Expansion of Invasive Group A Streptococcus M1UK Lineage in Active Bacterial Core Surveillance, United States, 2019‒2021

From 2015–2018 to 2019‒2021, hypertoxigenic M1UK lineage among invasive group A Streptococcus increased in the United States (1.7%, 21/1,230 to 11%, 65/603; p<0.001). M1UK was observed in 9 of 10 states, concentrated in Georgia (n = 41), Tennessee (n = 13), and New York (n = 13). Genomic cluster analysis indicated recent expansions.


DISPATCHES
T he M1 UK lineage of group A Streptococcus (GAS) is a hypertoxigenic clone within the serotype M1 GAS strain and has been associated with increased scarlet fever and invasive GAS (iGAS) disease incidence in the United Kingdom since 2014 (1)(2)(3).M1 UK carries 27 characteristic lineage-defining single-nucleotide variants (SNVs) that distinguish it from other globally circulating M1 GAS clones (1).By 2020, M1 UK had also became the dominant clone among M1 GAS in England (3), the Netherlands (4), and Australia (5) and showed substantial presence in Canada (6).
In the United States, M1 UK was identified as a minor clone of M1 iGAS isolates in the Active Bacterial Core surveillance (ABCs) system, a laboratory-and population-based surveillance system for invasive bacterial infections that is currently implemented in 10 US states (7), in 2015-2018 (8).Using genomic surveillance data in ABCs, we investigated the trend of M1 UK in 2019-2021 and documented the characteristics of iGAS infections caused by M1 UK .

The Study
We identified iGAS cases through ABCs and mapped whole-genome sequencing reads of M1 isolates against the M1 reference genome MGAS5005 to identify M1UK based on previously reported characteristic M1UK SNVs (1).We constructed phylogenetic trees by using kSNP3.0software (9).We identified genomic clusters by using a hierarchical cluster analysis with a cutoff value of 10 SNVs as described (10).We evaluated change of M1UK proportion among M1 iGAS over time by using the χ 2 test for trend in proportions (trend test).We used the Fisher exact test to assess equality of proportions.All p values were 2 sided, and we considered p<0.05 statistically significant.We performed all analyses by using R software version 3.4.3(The R Foundation for Statistical Computing, https://www.r-project.org).
The clusters displayed clear signatures of temporal and geographic relatedness (Appendix Figure 2).For example, the largest cluster, cluster_1, showed a sharp increase of cases at the beginning of 2020, followed by a rapid decrease.The second largest cluster, cluster 2, showed relatively stable case numbers spanning from the third quarter of 2018 to the third quarter of 2020.Within a genomic cluster, most M1 UK iGAS were identified in 1 or 2 states, suggesting a localized spread of the infection.
Patients infected by the M1 UK strain showed similar age, sex, and syndrome distribution compared with patients infected by non-M1 UK M1 GAS (Table ), except that M1 UK isolates were more likely to be found in patients with pneumonia (33% vs. 22%; p = 0.033).The case-fatality rate was high for M1 UK iGAS infection (22%) although it was not significantly different from that of non-M1 UK M1 iGAS (15%; p = 0.089).In subgroup analysis stratified by time (2015-2018, 2019-2021) and location (GA, TN, and NY only), M1 UK isolates were associated with higher proportions of speC, ssa, sda1, and pneumonia compared with non-M1 UK isolates in all 3 subgroups (Appendix Tables 1-3), except for speC in 2019-2021.The difference in subgroup analysis was generally not statistically significant, potentially caused by smaller sample size and reduced power in a subgroup.

Conclusions
This study demonstrates a substantial increase of M1 UK lineage during 2019-2021 in the ABCs sites in the United States.Additional data are needed to determine variance in M1 UK iGAS incidence across states outside the 10 states in ABCs.The proportion of M1 UK iGAS in ABCs remains much lower than that reported in England (3), Australia (5), and the Netherlands (4).We documented the mode of expansion for the M1 UK lineage in the United States by determining whether the 86 M1 UK iGAS cases could be explained by 1 recent introduction or multiple ones.We tracked the shape and characteristics of epidemiologic curves for each Expansion of iGAS M1 UK Lineage, United States cluster, which could help understand different patterns of disease transmission.The increase was associated with the formation and expansion of multiple genomic clusters in which each cluster was mostly found in only 1 or 2 states.The results suggested that the M1 UK clone might have been introduced and Expansion of iGAS M1 UK Lineage, United States circulated in different geographic locations in the United States, rather than spreading from a recent single introduction event.
In 2020, emm1 was the leading cause of iGAS only in Georgia and New York in ABCs.In that year, the proportion of M1 UK isolates among emm1 iGAS was 38% (16/42) in Georgia and 25% (5/20) in New York.It appeared that M1 UK lineage followed the same state preferences as M1 in general.In recent years, there were rapidly expanding clusters of emm types that were not historically so prevalent within several different states, mostly pattern E lineages (emm11,49,82,92,60) and pattern D lineages (emm83,59,81), which was associated with increasing proportions of disadvantaged persons and led to drastic changes in emm type distributions in those states (11,12).
Although the speC and ssa genes were associated with M1 UK isolates, they were present in <5% of these isolates, and the biologic role of this association is unclear.It is crucial to monitor the spread of this variant and the associated virulence determinants to inform development of effective prevention and treatment strategies.
This study used the Streptococcus pyogenes multilocus sequence typing website (https://pubmlst.org/organisms/streptococcus-pyogenes) hosted at the University of Oxford.

Figure 1 .
Figure 1.Expansion of M1 UK lineage in serotype M1 iGAS in the United States, 2015-2021.A) Counts and percentages of M1 UK isolates among M1 iGAS isolates in ABCs during 2015-2021.B) Number of M1 UK infections over time in 9 states that are part of the ABCs system.Key shows total number of M1 UK infections during 2015-2021 for each state.ABCs, Active Bacterial Core Surveillance System; iGAS, invasive group A Streptococcus disease; Q, quarter.

Figure 2 .
Figure 2. Genomic clusters of M1 UK invasive group A Streptococcus disease, United States, 2015-2021.Core-genome phylogenetic tree of 86 M1 UK invasive group A Streptococcus disease isolates and the reference M1 genome MGAS5005 was based on 462 core singlenucleotide variant sites generated by kSNP3.0software (9).Tip colors indicate 9 groups of genomically closely related isolates (genomic clusters).Key shows total number of M1 UK isolates in each cluster.Scale bar indicates expected nucleotide substitutions per site.

Table .
Strain and patient features of M1UK iGAS compared with other M1 iGAS in ABCs, United States, 2015-2021 Streptococcus disease.†By Fisher exact test.‡All strain features, including antimicrobial susceptibility, pyrogenic exotoxin genes, and other virulence factors, were inferred from whole-genome sequencing data.§Detecting genetic marker for the sda1 gene (GenBank accession no.AY452036.1),which is identical to the sdaD2 gene (M5005_Spy1415; GenBank accession no.AAZ52033.1).This study was supported by the Centers for Disease Control and Prevention.Major support was provided by the Centers for Disease Control and Prevention Emerging Infections Program and the Advanced Molecular Detection Initiative.Y.L., L.M., and B.B. contributed to study design; all authors contributed to data collection; Y.L. performed data analysis, produced the table and figures, and wrote the manuscript; and J.R., S.M., Z.L., S.C., B.J.M., B.B., J.O., C.J.G., and L.M. contributed to data analysis and interpretation.All authors reviewed and edited the manuscript.Dr. Yuan Li is a microbiologist and bioinformatician in the National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA.His primary research interests are integration of laboratory and epidemiologic data to inform disease surveillance, outbreak responses, and vaccine strategies.
*ABCs, Active Bacterial Core Surveillance System; iGAS, invasive group A