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      The Limitations of the Rheumatogenic Concept for Group A Streptococcus: Systematic Review and Genetic Analysis

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          Abstract

          Background

          The concept that a minority of group A streptococcus (GAS) emm types are more “rheumatogenic” than others has been widely disseminated. We aimed to provide a comprehensive list of acute rheumatic fever–associated GAS isolates and assess the presence of associated rheumatogenic motifs.

          Methods

          Articles reporting GAS emm-type or emm-type–specific antibody responses associated with rheumatic fever were identified from 1 January 1944 to 31 July 2018. The revised Jones criteria were used to define rheumatic fever with a maximum period of 4 weeks between disease onset and microbiological characterization. A database of 175 representative M-protein sequences was used to analyze the protein diversity of rheumatic fever–associated strains in a phylogenetic tree and to identify the presence of 10 previously recognized rheumatogenic motifs.

          Results

          We included 411 cases of rheumatic fever, for which microbiological characterization identified 73 different emm types associated with the disease. The classic rheumatogenic emm types represented only 12.3% of the 73 emm types and were responsible for 31.6% of the 411 clinical cases. Rheumatic fever–associated emm types were disseminated throughout the phylogeny, suggesting they belong to various genetic backgrounds. Rheumatic fever–associated motifs were present in only 15.1% of the rheumatic fever–associated emm types and only 24.8% of clinical cases.

          Conclusions

          The concept of rheumatogenicity should be extended to include strains other than those classically described. Our results highlight significant knowledge gaps in the understanding of rheumatic fever pathogenesis and suggest that a GAS vaccine candidate should offer broad coverage against a variety of GAS genetic variants in order to protect against this serious sequela.

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          Most cited references32

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          Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

          David Moher and colleagues introduce PRISMA, an update of the QUOROM guidelines for reporting systematic reviews and meta-analyses
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            Global, Regional, and National Burden of Rheumatic Heart Disease, 1990-2015.

            Rheumatic heart disease remains an important preventable cause of cardiovascular death and disability, particularly in low-income and middle-income countries. We estimated global, regional, and national trends in the prevalence of and mortality due to rheumatic heart disease as part of the 2015 Global Burden of Disease study.
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              Acute rheumatic fever and rheumatic heart disease

              Acute rheumatic fever (ARF) is the result of an autoimmune response to pharyngitis caused by infection with group A Streptococcus. The long-term damage to cardiac valves caused by ARF, which can result from a single severe episode or from multiple recurrent episodes of the illness, is known as rheumatic heart disease (RHD) and is a notable cause of morbidity and mortality in resource-poor settings around the world. Although our understanding of disease pathogenesis has advanced in recent years, this has not led to dramatic improvements in diagnostic approaches, which are still reliant on clinical features using the Jones Criteria, or treatment practices. Indeed, penicillin has been the mainstay of treatment for decades and there is no other treatment that has been proven to alter the likelihood or the severity of RHD after an episode of ARF. Recent advances - including the use of echocardiographic diagnosis in those with ARF and in screening for early detection of RHD, progress in developing group A streptococcal vaccines and an increased focus on the lived experience of those with RHD and the need to improve quality of life - give cause for optimism that progress will be made in coming years against this neglected disease that affects populations around the world, but is a particular issue for those living in poverty.
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                Author and article information

                Journal
                Clinical Infectious Diseases
                Oxford University Press (OUP)
                1058-4838
                1537-6591
                April 01 2020
                March 17 2020
                July 23 2019
                April 01 2020
                March 17 2020
                July 23 2019
                : 70
                : 7
                : 1453-1460
                Affiliations
                [1 ]Academic Children Hospital Queen Fabiola, Université libre de Bruxelles, Brussels, Belgium
                [2 ]Molecular Bacteriology Laboratory, Université libre de Bruxelles, Brussels, Belgium
                [3 ]Tropical Diseases Research Group, Murdoch Children’s Research Institute, Melbourne, Australia
                [4 ]Faculty of Medical and Health Sciences, The University of Auckland, New Zealand
                [5 ]Microbiological Diagnostic Unit Public Health Laboratory, University of Melbourne, Australia
                [6 ]Centre for International Child Health, University of Melbourne, Australia
                Article
                10.1093/cid/ciz425
                31334754
                c0ba3c28-cfda-4ae1-91f2-3ead6e017927
                © 2019

                https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

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