Canada-Wide Epidemic of emm74 Group A Streptococcus Invasive Disease

Abstract

Background: The number of invasive group A Streptococcus (iGAS) infections due to hitherto extremely rare type emm74 strains has increased in several Canadian provinces since late 2015. We hypothesized that the cases recorded in the different provinces are linked and caused by strains of an emm74 clone that recently emerged and expanded explosively.

Methods: We analyzed both active and passive surveillance data for iGAS infections and used whole-genome sequencing to investigate the phylogenetic relationships of the emm74 strains responsible for these invasive infections country-wide.

Results: Genome analysis showed that highly clonal emm74 strains, genetically different from emm74 organisms previously circulating in Canada, were responsible for a country-wide epidemic of >160 invasive disease cases. The emerging clone belonged to multilocus sequence typing ST120. The analysis also revealed dissemination patterns of emm74 subclonal lineages across Canadian provinces. Clinical data analysis indicated that the emm74 epidemic disproportionally affected middle-aged or older male individuals. Homelessness, alcohol abuse, and intravenous drug usage were significantly associated with invasive emm74 infections.

Conclusions: In a period of 20 months, an emm74 GAS clone emerged and rapidly spread across several Canadian provinces located more than 4500 km apart, causing invasive infections primarily among disadvantaged persons.

Keywords: Canada; emerging strain genotype; epidemic; group A Streptococcus; homeless; invasive disease; outbreak; populations at risk.

Figure 1.

Canada-wide expansion of emm74 group A Streptococcus invasive disease. A, Isolation of invasive group A Streptococcus (iGAS) isolates in all Canadian provinces and territories from January 2012 to June 2017. Bars show emm type distribution as a percentage of the total number of isolates in each year (first 6 months for year 2017). The percentage of emm74 iGAS isolates, which were rarely seen in Canada, strikingly increased starting in 2015, spiked in 2016, and continued to be isolated in high numbers by June 2017, causing thus far more than 160 invasive cases in several Canadian provinces. B, Geographical origin and temporal distribution of 168 emm74 isolates recovered in Canada from individual patients with emm74 iGAS disease. For the period 2012 to 2014, only 2 emm74 iGAS cases were recorded in Canada, 1 in the province of Alberta (May 2012) and 1 in the province of Ontario (January 2013). No further emm74 invasive disease cases were observed until 2 years later, when 2 emm74 iGAS strains were isolated in Saskatchewan during the second quarter of 2015. Then, beginning in late 2015 and continuing to June 2017, increasing numbers of emm74 iGAS were isolated in the provinces of British Columbia, Ontario, Alberta, and Quebec.

Figure 2.

Demographics of patients with type emm74 invasive disease in Canada and source of isolation of invasive emm74 group A Streptococcus invasive strains responsible for these infections. A, Age and sex of patients with emm74 iGAS disease in Canada for the period January 2012 to June 2017. Sex data were unavailable for 4 patients, and age was unavailable for 1 (indicated by NA). Overall, the distribution indicates that emm74 iGAS disease disproportionately affects adult middle-aged or older males. B, Anatomical source of isolation of the 168 emm74 iGAS isolates. Data are shown as percentage of the total number of isolates. The majority (n = 114, 67.9%) of isolates were recovered from blood, followed by abscesses and soft tissue (n = 32, 19%), synovial fluid (n = 11, 6.5%), peritoneal fluid (n = 3, 1.8%), and pleural fluid (n = 3, 1.8%). Five isolates (3%) were recovered from undetermined aspirates or from surgical specimens, collectively defined as “other” in the figure legend.

Figure 3.

Genomic features and phylogenetic relationships of emm74 invasive group A Streptococcus isolates. A, Genome atlas of emm74 group A Streptococcus (GAS) reference strain NGAS979. Data from innermost to outermost circles in the atlas are described in the figure legend, with the exception of the outermost circle, which depicts genome landmarks such as mobile genetic element (prophages, prophage remnants, and integrative-conjugative elements, indicated by red boxes) and virulence genes, including those encoding superantigens. The hasABC locus is indicated by a black box, the FCT locus by a yellow box, and the mga regulon by a dark pink box. GC skew -or (G-C)/(G+C)- is averaged over a moving window of 10 000 bp. B, Inferred phylogenetic relationships between emm74 GAS strains and 55 strains of 25 other emm types, for which complete genome sequences are available in GenBank. A neighbor-joining phylogenetic tree was constructed using 76 311 nonredundant biallelic single nucleotide polymorphism (SNP) loci identified in the genomes of the strains relative to the core genome of the reference emm74 strain NGAS979. Strain names and emm types for non-emm74 strains are indicated at the tip of the branches. The reference emm74 strain and all 136 emm74 invasive and noninvasive isolates recovered since October 2015 in Canada clustered tightly in a discrete epidemic cluster (indicated in red). All other emm74 isolates from Canada are depicted in orange. C, Inferred phylogenetic relationship among 147 emm74 GAS strains from Canada. A neighbor-joining phylogenetic tree was constructed using 10 224 nonredundant biallelic SNP loci identified in the genomes of the emm74 isolates relative to the core genome of the reference emm74 strain NGAS979. The 136 emm74 GAS isolates recovered in Canada since October 2015 for which we generated genome data (the epidemic cluster) are monoclonal and genetically distinct from previously isolated emm74 strain SNPs. We arbitrarily divided these nonepidemic emm74 isolates into 3 groups: a first group of “close outliers,” comprising 4 isolates from Ontario in 1996, 2002, and 2013, a more distantly related single isolate from Alberta isolated in 2012, a group of 5 highly divergent “distant outlier” emm74 isolates recovered in Alberta, Saskatchewan, and Ontario from invasive infections, and 1 noninvasive isolate from New Brunswick recovered in 2013. Provinces are indicated by different colors, as per the caption in (D). D, Diversification of the emm74 GAS epidemic clone. The neighbor-joining phylogenetic tree was constructed using 71 nonredundant SNP loci identified among the 136 epidemic emm74 isolates relative to the genome of the reference strain NGAS979. The circles are colored to indicate province of isolation, as per the figure caption, and their sizes are proportional to the number of isolates with identical genotypes. The location in the phylogenetic tree of the first emm74 invasive isolate in each province is indicated by an arrow. Abbreviations: CDS, coding DNA sequence; GC, Guanine-cytosine.