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Observational Study
. 2025 Aug 1;8(8):e2527717.
doi: 10.1001/jamanetworkopen.2025.27717.

Risk Factors for Severe Pediatric Invasive Group A Streptococcal Disease

Evelien B van Kempen  1   2   3 , Adam J Tulling  3 , Erik G J von Asmuth  3 , Leontien B van der Aa  4 , Else M Bijker  5   6 , Merijn Bijlsma  7 , Dorine M Borensztajn  8 , Caroline L H Brackel  9 , Brechje de Gier  10 , Marlies A van Houten  11 , Monique A M Jacobs  12 , Marianne Koenraads  13 , Anjali I G Kooter  14 , Ankie Lebon  15 , Jan W M van der Linden  16 , Lonneke van Onzenoort-Bokken  17 , Rianne Oostenbrink  3 , Joffrey van Prehn  18 , Nina M van Sorge  19   20 , Kim Stol  21 , Gerdien A Tramper-Stranders  22 , Aline R Verhage  23 , Kirsten N G van de Weijer  11 , Joanne G Wildenbeest  24 , Navin P Boeddha  25   26 , Mirjam van Veen  1 , Emilie P Buddingh  3
Affiliations
Observational Study

Risk Factors for Severe Pediatric Invasive Group A Streptococcal Disease

Evelien B van Kempen et al. JAMA Netw Open. .

Abstract

Importance: An increase in pediatric cases of invasive group A streptococcus (iGAS) disease was noted in the Netherlands starting in early 2022. GAS disease can range from mild to life-threatening invasive infections. Clinical and public health decisions rely on timely and detailed reporting of clinical data.

Objective: To determine risk factors associated with severe pediatric iGAS, defined as requiring admission to an intensive care unit and/or death, and to analyze pediatric iGAS incidence, presentations, and outcome between pre-COVID-19 pandemic (January 2015 to March 2020), COVID-19 pandemic (April 2020 to December 2021), and post-COVID-19 pandemic (January 2022 to June 2024) periods.

Design, setting, and participants: This observational, retrospective and prospective cohort study in 20 hospitals (tertiary and nontertiary) in the Netherlands was conducted from January 2015 to June 2024, with real-time reporting of data on the study website since January 2022. Children aged 0 to 17 years with iGAS (positive culture or polymerase chain reaction test and/or clinical presentation) were included.

Exposure: iGAS infection.

Main outcome and measures: The primary outcome was risk factors for severe iGAS; secondary outcomes included iGAS incidence rate and clinical phenotypes prior, during, and after the COVID-19 pandemic. Risk factors for severity and mortality were analyzed using univariable and multivariable logistic regression analyses, and incidence rate ratios (IRRs) between pre-COVID-19 and postCOVID-19 pandemic periods were calculated using Poisson regression.

Results: Of 617 children included, 351 (56.9%) were aged 0 to 4 years. For the 192 participants with detailed data collection, median (IQR) age was 4.2 (1.7-7.1) years and 91 (47.4%) were male. iGAS cases decreased during the COVID-19 pandemic and increased significantly in the post-COVID-19 period (IRR, 2.93; 95%, 2.46-3.49), as compared with the pre-COVID-19 pandemic period. By late 2023, the incidence of iGAS returned to pre-COVID-19 pandemic levels. Factors associated with increased risk of severe disease included a post-COVID-19 pandemic diagnosis (odds ratio [OR], 3.49; 95% CI, 2.31-6.26), pulmonary involvement (OR, 8.64; 95% CI, 5.50-13.55), streptococcal toxic shock syndrome (STSS; OR, 11.71; 95% CI, 4.39-31.18), and meningitis or encephalitis (OR, 4.38; 95% CI, 4.39-31.18). Clinical factors associated with increased risk of severe disease were reduced consciousness (OR, 7.61; 95% CI, 1.84-34.41), dyspnea (OR, 9.89; 95% CI, 3.04-32.14), abnormal auscultation (OR, 6.32; 95% CI, 2.18-18.32), and elevated C-reactive protein (OR, 6.32; 95% CI, 2.18-18.32), while estimated glomerular filtration rate was associated with a decreased risk (OR, 0.64; 95% CI, 0.49-0.84). Disease severity increased in post-COVID-19-pandemic cases, with higher mortality (13 of 294 cases [4.4%] vs 3 of 218 cases [1.4%]) and intensive care admission rates (113 of 294 cases [38.4%] vs 34 of 218 cases [15.6%]), as compared with pre-COVID-19 pandemic cases. Severity of pulmonary iGAS was similar in both periods. In the post-COVID-19 pandemic period, there was a significant increase in the incidence of pulmonary infections (IRR, 5.04; 95% CI, 3.27-7.97) , STSS (IRR, 10.30; 95% CI, 3.88-35.60), meningitis or encephalitis (IRR, 12.30; 95% CI, 4.14-52.70), and necrotizing fasciitis (IRR, 26.10; 95% CI, 5.14-475.00).

Conclusions and relevance: In this cohort study, risk factors for a complicated course of iGAS in children included pulmonary or central nervous system involvement, STSS, reduced consciousness or pulmonary clinical signs, elevated CRP, and decreased eGFR. Awareness of these risk factors is important to improve timely recognition of at-risk cases and improve clinical outcomes.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr van Kempen reported receiving personal fees from Merck Sharp & Dohme (honorarium for a presentation on paediatric iGAS at the Stand-Alone Scientific Symposium; March 9, 2023; Warsaw, Poland) outside the submitted work. Dr Bijker reported receiving grants for an investigator-initiated study on preterm immune system development and response to immunization from Merck Sharp & Dohme; receiving financial compensation (paid to institution) for participation in advisory committees for AstraZeneca and Merck Sharp & Dohme and for a conference talk by Bavarian Nordic; and being supported by a fellowship award from the European Society for Paediatric Infectious Diseases outside the submitted work. Dr Borensztajn reported receiving grants from NoordWest Ziekenhuisgroep outside the submitted work. Dr van Prehn reported grants from Merck Sharp & Dohme (paid to institution) outside the submitted work. Dr van Sorge reported receiving grants from the Dutch Health Council (Aspasia grant, Vici grant, and Infectieziektebestrijding grant, all paid to institution), LeDucq Foundation (iSpy network grant paid to institution), and Argenx (contract research, paid to institution); personal fees from Merck Sharp & Dohme and GSK (fee for service directly paid to the institution); having a patent for vaccine development against Streptococcus pyogenes (patent No. WO 2013/020090 A3; inventors, Nina van Sorge and Victor Nizet) licensed by Vaxcyte to the University of California, San Diego, with royalties paid from the University of California, San Diego; having a pending patent for antibodies (consulting fees paid to the institution by Amsterdam University Medical Center, Merck Sharp & Dohme, and GSK); and serving on science advisory panels for Pfizer (expert input on meningococcal vaccines; payment to institution), ItsME foundation (no honorarium), and Rapua (project facilitating Streptococcal A vaccine development for Aotearoa New Zealand; fee paid to institution) outside the submitted work. Dr Tramper-Stranders reported receiving grants from OM Pharma (investigator-initiated work) and Astra Zeneca (investigator-initiated work) outside the submitted work. Dr Wildenbeest reported having been an investigator for clinical trials sponsored by pharmaceutical companies including AstraZeneca, Merck, Pfizer, Sanofi, and Janssen (all funds have been paid to University Medical Center Utrecht [UMCU]); participating in advisory boards for Janssen and Sanofi; and being a speaker at Sanofi and Merck Sharp & Dohme (sponsored symposia with fees paid to UMCU) outside the submitted work. Dr Boeddha reported receiving grants from Merck Sharp & Dohme BV (research grant from an investigator-initiated studies program for a study on invasive pneumococcal infections in Suriname) outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Summary of Clinical Characteristics
Epidemiological curves of inclusions (age [A], mild vs severe disease [B], and clinical syndromes [C]) in the study period in hospitals participating in the retrospective as well as in the prospective part of the study. Severe disease was defined as intensive care unit (ICU) admission or death. Q indicates quarter.
Figure 2.
Figure 2.. Risk Factors for Severe Disease in Children With Invasive Group A Streptococcal Disease Infection
Severe disease was defined as intensive admission and/or mortality. Log odds ratios were calculated based on a univariable and multivariable logistic regression models. The multivariable model did not account for a prior medical history due to the fact this variable was only collected in case of obtainment of informed consent. NA indicates not applicable; STSS, streptococcal toxic shock syndrome.
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