Scope of Group A Streptococcal Meningitis Isolates Using Surveillance Data (2024)

Streptococcus pyogenes can cause a wide range of invasive infections, collectively referred to as invasive group A streptococcal infections. A rare but severe invasive group A streptococcal infection is meningitis, which has an estimated incidence in adults of 0.2 per 1 million individuals per year.^1,2 In several European countries and the US, an increase of invasive group A streptococcal infections has been observed since September 2022, with shifts in affected age groups and clinical presentations relative to historic observations.^3,4 We performed an epidemiological assessment of S pyogenes meningitis cases in the Netherlands, defined by culture-positive cerebrospinal fluid (CSF), using more than 40 years of national bacteriological surveillance data.

Active microbiological surveillance and molecular epidemiology of all-cause bacterial meningitis, including S pyogenes, is performed by the Netherlands Reference Laboratory for Bacterial Meningitis (NRLBM). We analyzed S pyogenes isolates cultured from CSF between January 1, 1982, and March 13, 2023. Typing of S pyogenes is based on sequence variation in 180 base pair of the emm gene and has been routinely performed since 2013 according to the US Centers for Disease Control and Prevention protocol.⁵ To distinguish between the recently identified toxicogenic M1_UK variant and M1_global strains,⁶ all emm1.0 isolates received between January 1, 2019, and December 20, 2022, were analyzed by whole-genome sequencing (Illumina HiSeq). Limited patient information was available with isolates; we analyzed municipality and change in age distribution over time. According to Dutch law (Medical Research Involving Human Subjects Act [WMO]), approval by a medical ethics committee was not necessary because cases were not subject to any actions or rules of conduct. No informed consent was requested and only anonymized data were used for the study.

Between 1982 and 2021, the NRLBM received 216 S pyogenes CSF isolates, with an annual mean of 5 isolates (range 1-15). In contrast, 19 S pyogenes CSF isolates were received in 2022, and 10 isolates between January 1 and March 13, 2023.

Among the 48 CSF isolates from 2013-2021, 19 different emm (sub)types were distinguished, with emm1.0 being the dominant type at 35% (n = 17; Figure). However, from the 29 S pyogenes CSF isolates received between 2022 and March 13, 2023, 25 (86%) isolates were emm1.0 (Figure). Using whole-genome sequencing for emm1.0 isolates received between 2019 and December 20, 2022, 15 of 19 isolates (79%) belonged to the toxicogenic M1_UK lineage, with all emm1.0 isolates received from May 2022 onward representing this variant. The 15 M1_UK isolates originated from different municipalities, spread across the Netherlands. The number of emm1.0 strains by age group for patients 0 through 17 years was 5 in 2013-2021 vs 6 in 2022-2023; for patients 18 through 59 years, 6 in 2013-2021 vs 7 in 2022-2023; and for patients 60 years and older, 6 in 2013-2021 vs 11 in 2022-2023.

Since 2022, an increase in S pyogenes meningitis, particularly caused by the emm1.0 type and M1_UK variant, has been observed in the Netherlands. This study considered meningitis based on S pyogenes cultured from CSF to provide a consistent comparison over time. Study limitations include the exclusion of patients with meningitis with only a positive S pyogenes blood culture, resulting in an underestimation of the overall national occurrence of S pyogenes meningitis, and the small number of CSF isolates with limited patient information, which precluded more in-depth statistical and clinical evaluation. Furthermore, submission bias to the NRLBM may have played a role, given the increased general submission of S pyogenes isolates throughout 2022. Data from other countries are needed to assess whether the observed increase in S pyogenes meningitis is more widespread.

The overrepresentation of emm1.0 among the received CSF isolates underlines the invasiveness of this emm type. Moreover, the dominance of the toxicogenic M1_UK variant among emm1.0 CSF isolates suggests replacement of circulating S pyogenes emm1.0 strains. Clinical studies are required to assess whether invasive group A streptococcal infections caused by the M1_UK variant are more severe. Clinicians are urged to be vigilant regarding the occurrence of meningitis with S pyogenes because incidence with the recently emerged M1_UK variant may be increasing.

Section Editors: Jody W. Zylke, MD, Deputy Editor; Kristin Walter, MD, Senior Editor.

Accepted for Publication: March 24, 2023.

Published Online: April 7, 2023. doi:10.1001/jama.2023.5927

Corresponding Author: Nina M. van Sorge, PhD, Department of Medical Microbiology and Infection Prevention, Netherlands Reference Laboratory for Bacterial Meningitis, Meibergdreef 9, IWO Bldg IA3.159, 1105 AZ Amsterdam, the Netherlands (n.m.vansorge@amsterdamumc.nl).

Author Contributions: Drs van Sorge and de Gier had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Vlaminckx, Freudenburg-de Graaf, van Sorge.

Acquisition, analysis, or interpretation of data: van der Putten, de Gier, van Sorge.

Drafting of the manuscript: van Sorge.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: van der Putten, de Gier.

Administrative, technical, or material support: van der Putten, Vlaminckx, van Sorge.

Supervision: Vlaminckx, van Sorge.

Conflict of Interest Disclosures: Dr van Sorge reported fees for service and consultancy with relation to bacterial meningitis surveillance for S pneumoniae, H influenzae, and N meningitidis paid directly to her institution from MSD (Merck) and GSK (GlaxoSmithKline); grants from Dutch Research Council Research (Aspasia, Vici), the NIH, and Amsterdam UMC Innovation outside the submitted work; holding a patent (WO 2013/020090 A3) licensed to the University of California San Diego on vaccine development against Streptococcus pyogenes; participating on the science advisory board of the ItsME foundation (no honorarium) and Rapua te me ngaro ka tau (paid to the institution; project facilitating strep A vaccine development for Aotearoa New Zealand); and owning personal stock in Genmab BV. No other disclosures were reported.

Data Sharing Statement: See Supplement.

Additional Contributions: We thank Agaath Arends-van ‘t Klooster, BASc, Wendy Bril-Keijzers, BASc, Ilse de Beer-Schuurman, BASc, Jolein Pleijster, BASc, and Claudia Burger, BASc, for sample processing and data collection at the NRLBM (Amsterdam UMCs, Department of Medical Microbiology and Infection Prevention). No compensation other than regular employee salary was provided for these contributions.