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Volume 31, Number 2—February 2025
Research

Streptococcus pyogenes emm Type 3.93 Emergence, the Netherlands and England

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Author affiliation: Amsterdam University Medical Center, Amsterdam, the Netherlands (M.A. Davies, A.P. van Dam, R. van Houdt, S. Matamoros, M. van den Berg, P.E. Habermehl, N.M. van Sorge); National Institute for Public Health and the Environment, Bilthoven, the Netherlands (B. de Gier); UK Health Security Agency, London, UK (R.L. Guy, J. Coelho, K. Moganeradj, Y. Ryan, S. Platt, H. Hearn, E. Blakey, D. Chooneea, T. Lamagni); University Medical Center Utrecht, Utrecht, the Netherlands (B.J.M. Vlaminckx)

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Abstract

A global increase in the incidence of invasive group A Streptococcus (iGAS) infections was observed after lifting of COVID-19 related restrictions in 2022, and type M1UK dominated in many countries. After seasonal declines in iGAS incidence during the summer of 2023, simultaneous, rapid expansion of a previously rare emm type 3.93 was seen beginning in November, increasing to 20% of all cases in England and 60% of all cases in the Netherlands within 4 months. emm3.93 was associated with iGAS in children 6–17 years of age and with increased risk for pneumonia or pleural empyema and meningitis in both countries. No excess risk of death was identified for emm3.93 compared with other types. Genomic analysis of historic and contemporary emm3.93 isolates revealed the emergence of 3 new clades with a potentially advantageous genomic configuration. Our findings demonstrate the value of molecular surveillance, including long-read sequencing, in identifying clinical and public health threats.

In several countries, including the Netherlands and England, an increase in invasive group A Streptococcus (iGAS) infections was observed after lifting of COVID-19 restrictions during 2022 and 2023 (1,2). The reason for this sudden upsurge has yet to be completely explained but likely resulted from a perfect storm scenario: an increased population susceptibility to Streptococcus pyogenes infections after 2 years of reduced circulation that coincided with an increased incidence of predisposing viral infections and further expansion of the emm1.0 sublineage M1UK (3), which produces increased amounts of the virulence factor and streptococcal pyrogenic exotoxin A compared with its progenitor, M1global (3). Similar to the case in other countries, emm1.0 was the dominant emm type in the Netherlands and England (1,4,5). However, beginning in June 2023, the proportion of emm1.0 among clinical S. pyogenes isolates diminished in the Netherlands and England, coinciding with a seasonal decrease in iGAS incidence. An increase in a previously rare type, emm3.93, was identified among iGAS patients in the Netherlands and England beginning in November 2023. We report a cross-border increase in iGAS with increased infections in particular age groups and specific clinical manifestations related to an emm3.93 variant that displays a previously unreported genome configuration.

Methods

S. pyogenes Isolate Collection, emm Typing, and Genome Sequencing

Beginning in April 2022, all medical microbiology laboratories in the Netherlands were asked to submit S. pyogenes isolates from patients with iGAS disease (defined as either the detection of S. pyogenes from a normally sterile site or from a nonsterile site in combination with a clinical manifestation of iGAS) to the Netherlands Reference Laboratory for Bacterial Meningitis (NRLBM; Amsterdam, the Netherlands) for emm typing as part of national bacterial surveillance. Isolates are submitted with limited patient information (patient birth year, sex, and postal code). In addition to recent isolates from prospective bacterial surveillance, we screened an existing bacterial isolate collection (4) consisting of S. pyogenes carriage isolates (2009–2023, n = 349) and iGAS disease (2009–2019, n = 272) for the presence of emm3.93. In England, medical microbiology laboratories were asked to submit S. pyogenes isolates to the UK Health Security Agency (London, UK) reference laboratory for emm typing as part of active surveillance.

We conducted emm genotyping according to US Centers for Disease Control and Prevention protocol (6) by using conventional PCR amplification and Sanger sequencing of a 180-bp domain encoding the 50 hypervariable codons that determine emm subtype. The emm3.93 sequence and information were provided by the National Health Service (NHS) of Greater Glasgow and Clyde, Scotland, UK. We found or generated short-read sequence (Illumina) data for 104 emm3.93 isolates, including 11 strains from the Netherlands, 9 from New Zealand, and 84 from England. In addition, we conducted long-read (Oxford Nanopore) sequencing on 14 of the emm3.93 isolates, 5 from the Netherlands and 9 from England, for hybrid assembly of the complete genome.

Raw sequencing data and complete genomes are available from the National Center for Biotechnology Information BioProject database (accession nos. PRJNA1125189, PRJEB43915, PRJEB13551, and PRJNA1100230). Sample accession numbers are provided (Appendix Table 1).

Genome Assembly

We processed raw Illumina reads by using Trimmomatic v0.39 (7) to remove adaptor sequences and bases of insufficient quality with the parameters ILLUMINACLIP:TruSeq3-SE:2:30:10 LEADING:3 TRAILING:3 SLIDINGWINDOW:4:15 MINLEN:36. We de novo assembled trimmed reads into scaffolds by using SPAdes v3.15.5 (8) and assessed assembly quality by using QUAST v5.0.2 (9). We processed raw Nanopore reads by using Porechop v0.2.4 (10) with default parameters and assembled the reads by using Flye v2.9.2 (11) with parameters -g 5.6m and -i 2. We created closed genomes by using hybrid assembly via Unicycler v0.4.8 (12) with default parameters.

Detection of Genomic Rearrangements

To determine the presence of the genomic inversion, we annotated complete genomes by using bakta (13) then aligned and visualized the genomes by using EasyFig (14) and its default use of blastn (15). We determined the location of prophage sequences MGAS315.1 (RefSeq accession no. NC_004584.1) and MGAS315.2 (RefSeq accession no. NC_004585.1) by using blastN with default parameters. We produced whole genome alignment dotplots by using the web interface version of D-GENIES (16) via the built-in aligner, Mashmap v2.0.

Core Single-Nucleotide Polymorphism Phylogenetic Analysis

We created a core single-nucleotide polymorphism (SNP) alignment by calling SNPs by using snippy v4.6.0 against the reference genome MGAS315 (RefSeq accession no. NC_004070.1) with default parameters. We used Gubbins v2.3.4 (17) to detect and mask sites of recombination and performed a phylogenetic inference by maximum likelihood on the subsequent alignment by IQ-TREE (18) using the general time-reversible plus gamma plus invariate sites substitution model and visualizing in iTOL v6.9 (19). We determined the lineage-defining SNPs to be synonymous, nonsynonymous, or insertion or deletion by using snippy. We created the SNP distance matrix by using SNP-dists v0.8.2 and performed the hierarchical clustering and visualization by using the R package pheatmap (The R Project for Statistical Computing).

Clinical Information of iGAS Patients

In the Netherlands, clinical manifestations of iGAS with S. pyogenes cultured from any site are notifiable by law since January 2023. Pseudonymized notifications, which contain information on the clinical manifestations, onset, and emm type (when available), are analyzed by the National Institute for Public Health and the Environment (Bilthoven, the Netherlands). Unknown emm types are supplemented by probabilistic linkage of notifications to the NRLBM data on the basis of birth year, gender, postal code, and date of diagnosis.

In England, iGAS has been a notifiable disease since April 2010 (20). Notifications include date of birth, sex, postal code, and date of specimen collection. Clinical manifestation information is not collected, but the focus of infection is inferred from the specimen type, in particular, cerebrospinal fluid, pleural fluid, and synovial fluid specimens. All iGAS notifications were submitted to the NHS Demographic Batch Tracing Service to identify the date of death (21). We calculated all-cause death by using all deaths within 7 days of a positive iGAS specimen, including all postmortem diagnoses. We used multivariable logistic regression to assess all-cause death and to compare emm3.93 with other contemporaneous emm types. We retrieved antimicrobial susceptibility testing results from routine laboratory surveillance data.

Ethics Statement

This study was conducted in accordance with the European Statements for Good Clinical Practice and the Declaration of Helsinki of the World Medical Association. In the Netherlands, invasive S. pyogenes isolates were collected as part of routine care. This study was not reviewed by an ethics review board because it is based on anonymized surveillance data. UK Health Security Agency have legal permission under Regulation 3 of the Health Service (Control of Patient Information) Regulations 2002 to process patient identifiable information without consent. This process considers the ethics and purpose of collecting and analyzing the data; therefore, ethics approval was not separately sought for this work.

Results

emm3.93 Epidemiology Among iGAS Patients

Figure 1

Absolute number of Streptococcus pyogenes isolates recovered from patients with invasive group A Streptococcus, by emm type and month, February 1, 2023–March 31, 2024. A) The Netherlands; B) England.

Figure 1. Absolute number of Streptococcus pyogenes isolates recovered from patients with invasive group A Streptococcus, by emmtype and month, February 1, 2023–March 31, 2024. A)...

Figure 2

Proportion of emm types 1.0 and 3.93 among all typed invasive Streptococcus pyogenes isolates in the Netherlands and England, February 1, 2023–March 31, 2024.

Figure 2. Proportion of emm types 1.0 and 3.93 among all typed invasive Streptococcus pyogenes isolates in the Netherlands and England, February 1, 2023–March 31, 2024.

We extracted iGAS notifications with disease onset during November 1, 2023–March 31, 2024, from the notification databases of the Netherlands on April 11, 2024 (798) cases and England on April 12, 2024 (1,510 cases). Of reported cases, 665 (83.3%) isolates from the Netherlands and 1,351 (89.5%) isolates from England had a known emm type. In both countries, the monthly number of submitted S. pyogenes isolates from iGAS patients showed a seasonal decrease during June–October 2023, coinciding with a decrease in the proportion of emm1.0 isolates (Figure 1). Beginning in November 2023, iGAS cases increased in line with usual seasonal patterns (Figure 1). Of note, the proportion of emm3.93 among typed iGAS isolates in the Netherlands increased from 8% (6/73) in November 2023 to 61% (126/207) in February 2024 and in England from 4% (8/219) in November 2023 to 24% (66/274) in March 2024 (Figure 1, 2). From available S. pyogenes isolates from the Netherlands in iGAS patients and asymptomatic carriers (2009–2019), emm3.93 was rare, with only 6/577 (1%) typed strains. Similarly, emm3.93 only constituted 3% (400/11,194) of S. pyogenes isolates in England during 2016–2019. A short upsurge in prevalence to 9% (224/2,597) was seen in 2018, but afterward, emm3.93 strains decreased to <1% of typed isolates per year (22). Phenotypic antimicrobial susceptibility testing demonstrated low resistance to clindamycin (1.4%, 95% CI 0.0%–7.4%), erythromycin (1.4%, 95% CI 0.0%–7.5%), or tetracycline (0%, 95% CI 0%–4.4%) in emm3.93 specimens in England during November 2023–March 2024.

Clinical Manifestations and Case-Fatality Rate of emm3.93 Compared with Other emm Types

A multivariable logistic regression model with covariates age group, sex, and month of disease onset revealed that children 6–17 years of age had higher risk for iGAS caused by emm3.93 than for other emm types in both countries (Table 1). In addition, in England, emm3.93 also affected children 0–5 years of age more often (adjusted odds ratio [aOR] 1.7, 95% CI 1.1–2.8) (Table 1). Type emm3.93 was recovered less often from patients 18–44 years of age in both countries (Table 1). There was a slight association of emm3.93 with female sex compared with other types (aOR 1.4, 95% CI 1.0–1.8) in England, which was not observed in the Netherlands (Table 1).

Regarding clinical manifestations, emm3.93 was associated with pneumonia or pleural empyema in both countries and with streptococcal toxic shock syndrome (aOR 2.2, 95% CI 1.1–4.3) in the Netherlands (Table 1). Furthermore, emm3.93 was associated with an increased risk for meningitis (Table 1), which was significant in England (aOR 28.6, 95% CI 2.6–320.1) but not in the Netherlands (aOR 2.7, 95% CI 0.9–8.8). In the Netherlands, emm3.93 was less often recovered from patients with skin or soft tissue infections or puerperal iGAS infection (aOR 0.5, 95% CI 0.3–0.8) (Table 1).

All-cause 7-day case-fatality rate data were available for England only. Case-fatality rate for emm3.93 was 13.8% (95% CI 9.6%–18.9%, 32/232) compared with 12.0% (95% CI 10.2%–14.1%, 127/1,059) for other types during November 2023–March 2024. A multivariable logistic regression adjusting for age, sex, specimen month, and emm type (emm3.93 or other) did not identify a significant difference for 7-day deaths between types (aOR 1.2, 95% CI 0.8–1.8); however, significant differences were noted by age, group, and sex (Table 2).

Genomic Analysis of emm3.93 Isolates in 3 Emergent Clades

Figure 3

Genetic information about emm3.93 Streptococcus pyogenes isolates collected in the Netherlands and England, February 1, 2023–March 31, 2024, and reference isolates. A) Maximum-likelihood phylogenetic tree of 114 parsimony informative sites and 255 distinct site patterns from the core genome single-nucleotide polymorphism alignment of 104 emm3.93 isolates from the Netherlands, England, and New Zealand (2009–2024), compared with MGAS315 reference genome (RefSeq accession no. GCF_000007425). The tree was rooted on MGAS315, and colored rings outside the tree represent year of isolation, country, source, and presence of genomic inversion around the ter. Scale bar represents substitutions per site. B) Schematic of the 4 genomic conformations detected in the emm3 lineage. When compared with the consensus reference genome of strain MGAS315, an inversion around both the ori and ter, or around the ter alone (as detected in 11/12 surge isolates) is observed. Genome ABC020055975 indicates a strain lacking prophages MGAS315.1 and MGAS315.2 but with a detected inversion around the ori. G, MGAS315.1; H, MGAS315.2.

Figure 3. Genetic information about emm3.93 Streptococcus pyogenesisolates collected in the Netherlands and England, February 1, 2023–March 31, 2024, and reference isolates. A) Maximum-likelihood phylogenetic tree of 114...

Phylogenetic analysis of the core SNP genomes of 104 emm3.93 of ST315 from the Netherlands, England, and New Zealand showed that recently-expanded emm3.93 isolates clustered into 3 distinct clades (Figure 3, panel A). Clades were determined as clusters containing <10 core SNPs difference whereas between-clade SNP distance was typically 20–50 SNPs (Appendix Figure 1). Lineage-defining SNPs were determined by clade-specific SNP annotations against reference strain MGAS315 (Appendix Table 2). Clades 1 and 2 only contained isolates from England, whereas clade 3 consisted of a mix of isolates from the Netherlands and England (Figure 3, panel A).

We explored possible genomic rearrangements because previous studies have described distinct genome configurations among emm3 consensus reference genomes MGAS315 and SSI-1, where SSI-1 contained large-scale genomic rearrangements compared with MGAS315 (23). Hybrid genome assembly for 14 S. pyogenes emm3.93 isolates (5 from the Netherlands and 9 from England) revealed that 12 isolates shared a genomic configuration that differed from MGAS315 by a ≈200-kb inversion around the terminus (ter) and from SSI-1 by a ≈521-kb inversion around the origin of replication (ori) (Figure 3, panel B; Appendix Figure 2). Of the 12 isolates, 11 belonged to emm3.93 surge isolates in each of the 3 clades and 1 was obtained from a patient with invasive disease from 2017 in England (Figure 3, panel A). The 200-kb genomic inversion around the ter is prophage-mediated and results in the movement of phage-encoded superantigen gene ssa and holin genes between prophages MGAS315.1 and MGAS315.2 (24) (Figure 3, panel B). The ≈521-kb inversion around the ori is spanned by 2 repeat regions of 6,200 bp (Figure 3, panel B). The inversions around the ori and the ter can occur independently, as indicated by strain ABC020055675, which lacks prophages MGAS315.1 and MGAS315.2 (Figure 3, panel B; Appendix Figure 2). Of interest, the genomic configuration of the remaining 2 isolates was identical to the consensus MGAS315 genome (Appendix Figure 2). One isolate was obtained from a patient with invasive disease in 2017 in the Netherlands with a common ancestor to clade 3 and the other from a patient with noninvasive infection from clade 1 (Figure 3, panel A). Although we analyzed a limited number of strains, our observations suggest the described genome configuration in the 11 recent emm3.93 isolates confers a survival advantage to S. pyogenes.

Discussion

We report the rapid synchronous upsurge of S. pyogenes emm type 3.93 in the Netherlands and England during November 2023–March 2024. Epidemiologic analysis showed that emm3.93 was isolated more often from children 6–17 years of age with iGAS in both countries. The data from the Netherlands revealed a significant association between emm3.93 and pneumonia or pleural empyema, which was corroborated by an increase of emm3.93 among pleural isolates in England. Although the numbers were low, emm3.93 showed an increased risk for causing meningitis, which was significant in the data from England. Furthermore, emm3.93 was associated with streptococcal toxic shock syndrome in the Netherlands. Despite those concerning associations, the data from England showed no significant elevation in 7-day mortality for emm3.93 compared with mortality associated with other contemporaneous emm types.

Genomic analysis revealed 3 distinct clades among recent emm3.93 surge isolates. Clades 1 and 2 consisted only of isolates from England, whereas emm3.93 clade 3 contained a mix of isolates from the Netherlands and England. This analysis contrasts with previous analysis of the post–COVID-19 emm1 iGAS isolates, which showed predominantly country-specific surges of emm1 and little evidence of transmission of UK isolates to the Netherlands (4,5). This finding suggests that emm3.93 has had cross-border transmission events.

Analysis of complete genomes revealed a shared genomic configuration in all but 1 recent isolate from the 3 observed clades. When compared with other publicly available emm3 consensus reference genomes, the genomic configuration differed by either a ≈200-kb inversion around the ter or a ≈521-kb inversion around the ori. An identical genomic configuration was also identified in an invasive emm3.93 isolate from England from 2017, suggesting that this genome configuration was already circulating in the population before the surge. Of interest, emm3.93 caused a small surge of iGAS in England in 2018 (22) but did not expand to the levels observed in 2023–2024, nor did other countries report an increase in iGAS caused by emm3.93. We speculate that this 2017 isolate from England could have been a precursor to the 2023–2024 surge isolates but did not have a major advantage in the pre–COVID-19 climate because of sufficient population immunity.

Inverted repeats between prophages MGAS315.1 and MGAS315.2 have likely permitted the observed prophage-mediated homologous recombination. This phenomenon has been observed before in emm3.1 strains, which contained an alternative large-scale genomic rearrangement of 1 Mb because of chromosomal inverted repeats and was associated with invasive disease (23). However, because the inversion around the ori is also detected in an isolate without prophages MGAS315.1 and MGAS315.2 and without the inversion around the ter, we propose an updated view of the relationship between genomic configurations within emm3 S. pyogenes.

Because only single complete genomes are available of each of the reference strains, only a snapshot of the genomic configuration is being represented and then determined as consensus. Although our analysis of the individual isolates did not indicate a mixed population of inverted and noninverted genomes, care should be taken when interpreting the stability of an inversion that may occur in recombination hot spots with inverted homologous regions (25), because the switch back to its previous configuration may occur stochastically. For example, a recent emergent emm82 strain was detected to display an array of genome configurations among closely related isolates (26). Regardless, further information on the frequencies and selective pressures that cause inversions needs to be determined to make strong associations with epidemiologic data. Our dataset provided 2 observations that may suggest the observed genome configuration in the surge isolates conferred a survival benefit or affected virulence (27). First, an isolate from 2017 sharing a close common ancestor with the strains in clade 3 lacked the ≈200-kb inversion around the terminus and did not expand among iGAS patients. Second, we identified a single recent isolate in clade 1 without the surge-associated genomic configuration. Because the isolate was collected from a noninvasive wound swab, we speculate that specific genomic inversions are preferentially selected for during an infection pathway. The orientation in the recent surge isolates may affect virulence potential by shifting the location of the phage-encoded superantigen gene ssa, which was previously shown to be pyrogenic and toxic in rabbits (28). Additional research is needed to demonstrate if the observed genomic inversion affects ssa expression. Regardless, this clade 1 isolate demonstrates the dynamic nature and stochasticity of genome rearrangements within the emm3 population.

The first limitation of our study is the difference between the clinical data collected in the Netherlands and England with the lack of formal registration for death after infection in the Netherlands. The second limitation is the low number of genomes sequenced from isolates from the Netherlands collected during the recent outbreak. Although all 4 recent emm3.93 isolates from the Netherlands are in a single clade, other nonsequenced isolates might fall into the other outbreak-associated clades.

In conclusion, combined epidemiologic and molecular surveillance is key to detect emergence of new or more virulent S. pyogenes variants and to rapidly assess their clinical and epidemiologic relevance. emm typing revealed a replacement of emm1.0 by emm3.93 as the dominant type from November 2023 onwards, continuing over a few months. It is possible that population immunity to emm1.0 developed during 2023, leaving increased susceptibility to potentially new virulence traits of the new clades of emm3.93. Alternatively, the genomic inversion may have resulted in a competitive advantage of emm3.93 over emm1.0. In the context of the current upsurge of S. pyogenes emm3.93, international collaboration proved invaluable to assess the spread of the new clades and provide a more comprehensive picture of the associations of emm3.93 with both clinical manifestations and case fatality. In addition, a combination of long- and short-read sequencing was necessary to reveal the extent of genetic diversity for the emerged emm3.93 clades.

Dr. Davies is a postdoctoral fellow with the Amsterdam University Medical Center. His current work focuses on streptococcal genomics in the context of public health and disease pathogenesis.

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Acknowledgments

We thank Roisin Ure for providing the emm3.93 sequence and information. We thank Una Ren and our colleagues of the Institute of Environmental Science and Research in New Zealand for sharing genome sequences of recent emm3.93 strains. We thank all microbiology laboratories for submitting isolates to the UK Health Security Agency national reference laboratory and the Netherlands Reference Laboratory for Bacterial Meningitis. This report would not have been possible without the contribution of clinical and laboratory colleagues across the healthcare systems in England and the Netherlands. We thank the Centers for Disease Control for maintaining and updating the emm database.

This study was funded in part by the Dutch Research Council through the research program Infectieziektebestrijding 3 (BEATGAS project grant no. #10150022310004, awarded to N.M.v.S, M.A.D, B.d.G, and B.J.M.V). This study was funded in part by the Dutch Ministry of Health, Welfare, and Sport. All work was performed as part of service delivery of the contributing authors for UK Health Security Agency.

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Cite This Article

DOI: 10.3201/eid3102.240880

Original Publication Date: January 22, 2025

1These authors contributed equally.

Table of Contents – Volume 31, Number 2—February 2025

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Nina M. van Sorge, Amsterdam UMC, Department of Medical Microbiology and Infection Prevention, Meibergdreef 9 IWO building, 1105 AZ Amsterdam, the Netherlands

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