significant age-dependent differences were observed in Wistar rats in all the behavioral tests except for food manipulation. Therefore, Lewis rats were selected for further experiments to determine the effect of GAS. After exposure to GAS, Lewis rats demonstrated neurobehavioral abnormalities and cardiac pathology akin to SC and ARF/RHD, respectively., Conclusion: We have characterised a new model that provides longitudinal stability of age-dependent behavior, to simultaneously investigate both neurobehavioral and cardiac abnormalities associated with post-streptococcal complications., Competing Interests: No conflicts of interest relevant to this manuscript were reported., (© 2021 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Rheumatic heart disease (RHD) is a serious and long-term consequence of acute rheumatic fever (ARF), an autoimmune sequela of a mucosal infection by Streptococcus pyogenes (Group A Streptococcus, Strep A). The pathogenesis of ARF and RHD is complex and not fully understood but involves host and bacterial factors, molecular mimicry, and aberrant host innate and adaptive immune responses that result in loss of self-tolerance and subsequent cross-reactivity with host tissues. RHD is entirely preventable yet claims an estimated 320 000 lives annually. The major burden of disease is carried by developing nations and Indigenous populations within developed nations, including Australia. This review will focus on the epidemiology, pathogenesis and treatment of ARF and RHD in Australia, where: streptococcal pyoderma, rather than streptococcal pharyngitis, and Group C and Group G Streptococcus, have been implicated as antecedents to ARF; the rates of RHD in remote Indigenous communities are persistently among the highest in the world; government register-based programs coordinate disease screening and delivery of prophylaxis with variable success; and researchers are making significant progress in the development of a broad-spectrum vaccine against Strep A., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Sydenham chorea, also known as St. Vitus dance, is a major clinical criterion for the diagnosis of acute rheumatic fever. Clinically, it results in a combination of movement disorders and complex neuropsychiatric symptoms. Cardiac damage due to rheumatic fever may also predispose to neurologic complications later in life. Rheumatic heart disease (RHD) is associated with heart remodeling, cardiac arrhythmias, and ischemic stroke. Furthermore, chronically damaged heart valves are predisposed to infection. Septic brain embolism, a known complication of infective endocarditis, may result in brain ischemia, hemorrhage, and spread of the infection to the brain., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A 42-year-old man presented with fever, sore throat, rash and painful right knee swelling, preceded by self-medication with oral steroids. Blood and knee cultures yielded group A Streptococcus After 2 weeks of intravenous antibiotics and two arthroscopic knee debridements, he continued to experience spiking fevers, and electrocardiographic changes developed. We postulate that the patient suffered from the first presentation of acute rheumatic fever, following an invasive group A bacteraemic streptococcal infection. The possible role of cardiac magnetic resonance imaging in the diagnosis of rheumatic carditis is discussed., (© Royal College of Physicians 2020. All rights reserved.)

Streptococcal serology is a cornerstone in the diagnosis of acute rheumatic fever (ARF), a postinfectious sequela associated with group A Streptococcus infection. Current tests that measure anti-streptolysin O (ASO) and anti-DNaseB (ADB) titers require parallel processing, with their predictive value limited by the low rate of decay in antibody response. Accordingly, our objective was to develop and assess the diagnostic potential of a triplex bead-based assay, which simultaneously quantifies ASO and ADB together with titers for a third antigen, SpnA. Our previous cytometric bead assay was transferred to the clinically appropriate Luminex platform by coupling streptolysin O, DNaseB, and SpnA to spectrally unique magnetic beads. Sera from more than 350 subjects, including 97 ARF patients, were used to validate the assay and explore immunokinetics. Operating parameters demonstrate that the triplex assay produces accurate and reproducible antibody titers which, for ASO and ADB, are highly correlative with existing assay methodology. When ARF patients were stratified by time (days following hospital admission), there was no difference in ASO and ADB between <28 and 28+ day groups. However, for anti-SpnA, there was a significant decrease ( P < 0.05) in the 28+ day group, indicative of faster anti-SpnA antibody decay. Anti-SpnA immunokinetics support very recent group A Streptococcus infection and may assist in diagnostic classification of ARF. Further, bead-based assays enable streptococcal serology to be performed efficiently in a high-throughput manner., (Copyright © 2020 American Society for Microbiology.)

Group A Streptococcus (GAS) pharyngitis is a key initiator of acute rheumatic fever (ARF). In New Zealand, ARF cases occur more frequently among persons of certain ethnic and socioeconomic groups. We compared GAS pharyngitis estimates (1,257,058 throat swab samples) with ARF incidence (792 hospitalizations) in Auckland during 2010-2016. Among children 5-14 years of age in primary healthcare clinics, GAS pharyngitis was detected in similar proportions across ethnic groups (≈19%). Relative risk for GAS pharyngitis was moderately elevated among children of Pacific Islander and Māori ethnicities compared with those of European/other ethnicities, but risk for ARF was highly elevated for children of Pacific Islander and Māori ethnicity compared with those of European/other ethnicity. That ethnic disparities are much higher among children with ARF than among those with GAS pharyngitis implies that ARF is driven by factors other than rate of GAS pharyngitis alone.

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.

Acute rheumatic fever (ARF) and its sequela, rheumatic heart disease (RHD), have largely disappeared from high-income countries. However, in New Zealand (NZ), rates remain unacceptably high in indigenous Māori and Pacific populations. The goal of this study is to identify potentially modifiable risk factors for ARF to support effective disease prevention policies and programmes. A case-control design is used. Cases are those meeting the standard NZ case-definition for ARF, recruited within four weeks of hospitalisation for a first episode of ARF, aged less than 20 years, and residing in the North Island of NZ. This study aims to recruit at least 120 cases and 360 controls matched by age, ethnicity, gender, deprivation, district, and time period. For data collection, a comprehensive pre-tested questionnaire focussed on exposures during the four weeks prior to illness or interview will be used. Linked data include previous hospitalisations, dental records, and school characteristics. Specimen collection includes a throat swab (Group A Streptococcus), a nasal swab (Staphylococcus aureus), blood (vitamin D, ferritin, DNA for genetic testing, immune-profiling), and head hair (nicotine). A major strength of this study is its comprehensive focus covering organism, host and environmental factors. Having closely matched controls enables the examination of a wide range of specific environmental risk factors.

Background: Group A streptococcus (GAS) is the most frequent cause of bacterial pharyngitis in school-aged children. The postinfection sequel as acute rheumatic fever (ARF) and rheumatic heart disease that cause morbidity and mortality among young people is public health concerns in several developing countries. Asymptomatic carriage state of GAS is not fully understood in terms of host and bacterial factors. Although the ability of transmitting GAS of the asymptomatic carriers is relatively low, they may present the reservoir of the epidemic. A fraction of GAS carriers is difficult to estimate in practice and may greatly vary between populations. Understanding the role of carriage on the transmission dynamic of GAS is important for assessing the public health impact of the ARF., Method: This study investigates the effect of GAS carriers on both the transmission and dynamic of ARF cases by using a mathematical model., Result: We derive the sufficient conditions for which the GAS can spread or extinct from the naive population under the variation of the fraction of symptomatic cases over the incidence of GAS. The threshold is possible to occur in general, but the last condition which is rather restrictive and involves parameter uncertainty. The increasing of carriers in the endemic state leads to the reduction in magnitude of the reproduction number and the number of ARF patients. We demonstrate that the adjustment of parameters can be carried out by the use of endemic state and some specific data., Conclusion: We show theoretically that the presence of asymptomatic carriers may induce the epidemic threshold and reduce the virulence of GAS and the prevalence of ARF.

Background: Group A Streptococcal (GAS) infections cause the autoimmune disease acute rheumatic fever (ARF), which can progress to chronic rheumatic heart disease (RHD). Treating pharyngitis caused by GAS with antibiotics is important in preventing ARF. However, it is difficult to distinguish these infections from GAS carriers. There is growing evidence for GAS skin infections as a cause of ARF. This study will identify the incidence of true GAS pharyngitis and serological responses to GAS skin infections. The effectiveness of antibiotics for these conditions will be explored, and modifiable risk factors. Serum antibody titres indicating the upper limits of normal (ULN for ASO/ADB antibodies) will be established alongside carriage rates in asymptomatic children., Methods: This is a prospective disease incidence study, with an associated case-control study. The study population includes 1000 children (5-14 years) from Auckland, New Zealand, 800 of whom have visited their healthcare professional, resulting in a throat or skin swab for GAS, and 200 who are asymptomatic. The conditions of interest are GAS throat swab positive pharyngitis (n = 200); GAS carriage (n = 200); GAS negative throat swab (n = 200); GAS skin infections (n = 200); and asymptomatic controls (n = 200). All participants, except asymptomatic controls, will have acute and convalescent serological testing for ASO/ADB titres (collected < 9 days, and 2-4 weeks following symptom onset, respectively), alongside viral PCR from throat swabs. Asymptomatic controls will have ASO/ADB titres measured in one blood specimen and a throat swab for microbial culture. Caregivers of children will be interviewed using a questionnaire and any GAS isolates identified will be emm typed. The persistence of GAS antibodies will also be investigated., Discussion: Findings from this study will fill critical gaps in scientific knowledge to better understand the pathophysiology of ARF, improve clinical management of GAS infections, and design more effective ARF prevention programmes. In particular it will measure the incidence of true, serologically confirmed GAS pharyngitis; assess the immune response to GAS skin infections and its role as a cause of ARF; examine the effectiveness of oral antibiotics for treating GAS pharyngitis and carriage; and identify whether risk factors for GAS infections might provide intervention points for reducing ARF.

Objectives: We report a cluster of acute rheumatic fever (ARF) cases and the public health response in a high-burden Australian setting., Methods: 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., Results: 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., Conclusions: The incidence of ARF during this cluster was very high. Carriage and infection with GAS was observed, but no outbreak strain identified. Implications for public health: 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., (© 2019 The Authors.)

Streptococcus pyogenes is a human-specific and globally prominent bacterial pathogen that despite causing numerous human infections, this bacterium is normally found in an asymptomatic carrier state. This review provides an overview of both bacterial and human factors that likely play an important role in nasopharyngeal colonization and pharyngitis, as well as the development of acute rheumatic fever and rheumatic heart disease. Here we highlight a recently described role for bacterial superantigens in promoting acute nasopharyngeal infection, and discuss how these immune system activating toxins could be crucial to initiate the autoimmune process in rheumatic heart disease., (Copyright © 2018. Published by Elsevier B.V.)

Objectives: Streptococcal serology provides evidence of prior Group A Streptococcus (GAS) exposure, crucial to the diagnosis of acute rheumatic fever (ARF) and post-streptococcal glomerulonephritis. However, current tests, which measure anti-streptolysin-O and anti-DNaseB antibodies, are limited by false positives in GAS endemic settings, and incompatible methodology requiring the two tests to be run in parallel. The objective was to improve streptococcal serology by combining the novel GAS antigen, SpnA, with streptolysin-O and DNaseB in a contemporary, bead-based immunoassay., Methods: Recombinant streptolysin-O, DNAseB and SpnA were conjugated to polystyrene beads with unique fluorescence positions so antibody binding to all three antigens could be detected simultaneously by cytometric bead array. Multiplex assays were run on sera collected in three groups: ARF; ethnically matched healthy children; and healthy adults., Results: The ability of the antigens to detect a previous GAS exposure in ARF was assessed using the 80th centile of the healthy children group as cut-off (upper limit of normal). SpnA had the highest sensitivity at 88%, compared with 75% for streptolysin-O and 56% for DNaseB., Conclusions: SpnA has favorable immunokinetics for streptococcal serology, and can be combined with anti-streptolysin-O and anti-DNaseB in a multiplex format to improve efficiency and accuracy., (Copyright © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

There is a pressing need to reduce the high global disease burden of rheumatic heart disease (RHD) and its harbinger, acute rheumatic fever (ARF). ARF is a classical example of an autoimmune syndrome and is of particular immunological interest because it follows a known antecedent infection with group A streptococcus (GAS). However, the poorly understood immunopathology of these post-infectious diseases means that, compared to much progress in other immune-mediated diseases, we still lack useful biomarkers, new therapies or an effective vaccine in ARF and RHD. Here, we summarise recent literature on the complex interaction between GAS and the human host that culminates in ARF and the subsequent development of RHD. We contrast ARF with other post-infectious streptococcal immune syndromes - post-streptococcal glomerulonephritis (PSGN) and the still controversial paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), in order to highlight the potential significance of variations in the host immune response to GAS. We discuss a model for the pathogenesis of ARF and RHD in terms of current immunological concepts and the potential for application of in depth "omics" technologies to these ancient scourges., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Group A Streptococcus (GAS) strains are lately classified on the basis of sequence variations in the emm gene encoding the M protein, but despite the high number of distinct emm genotypes, the spectrum of phenotypes varying from invasive suppurative to non-suppurative GAS-related disorders has still to be defined. The relationship of GAS types with the uprising of acute rheumatic fever (ARF), a multisystemic disease caused by misdirected anti-GAS response in predisposed people, is also obscure. Studies published over the last 15 years were retrieved from PubMed using the keywords: "Streptococcus pyogenes" or "group A Streptococcus" and "acute rheumatic fever": the prevalence of peculiar emm types across different countries of the world is highly variable, depending on research designs, year of observation, country involved, patients' age, and gender. Most studies revealed that a relatively small number of specific emm/M protein types can be considered "rheumatogenic", as potentially characterized by the possibility of inducing ARF, with remarkable differences between developing and developed countries. The association between emm types and post-streptococcal manifestations is challenging, however surveillance of disease-causing variants in a specific community with high rate of ARF should be reinforced with the final goal of developing a potential primary prophylaxis against GAS infections., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Rheumatic fever (RF) and rheumatic heart disease (RHD) are the multisystem autoimmune sequel of group A streptococci (GAS) infection of the upper respiratory passages, mainly tonsillopharyngitis. The major receptor on the surface of human palatine tonsil for GAS is fibronectin (FN; adhesin receptor). Early detection of RF susceptibility is considered as an important aim of this study. Therefore, the present study aimed to use FN immunoreactivity (FN-ir) as a marker for early detection of rheumatic susceptible children with palatine tonsil crypts surface epithelium. A total of 30 palatine tonsillar specimens were obtained from children aged from 3 to 15 years. Histological studies showed moderate vascular changes and more than four apparent epithelial disruptions in the crypt epithelium. FN-ir showed a significant increase in FN in the basal layers of surface epithelium, subepithelial connective tissue and interfollicular areas. Tonsils of children in rheumatic families showed significant increase in FN in subepithelial connective tissue areas with more than one apparent crypt epithelial disruption compared to normal children. We can conclude that FN plays a central role in the RF and differentially distributed in the functional compartments of the palatine tonsil in children with RHD, so FN-ir can be used as a marker for rheumatic susceptibility., (© The Author(s) 2012.)

Acute rheumatic fever is an inflammatory sequela of Group A Streptococcal pharyngitis that affects multiple organ systems. The incidence of acute rheumatic fever has been declining even before the use of antibiotics became widespread, however the disease remains a significant cause of morbidity and mortality in children, particularly in developing countries and has been estimated to affect 19 per 100,000 children worldwide. Acute rheumatic fever is a clinical diagnosis, and therefore subject to the judgment of the clinician. Because of the variable presentation, the Jones criteria were first developed in 1944 to aid clinicians in the diagnosis of acute rheumatic fever. The Jones criteria have been modified throughout the years, most recently in 1992 to aid clinicians in the diagnosis of initial attacks of acute rheumatic fever and to minimize overdiagnosis of the disease. Diagnosis of acute rheumatic fever is based on the presence of documented preceding Group A Streptococcal infection, in addition to the presence of two major manifestations or one major and two minor manifestations of the Jones criteria. Without documentation of antecedent Group A Streptococcal infection, the diagnosis is much less likely except in a few rare scenarios. Carditis, polyarthritis and Sydenham's chorea are the most common major manifestations of acute rheumatic fever. However, despite the predominance of these major manifestations of acute rheumatic fever, there can be significant overlap with other disorders such as Lyme disease, serum sickness, drug reactions, and post-Streptococcal reactive arthritis. This overlap between disease processes has led to continued investigation of the pathophysiology as well as development of new biomarkers and laboratory studies to aid in the diagnosis of acute rheumatic fever and distinction from other disease processes., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Acute rheumatic fever (ARF), a consequence of group A streptococcal (GAS) pharyngitis, is characterized by nonsuppurative inflammatory lesions of the joints as well as subcutaneous and cardiac tissues. Although the overall incidence of ARF in the United States has declined in recent years, there have been reports of outbreaks in closed populations, as well as sporadic cases. Traditionally considered a disease of children, adults may also acquire the disease. Because of declining incidence and a presentation that may overlap with other conditions, ARF may not be considered in the differential diagnosis. Failure to recognize ARF may result in delayed diagnosis and recurrent disease., Objective: This report is designed to assist emergency physicians in identifying components of the history and physical examination that are important to making a timely diagnosis of ARF., Case Report: An otherwise healthy man presented to the emergency department (ED) with clinical findings consistent with ARF. Despite presentation to the ED on three occasions, during which he was treated for various conditions, it was not until the 3(rd) encounter that the diagnosis of ARF was considered., Conclusion: Failure to recognize ARF may result in repeated ED visits, delayed diagnosis, and prolonged patient discomfort. Recognition of the condition is important to prevent recurrent disease., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are autoimmune conditions triggered by Group A Streptococcus skin or throat infections. If ARF/RHD is undetected, misdiagnosed or antibiotic treatment is not provided early, patients may develop cardiac failure, leading to premature death. Although it is an easily preventable disease, ARF/RHD remains the most significant cause of heart disease-associated deaths in people under 25 years old, both in low- and middle-income countries and among First Nations in high-income countries. Up to 30% of the patients with ARF/RHD present with a neurobehavioral condition – Sydenham's chorea (SC). The clinical course of SC is mostly self-limiting and is characterized by the onset of involuntary choreiform movements and neuropsychiatric features such as obsessive-compulsive disorder, tics, depression and anxiety, psychosis, and attention-deficit hyperactivity disorder. While the precise mechanism as to why only a proportion of patients with ARF/RHD develop SC remains unknown, an impaired blood–brain barrier is considered to play a central role in its development. The most well-characterized neurobehavioral outcome is stroke which may occur in isolation or as part of systemic thromboembolism. Both infective endocarditis and mitral valve disease with or without aortic valve disease increase the embolic and ischemic stroke risk. ARF/RHD is known to significantly impact the quality of life with neuropsychiatric consequences. Another neurobehavioral syndrome which occurs in the absence of ARF/RHD is "pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections" (PANDAS). PANDAS has been categorized as a subset of pediatric acute-onset neuropsychiatric syndromes. However, establishing a diagnosis of PANDAS has been challenging. In this review, we discuss the current status of our understanding regarding the different manifestations of poststreptococcal neurobehavioral changes. Particular attention is given to ARF/RHD-associated SC, and we highlight the areas for further research to understand the association between poststreptococcal sequelae and neurobehavioral abnormalities. [ABSTRACT FROM AUTHOR]

Group A Streptococcus (GAS), or Streptococcus pyogenes, is a gram-positive bacterium that extensively colonises within the human host. GAS is responsible for causing a range of human infections, such as pharyngitis, impetigo, scarlet fever, septicemia, and necrotising fasciitis. GAS pathogens have the potential to elicit fatal autoimmune sequelae diseases (including rheumatic fever and rheumatic heart diseases) due to recurrent GAS infections, leading to high morbidity and mortality of young children and the elderly worldwide. Antibiotic drugs are the primary method of controlling and treating the early stages of GAS infection; however, the recent identification of clinical GAS isolates with reduced sensitivity to penicillin-adjunctive antibiotics and increasing macrolide resistance is an increasing threat. Vaccination is credited as the most successful medical intervention against infectious diseases since it was discovered by Edward Jenner in 1796. Immunisation with an inactive/live-attenuated whole pathogen or selective pathogen-derived antigens induces a potent adaptive immunity and protection against infectious diseases. Although no GAS vaccines have been approved for the market following more than 100 years of GAS vaccine development, the understanding of GAS pathogenesis and transmission has significantly increased, providing detailed insight into the primary pathogenic proteins, and enhancing GAS vaccine design. This review highlights recent advances in GAS vaccine development, providing detailed data from preclinical and clinical studies across the globe for potential GAS vaccine candidates. Furthermore, the challenges and future perspectives on the development of GAS vaccines are also described. [ABSTRACT FROM AUTHOR]

Although rapid antigen tests (RADTs) for group A streptococcus (GAS) can help diagnose group A streptococcal pharyngitis, little is known about the inappropriate use of these RADTs. This retrospective observational study compared the appropriate vs. inappropriate use of RADTs in patients who had a RADT between January 2019 and August 2022. RADTs for patients with a low Centor score of 0–1 point were deemed inappropriate. Of the 1015 patients, 380 (37.4%) had inappropriate RADTs. Patients with asthma were associated with an increased risk of inappropriate testing. In contrast, during the coronavirus 2019 pandemic, outpatients and residents were associated with a reduced risk of inappropriate testing. Consequent to the inappropriate use of RADTs, 162 (16.0%) patients received potentially inappropriate antibiotics. Our results suggest that diagnostic stewardship for pharyngitis, including education for healthcare workers, is needed to reduce inappropriate test ordering and prevent unnecessary care. [ABSTRACT FROM AUTHOR]

Streptococcus pyogenes (group A Streptococcus; GAS), a Gram-positive coccal bacterium, poses a significant global disease burden, especially in low- and middle-income countries. Its manifestations can range from pharyngitis and skin infection to severe and aggressive diseases, such as necrotizing fasciitis and streptococcal toxic shock syndrome. At present, although GAS is still sensitive to penicillin, there are cases of treatment failure for GAS pharyngitis, and antibiotic therapy does not universally prevent subsequent disease. In addition to strengthening global molecular epidemiological surveillance and monitoring of antibiotic resistance, developing a safe and effective licensed vaccine against GAS would be the most effective way to broadly address GAS-related diseases. Over the past decades, the development of GAS vaccines has been stalled, mainly because of the wide genetic heterogeneity of GAS and the diverse autoimmune responses to GAS. With outbreaks of scarlet fever in various countries in recent years, accelerating the development of a safe and effective vaccine remains a high priority. When developing a GAS vaccine, many factors need to be considered, including the selection of antigen epitopes, avoidance of self-response, and vaccine coverage. Given the challenges in GAS vaccine development, this review describes the important virulence factors that induce disease by GAS infection and how this has influenced the progression of vaccine development efforts, focusing on several candidate vaccines that are further along in development. [ABSTRACT FROM AUTHOR]

Group A Streptococcus (GAS) is a human pathogenic bacterium that can trigger a wide range of diseases, including the autoimmune diseases acute rheumatic fever and rheumatic heart disease, causing major morbidity and mortality in many low‐ and middle‐income countries. Primary intervention programs have had limited success thus far, and a licensed vaccine has yet to be developed. The pilus of GAS is known to be involved in host cell adhesion, biofilm formation and immune evasion. We have a mucosal vaccine in development that expresses the pilus of GAS on the surface of the nonpathogenic bacterium Lactococcus lactis. To expand strain coverage, we combined seven L. lactis constructs, each expressing a different GAS pilus variant, and investigated the systemic and mucosal immune responses following immunization. Mice immunized with this combination showed specific immunoglobin G and immunoglobin A responses to the GAS pilus proteins of vaccine strains, at levels comparable to mice immunized with a single construct. Cross‐reactivity to pilus proteins of nonvaccine strains was also evident. Furthermore, protective efficacy against a homologous strain of GAS in a murine nasopharyngeal colonization model was observed. Overall, this study provides further evidence for using pilus‐expressing lactic acid bacteria as a vaccine to prevent upper respiratory tract GAS infections. [ABSTRACT FROM AUTHOR]

Introduction: Group A streptococcus (Streptococcus pyogenes) is one of the most lethal bacterial pathogens of humans, with increased risk of progression to septic shock and multiorgan failure in the pregnant population. The objective of this study is to systematically review the outcomes and management strategies for pregnancy and puerperal group A streptococcus infections in an effort to provide further guidance for prevention and treatment of a rare but lethal infection worldwide. Material and methods: A comprehensive search using puerperium and streptococcus pyogenes terms was completed across several registered databases. A total of 902 articles investigating pregnancy and puerperal group A streptococcus infection were identified, with 40 studies fulfilling inclusion criteria of original research articles in humans published from 1990 onwards reporting four or more unique cases of group A streptococcus in pregnancy or postpartum. This study was registered in PROSPERO: CRD42020198983. Results: A total of 1160 patients with pregnancy and puerperal group A streptococcus infection were identified. Most infections occurred postpartum (91.9%), with 4.7% reported antepartum and 0.6% intrapartum. Bacteremia was present in 49.0% of patients and endometritis in 45.9%. Puerperal sepsis was described in 28.2% of cases and progressed to streptococcal toxic shock syndrome in one‐third of such cases. Overall, the case fatality ratio was 2.0%, with one‐third of the deaths from antenatal cases including 3/22 (13.6%) cases of septic abortion and 10/46 (21.7%) antenatal cases of group A streptococcus infection. Conclusions: Group A streptococcus infection remains an important contributor to pregnancy and puerperal morbidity and mortality. Early recognition, diagnosis and aggressive management are important for favorable outcomes given the serious risk of sepsis and streptococcal toxic shock syndrome. [ABSTRACT FROM AUTHOR]

To identify the clinical characteristics of pregnancy associated group A streptococcus (GAS) infection and predictors for intensive care unit (ICU) admission. A retrospective cohort study of culture-proven pregnancy-related GAS infections in tertiary hospital Electronic medical records were reviewed, for cases of cultures positive GAS that were identified between January 2008 and July 2021. A GAS infection was defined by the isolation of the pathogen from a sterile liquid or tissue site. Blood and urine cultures were obtained from all patients with peripartum hyperpyrexia (fever >38 °C). Medical Personnel screening included cultures of the throat, rectum, and skin lesions (if present). In cases of hemodynamic instability patients were transferred ad hoc to ICU, according to the obstetrician and intensivist judgment. Of the 143,750 who delivered during the study period, 66 (0.04%) were diagnosed as having a pregnancy associated GAS infection. Of these, 57 patients presented postpartum, and represented the study cohort. The most common presenting signs and symptoms among puerperal GAS, were postpartum pyrexia (72%), abdominal pain (33%), and tachycardia (>100 bpm, 22%). 12 women (21.0%) developed streptococcal toxic shock syndrome (STSS. Predictors for STSS and ICU admission were: antibiotic administration >24 h from presentation postpartum, tachycardia, and a C-reactive protein level >200 mg/L. Women that received antibiotic prophylaxis during labor had a significantly lower rate of STSS (0 vs 10, 22.7%; p =.04). Deferral of medical intervention >24 h from the first registered abnormal sign had the most important impact on deterioration of women with invasive puerperal GAS. Antibiotic prophylaxis during labor in women with GAS may reduce associated complications. [ABSTRACT FROM AUTHOR]

IntroductionThe incidences of acute rheumatic fever (ARF) and rheumatic heart disease (RHD), which were leading causes of death in children in the 1920s, have decreased substantially. Considering the recent resurgence of scarlet fever and increased incidence of streptococcal pharyngitis in children, an investigation of the current status of ARF and RHD may be worthwhile.ObjectiveTo summarize the prevalence trends, pathogenic factors, and prevention strategies for ARF and RHD in children.MethodsA selective search of literature published between January 1920 and February 2023 was done in PubMed, using the terms “acute rheumatic fever”, “rheumatic heart disease”, “group A Streptococcus”, “pharyngitis”, “pharyngeal tonsillitis”, “scarlet fever”, “impetigo”, “obstructive sleep apnea syndrome” and “child”.ResultsOvercrowded homes and inadequate sanitation led to recurrent group A streptococcal infection, and the causal relationship between group A streptococcal infection and ARF/RHD was well established. Streptococcal infectious diseases, such as group A streptococcal pharyngeal tonsillitis, SF, impetigo, and obstructive sleep apnea syndrome, were associated with the occurrence of ARF and RHD. ARF and RHD were still prevalent in young people of developing countries and economically poor populations of high-income countries. Universal disease registration systems were critical to locating disease outbreaks, tracking disease transmission, and identifying high-risk populations. Four-level prevention strategies were effective in reducing the incidence and mortality of ARF and RHD.ConclusionsRegistry and preventive measures for ARF and RHD should be strengthened in areas of dense population; poor sanitation; resurgence of SF; and high incidence of streptococcal pharyngitis, impetigo, and obstructive sleep apnea syndrome.

A ubiquitous human pathogen, Streptococcus pyogenes (Group A Streptococcus, GAS) causes infections from mild pharyngitis to severe septic infections. Acute kidney injury (AKI) is a condition of prompt decline of renal function. The aim of the present study was to report the incidence and outcome of AKI in GAS bacteraemia and to evaluate the diagnostic value of serum C-reactive protein as an indicator of AKI. All adult patients with GAS bacteraemia treated at Turku University Hospital from 2007 to 2018 were identified and their patient records were scrutinised. Of 195 included patients, 38 (19.5%) had AKI stage 1, 20 (10.3%) AKI stage 2 and 26 (13.3%) AKI stage 3 and 111 (56.9%) did not have AKI. The adjusted seven-day mortality was significantly higher in AKI stages 2 and 3 compared to the non-AKI group (15% and 19% vs. 3.6%; p =.046 and.006, respectively). Of the survivors, 95.8% met the criteria of renal recovery at discharge. The higher the AKI stage, the higher was the mean serum CRP level on admission. The optimal cut-off for CRP to identify patients with AKI stage 2 or 3 was ≥244 mg/l (sensitivity 82.6% and specificity 75.8%). AKI is common in patients with GAS bacteraemia and the severity of AKI correlates with the CRP level on admission. The mortality of patients with GAS bacteraemia and AKI is significantly higher than of patients without AKI. Most survivors, however, show renal recovery. AKI is common in group A Streptococcal bacteraemia and increases mortality compared to bacteraemia alone. However, renal recovery is also common. A high CRP level on admission correlates significantly positively with the degree of severity of AKI. [ABSTRACT FROM AUTHOR]

Group A Streptococcus (Strep A) causes both uncomplicated and severe invasive infections, as well as the post-infection complications acute rheumatic fever and rheumatic heart disease. Despite the high global burden of disease resulting from Strep A infections, there is not a licensed vaccine. A 30-valent M protein-based vaccine has previously been shown to be immunogenic in animal models and in a Phase I clinical trial (NCT02564237). Here, we assessed the immunogenicity of a 30-valent messenger (m)RNA vaccine designed to express the same M peptide targets as the 30-valent protein vaccine and compared it with the protein vaccine. Female New Zealand white rabbits were immunized with one of four vaccine formulations (3 doses of each formulation at days 1, 28, and 56): soluble mRNA (100 μg/animal), C-terminal transmembrane mRNA (100 μg/animal), protein vaccine (400 μg/animal), or a non-translatable RNA control (100 μg/animal). Serum was collected one day prior to the first dose and on days 42 and 70. Rabbit serum samples were assayed for antibody levels against synthetic M peptides by ELISA. HL-60 opsonophagocytic killing (OPK) assays were performed to assess functional antibody levels. Serum IgG levels were similar for the mRNA and protein vaccines. The CtTM version of the mRNA vaccine elicited slightly higher antibody levels than the mRNA designed to express soluble proteins. OPK activity was similar for the mRNA and protein vaccines, regardless of M type. The total antibody responses and functional antibody levels elicited by the 30-valent mRNA Strep A vaccines were similar to those observed following immunization with the analogous protein vaccine. The mRNA vaccine platform provides potential advantages to protein-based vaccines including inherent adjuvant activity, increased production efficiency, lower cost, and the potential to rapidly change epitopes/peptides, all of which are important considerations related to multivalent Strep A vaccine development. [ABSTRACT FROM AUTHOR]

Streptococcus pyogenes (group A Streptococcus; GAS), a Gram-positive coccal bacterium, poses a significant global disease burden, especially in low- and middle-income countries. Its manifestations can range from pharyngitis and skin infection to severe and aggressive diseases, such as necrotizing fasciitis and streptococcal toxic shock syndrome. At present, although GAS is still sensitive to penicillin, there are cases of treatment failure for GAS pharyngitis, and antibiotic therapy does not universally prevent subsequent disease. In addition to strengthening global molecular epidemiological surveillance and monitoring of antibiotic resistance, developing a safe and effective licensed vaccine against GAS would be the most effective way to broadly address GAS-related diseases. Over the past decades, the development of GAS vaccines has been stalled, mainly because of the wide genetic heterogeneity of GAS and the diverse autoimmune responses to GAS. With outbreaks of scarlet fever in various countries in recent years, accelerating the development of a safe and effective vaccine remains a high priority. When developing a GAS vaccine, many factors need to be considered, including the selection of antigen epitopes, avoidance of self-response, and vaccine coverage. Given the challenges in GAS vaccine development, this review describes the important virulence factors that induce disease by GAS infection and how this has influenced the progression of vaccine development efforts, focusing on several candidate vaccines that are further along in development.

Abstract Objectives: To explore the acceptability of a novel, outreached‐based approach to improve primary and primordial prevention of Strep A skin sores, sore throats and acute rheumatic fever in remote Aboriginal communities. Methods: A comprehensive prevention program delivered by trained Aboriginal Community Workers was evaluated using approximately fortnightly household surveys about health and housing and clinical records. Results: Twenty‐seven primary participants from three remote Aboriginal communities in the Northern Territory consented, providing 37.8 years of retrospective baseline data and 18.5 years of prospective data during the study period. Household members were considered to be secondary participants. Five Aboriginal Community Workers were trained and employed, delivering a range of supports to households affected by acute rheumatic fever including environmental health support and education. Clinical record audit and household self‐report of Strep A infections were compared. No association between clinical‐ and self‐report was identified. Conclusions: Ongoing participation suggests this outreach‐based prevention program was acceptable and associated with improved reporting of household maintenance issues and awareness of prevention opportunities for Strep A infections. Implications for public health: Biomedical, clinic‐based approaches to the management of Strep A infections in remote communities can be usefully augmented by outreach‐based supports delivered by Aboriginal Community Workers responding to community needs.

Group A Streptococcus (Strep A) is responsible for a significant global health and economic burden. The recent prioritization of Strep A vaccine development by the World Health Organization has prompted global research activities and collaborations. To progress this prioritization, establishment of robust surveillance for Strep A to generate updated regional disease burden estimates and to establish platforms for future impact evaluation is essential. Through the activities of the Strep A Vaccine Global Consortium (SAVAC), we have refined and harmonized surveillance protocols for 7 Strep A disease endpoints with a view that these will form part of surveillance standards for ongoing research and public health activities. [ABSTRACT FROM AUTHOR]