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

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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Immunopathological mechanisms in bacterial-host interactions

Philosophical Transactions of the Royal Society of London Series B Biological Sciences ◽

10.1098/rstb.1983.0091 ◽

1983 ◽

Vol 303 (1114) ◽

pp. 177-187 ◽

Cited By ~ 6

Keyword(s):

Rheumatic Fever ◽

Group A Streptococcus ◽

Biological Properties ◽

Antigenic Determinants ◽

Bacterial Host ◽

Poststreptococcal Glomerulonephritis ◽

Host Interactions ◽

Disease States ◽

Group A ◽

Specific Tissue

The ability of bacteria to cause immunopathological damage in the host may take a variety of forms. These pathways may be conveniently grouped under three major headings: (1) organisms that can cause damage via shared antigenic determinants between host and bacterium; (2) those organisms that suppress the host’s response; and (3) organisms that release substances with specific biological properties or have receptors for specific tissue sites. The group A streptococcus is among the most versatile of these bacteria because it appears that it may use all three pathways in various streptococcal-related disease states. In rheumatic fever and chorea it appears that cross-reactive antigens play a major role in inducing immunopathological damage in that there is both a heightened humoral and cellular reaction by the host to these cross-reactive determinants. Recent evidence also indicates that rheumatic fever individuals express certain B cell antigens that may be associated with susceptibility to the disease. In the other complications of streptococcal infections, namely poststreptococcal glomerulonephritis, the bacterium uses both suppression of the host’s immune response and the excretion of a particular protein common to all nephritis-associated strains to achieve its immunopathological damage. In this context, other examples of bacterial-host interactions will be discussed as evidence for the common pathways used by microbes to cause immunopathological damage in the host.

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Unexpected relationships between frequency of antimicrobial resistance, disease phenotype and emm type in group A Streptococcus

Microbial Genomics ◽

10.1099/mgen.0.000316 ◽

2019 ◽

Vol 5 (11) ◽

Cited By ~ 1

Author(s):

Misu A. Sanson ◽

Olga R. Macias ◽

Brittany J. Shah ◽

Blake Hanson ◽

Luis Alberto Vega ◽

...

Keyword(s):

Antimicrobial Resistance ◽

Group A Streptococcus ◽

Disease Phenotype ◽

Group A ◽

Emm Type

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Toll-like Receptor 2-and 4-Mediated Reciprocal Th17 and Antibody Responses to Group A Streptococcus Infection

The Journal of Infectious Diseases ◽

10.1093/infdis/jiw598 ◽

2016 ◽

pp. jiw598 ◽

Cited By ~ 3

Author(s):

Xiaoshuang Wang ◽

Xin Fan ◽

Shuai Bi ◽

Ning Li ◽

Beinan Wang

Keyword(s):

Group A Streptococcus ◽

Antibody Responses ◽

Toll Like Receptor ◽

Group A ◽

Toll Like Receptor 2

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Evaluation of safety and immunogenicity of a group A streptococcus vaccine candidate (MJ8VAX) in a randomized clinical trial

PLoS ONE ◽

10.1371/journal.pone.0198658 ◽

2018 ◽

Vol 13 (7) ◽

pp. e0198658 ◽

Cited By ~ 20

Author(s):

Silvana Sekuloski ◽

Michael R. Batzloff ◽

Paul Griffin ◽

William Parsonage ◽

Suzanne Elliott ◽

...

Keyword(s):

Clinical Trial ◽

Randomized Clinical Trial ◽

Vaccine Candidate ◽

Group A Streptococcus ◽

Group A

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Rheumatic Fever Article Questioned

PEDIATRICS ◽

10.1542/peds.74.6.1133a ◽

1984 ◽

Vol 74 (6) ◽

pp. 1133-1134

Author(s):

SYLVIA P. GRIFFITHS

Keyword(s):

Rheumatic Fever ◽

Intramuscular Injection ◽

Group A Streptococcus ◽

Penicillin G ◽

Benzathine Penicillin ◽

Benzathine Penicillin G ◽

Group A

To the Editor.— The suggestion of Nordin1 that there may be a need to re-evaluate the current recommended prophylaxis for children with rheumatic fever is valid, particularly if carefully planned and controlled studies could be carried out. However, the author's contention that "It has been assumed that the levels of penicillin [following monthly intramuscular injection of 1.2 million units of benzathine penicillin G] are adequate to prevent reinfection with group A streptococcus, and hence to prevent recurrences of rheumatic fever" has always been qualified by others.

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Distribution of emm type and antibiotic susceptibility of group A streptococci causing invasive and noninvasive disease

Journal of Medical Microbiology ◽

10.1099/jmm.0.2008/002642-0 ◽

2008 ◽

Vol 57 (11) ◽

pp. 1383-1388 ◽

Cited By ~ 43

Author(s):

Takeaki Wajima ◽

Somay Y. Murayama ◽

Katsuhiko Sunaoshi ◽

Eiichi Nakayama ◽

Keisuke Sunakawa ◽

...

Keyword(s):

Streptococcus Pyogenes ◽

Macrolide Antibiotic ◽

Group A Streptococcus ◽

Acute Otitis Media ◽

Toxic Shock ◽

Medical Institutions ◽

Invasive Infections ◽

Group A ◽

Resistant Strains ◽

Emm Type

To determine the prevalence of macrolide antibiotic and levofloxacin resistance in infections with Streptococcus pyogenes (group A streptococcus or GAS), strains were collected from 45 medical institutions in various parts of Japan between October 2003 and September 2006. Four hundred and eighty-two strains from patients with GAS infections were characterized genetically. Strains were classified into four groups according to the type of infection: invasive infections (n=74) including sepsis, cellulitis and toxic-shock-like syndrome; acute otitis media (AOM; n=23); abscess (n=53); and pharyngotonsillitis (n=332). Among all strains, 32 emm types were identified; emm1 was significantly more common in invasive infections (39.2 %) and AOM (43.5 %) than in abscesses (3.8 %) or pharyngotonsillitis (10.2 %). emm12 and emm4 each accounted for 23.5 % of pharyngotonsillitis cases. Susceptibility of GAS strains to eight β-lactam agents was excellent, with MICs of 0.0005–0.063 μg ml−1. Macrolide-resistant strains accounted for 16.2 % of all strains, while the percentages of strains possessing the resistance genes erm(A), erm(B) and mef(A) were 2.5 %, 6.2 % and 7.5 %, respectively. Although no strains with high resistance to levofloxacin were found, strains with an MIC of 2–4 μg ml−1 (17.4 %) had amino acid substitutions at either Ser-79 or Asp-83 in ParC. These levofloxacin-intermediately resistant strains included 16 emm types, but macrolide-resistant strains were more likely than others to represent certain emm types.

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1891. Invasive Group A Streptococcus Infections Among Residents of Multiple Nursing Homes—Denver, Colorado, 2017–2018

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz359.121 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S55-S56

Author(s):

Osatohamwen Idubor ◽

Nisha B Alden ◽

Srinivas Nanduri ◽

Abimbola Ogundimu ◽

Sukarma S S Tanwar ◽

...

Keyword(s):

Nursing Homes ◽

Infection Control ◽

Group A Streptococcus ◽

Multiple Infection ◽

Invasive Group ◽

Increased Risk ◽

Group A ◽

Sterile Site ◽

Colorado Department ◽

Emm Type

Abstract Background Older adults residing in nursing homes (NH) are at increased risk for invasive group A Streptococcus (GAS) infections due to advanced age, presence of wounds, and comorbidities; approximately one-third of infected patients die. Beginning in 2015, increasing numbers of GAS infections in NH residents and several NH clusters were reported from the Denver metropolitan area. Colorado Department of Public Health and Environment (CDPHE) and CDC investigated to characterize cases and assess if outbreaks resulted from interfacility transmission. Methods We reviewed data from Active Bacterial Core surveillance (ABCs) in the 5-county Denver area from January 2017 to June 2018. We defined a case as isolation of GAS from a normally sterile site in an NH resident. GAS isolates underwent whole-genome sequencing (WGS) at CDC’s Streptococcus Laboratory to determine emm types for genotyping. Among isolates with the same emm type, pairwise single-nucleotide polymorphism (SNP) distances were calculated using Nucmer software. In October 2018, a CDPHE-CDC team assessed infection control at NHs with cases of the most common emm type. Results Over 18 months, among >100 NHs in the Denver area, ≥1 GAS case was identified in 29 NHs, with 6 having ≥3 cases. During this period, 68 cases in NH residents were identified. WGS identified 17 emm types among isolates from these cases; most common was emm11.10 (34%, n = 22), a rare subtype in ABCs. All emm11.10 isolates had nearly identical genomes (average pairwise SNP distance: 3.2), and were isolated from 10 NHs, with 2 NHs having ≥ 4 cases. Multiple infection control lapses were noted during site visits to 8 NHs. Conclusion Multiple outbreaks due to GAS were noted in 5-county Denver area NHs in 2017–2018. WGS of surveillance isolates identified a rarely seen emm subtype 11.10 from multiple facilities with temporal and genomic clustering suggesting interfacility GAS transmission. Disclosures All Authors: No reported Disclosures.

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