High Incidence of Invasive Group A Streptococcus Disease Caused by Strains of Uncommon emm Types in Thunder Bay, Ontario, Canada

Abstract

An outbreak of type emm59 invasive group A Streptococcus (iGAS) disease was declared in 2008 in Thunder Bay District, Northwestern Ontario, 2 years after a countrywide emm59 epidemic was recognized in Canada. Despite a declining number of emm59 infections since 2010, numerous cases of iGAS disease continue to be reported in the area. We collected clinical information on all iGAS cases recorded in Thunder Bay District from 2008 to 2013. We also emm typed and sequenced the genomes of all available strains isolated from 2011 to 2013 from iGAS infections and from severe cases of soft tissue infections. We used whole-genome sequencing data to investigate the population structure of GAS strains of the most frequently isolated emm types. We report an increased incidence of iGAS in Thunder Bay compared to the metropolitan area of Toronto/Peel and the province of Ontario. Illicit drug use, alcohol abuse, homelessness, and hepatitis C infection were underlying diseases or conditions that might have predisposed patients to iGAS disease. Most cases were caused by clonal strains of skin or generalist emm types (i.e., emm82, emm87, emm101, emm4, emm83, and emm114) uncommonly seen in other areas of the province. We observed rapid waxing and waning of emm types causing disease and their replacement by other emm types associated with the same tissue tropisms. Thus, iGAS disease in Thunder Bay District predominantly affects a select population of disadvantaged persons and is caused by clonally related strains of a few skin and generalist emm types less commonly associated with iGAS in other areas of Ontario.

FIG 1

Reported incidence rates of invasive group A streptococcal disease per 100,000 population in Thunder Bay, in the metropolitan region of Toronto/Peel, and in the province of Ontario, from 2001 to 2013. The incidence of iGAS disease in Thunder Bay sharply increased in 2007, and it peaked in 2008 coincidentally with the declaration of a local outbreak of emm59 invasive disease. An extensive chart review revealed incidence rates of iGAS disease in Thunder Bay that were 3 to 6 times those in Toronto/Peel and the provincial average between 2010 and 2013, years in which the isolation of emm59 strains was minimal.

FIG 2

(A) emm type distribution of isolates causing iGAS disease in Thunder Bay, in metropolitan Toronto/Peel, and in the rest of Ontario during the period of 2011 to 2013. Strains of emm1 GAS were among the top 6 emm types responsible for iGAS disease in all geographical areas. The other top 5 emm types (emm82, emm83, emm87, emm101, and emm114) associated with iGAS disease in Thunder Bay were not observed among the top 6 emm types causing disease in the metropolitan region of Toronto/Peel or in the rest of Ontario. There were significant differences in the emm type distribution between Thunder Bay and Toronto/Peel (chi-square test, P < 0.0001). (B) Source of isolation of iGAS strains from Thunder Bay, Toronto/Peel, and the rest of Ontario. Most strains were isolated from blood in all three geographical areas. However, proportionally fewer strains were isolated from blood, and more were isolated from synovial fluid (SF), in Thunder Bay. CSF, cerebrospinal fluid; other, other sources included pleural fluid and undetermined autopsy tissue. (C) Tissue tropism of iGAS strains isolated from 2011 to 2013 in Thunder Bay, Toronto/Peel, and the rest of Ontario. Significant differences were observed for skin, throat, and generalist groups (defined according to references 11–13) between Thunder Bay and Toronto/Peel plus the rest of Ontario (chi-square test, P < 0.05). Unknown, nontypeable strains.

FIG 3

(A) emm distribution of strains isolated in Thunder Bay from severe skin and soft tissue infections that did not meet the criteria for iGAS disease during 2011 to 2013. The emm type distribution closely resembles the overall distribution of emm types associated with iGAS disease in Thunder Bay during the period. (B) emm type distribution of an extended GAS collection comprising strains causing invasive disease and severe skin and soft tissue infections that did not meet the criteria for iGAS disease during 2011 to 2013. In 2011, the 4 most frequently identified emm types in Thunder Bay were emm82 (23.1%), emm83 (20.5%), emm87 (10.3%), and emm114 (7.7%). In 2012, the most frequently identified emm types were emm87, emm82, emm101, and emm89 (25%, 22.2%, 16.7%, and 8.3%, respectively). Strains of emm4, emm1, emm101, and emm11 predominated in 2013 (18.2%, 15.9%, 13.6%, and 11.4%, respectively). When the 3 years are taken together, the most frequently isolated emm types were emm82 (16%), emm101 (10.9%), emm87 (9.2%), emm1 (7.6%), emm4 (6.7%), emm114 (5.9%), and emm83 (5%).

FIG 4

Genome atlases and phylogenetic relationships of GAS strains whose genomes were sequenced to closure. Strains NGAS596 (emm82) (A), NGAS327 (emm83) (B), NGAS743 (emm87) (C), NGAS638 (emm101) (D), and NGAS322 (emm114) (E). Data from innermost to outermost circles in the atlases are described in the figure itself, with the exception of the outermost circle, which depicts genome landmarks such as prophages, genes used on the GAS multilocus-sequence typing scheme, and other genes of interest. RD322.1 is an integrative-conjugative element. GC (guanine-cytosine) skew, or (G−C)/(G+C), averaged over a moving window of 10,000 bp. (F) Neighbor-joining tree constructed using 68,511 single-nucleotide polymorphisms identified among all closed GAS genomes available in GenBank against the genome of emm59 reference strain MGAS15252. CDS, coding DNA sequence.

FIG 5

Inferred phylogenetic relationship among GAS strains recovered in Thunder Bay from invasive disease cases and from cases of severe soft tissue infection. Neighbor-joining phylogenetic trees for each of emm82 (A), emm83 (B), emm87 (C), emm101 (D), emm114 (E), and emm4 (F) strains were constructed using nonredundant, whole-genome single-nucleotide polymorphism (SNP) loci (emm82, 56 SNPs; emm83, 259 SNPs; emm87, 59 SNPs; emm101, 29 SNPs; emm114, 12 SNPs; emm4, 7 SNPs) identified against their corresponding reference genomes. Strains from 2011 are depicted in orange, those from 2012, in purple, and those from 2013, in gray. See the supplemental material for details about methods.