Paediatric invasive group A streptococcal infections and associations with viral infections in 15 European countries after lifting non-pharmaceutical interventions against SARS-CoV-2: an interrupted time-series analysis

Abstract

Background: After lifting non-pharmaceutical interventions (NPIs) against the transmission of SARS-CoV-2, various countries experienced an increase in invasive Group A Streptococcal (iGAS) infections. We aimed to characterise the paediatric outbreak across Europe and to analyse the influence of viral infections.

Methods: We conducted an interrupted time-series analysis based on data from 15 European countries from the PEGASUS consortium. We assessed the evolution of the number of iGAS cases aged 1 month to 18 years between 01/01/2018 and 03/31/2024, comparing the post-NPIs period (01-04-2022 until 31-03-2024) to the baseline period (01-01-2018 until 31-03-2020). Further analyses were performed by country, clinical phenotype, age and severity, including sensitivity analyses. We then explored whether certain iGAS phenotypes correlated with trends in RSV, influenza and VZV across countries over time using Google Trends data.

Findings: We included 2091 iGAS cases over the study period; 79 children (3.6%) died and 580 (27.7%) required PICU admission. We estimated an overall increase of +229.8% (95% CI (141.9-341.6)) among iGAS cases from October 2022 to March 2024, compared to the baseline period. The observed increases varied across clinical phenotypes, ranging from +62.7% (95% CI (8.3-157.9)) for osteo-articular infections to +238.7% (95% CI 75.8-464.8) for pneumonia. We observed a strong correlation between the incidence of iGAS pneumonia and RSV (Rho: 0.57, 95% CI [0.11-0.79]) and influenza (Rho 0.69, 95% CI 0.35-0.87); and between skin and soft tissue infections and VZV (Rho: 0.73, 95% CI [0.42-0.89]).

Interpretation: The patterns observed across Europe during this outbreak demonstrate an association between respiratory viruses as well as VZV, and iGAS.

Funding: This study has received funding from ESPID, INOPSU and the Northwest Clinics. The COPP study group was supported by grants of the Dutch National Health Council (ZonMW) project number 10430072110007 and the Christine Bader Foundation.

Keywords: Europe; Flu; Group A streptococcus; Immunity debt; Influenza; Invasive streptococcal disease; Non pharmaceutical interventions; Outbreak; Paediatrics; RSV; Respiratory syncytial virus; Streptococcus pyogenes; VZV; Varicella; Viral infections; Viruses.

Fig. 1

Evolution of the monthly number of iGAS cases from January 1st, 2018, to March 31st, 2024, assessed by interrupted time series analyses, N = 2091. For the study, we defined three study periods: the baseline period: from January 1st, 2018, to March 31st, 2020, the NPIs period from April 1st, 2020, to March 31st, 2022, and the post-NPIs period: from October 1st, 2022, to March 31st, 2024. The effect of the implementation of NPIs was considered immediate, while the effect of their lifting was considered delayed and not expected to be immediate. Thus, we defined a lag period of 6 months from April 1st to September 30th 2022, highlighted in grey. The black line corresponds to the observed monthly number of iGAS cases. The red line corresponds to the fitted value of the monthly number of cases with its 95% confidence interval. The dashed blue line and its 95% confidence interval corresponds to the expected number of iGAS cases during the post-NPIs period, if no NPIs had been implemented. Abbreviation: NPIs, Non-pharmaceutical interventions; iGAS, invasive Group A streptococcus.

Fig. 2

Evolution of the monthly number of iGAS cases by clinical phenotypes from January 1st 2018 to March 31st 2024 assessed by interrupted time series analyses. a: Bacteriemia and sepsis, including STSS (N = 797); b: ENT and abscesses cases (N = 534); c: Osteo-articular cases (N = 337); d: Pneumonia cases (N = 473); e: Cutaneous cases, including necrotizing fasciitis (N = 443). For the study, we defined three study period: baseline period (January 1st, 2018, to March 31st, 2020), NPIs period (April 1st, 2020, to March 31st, 2022), and post-NPIs period (October 1st 2022 to March 31st, 2024.) The effect of the lifting of NPIs was considered delayed, thus, we defined a lag period of 6 months (April 1st to September 30th, 2022). The black line corresponds to the observed monthly number of iGAS cases. The red line corresponds to the fitted value of the monthly number of cases with the 95% confidence interval. The dashed blue line and its 95% confidence interval corresponds to the expected number of iGAS cases during the post-NPIs period, if no NPIs had ever been implemented. Abbreviation: NPIs, Non-pharmaceutical interventions; iGAS, invasive Group A streptococcus; ENT, Ear-Nose-throat; STSS, streptococcal toxic shock syndrome; SSTI, Skin and soft tissue infections.

Fig. 3

Correlation between the evolution of viruses (Influenza, RSV and varicella) and clinical phenotypes of iGAS. a: Evolution of iGAS pneumonia cases (N = 473), Influenza and RSV from January 1st, 2018, to March 31st, 2024. b: Graphical representation of the Pearson correlation between the monthly number of iGAS pneumonia cases and the relative trend of viruses (Influenza, RSV and VZV) during the post NPIs period. c: Evolution of SSTI iGAS cases (N = 443) and VZV from January 1st, 2018, to March 31st, 2024. d: Graphical representation of the Pearson correlation between the monthly number of SSTI iGAS cases and the relative trend of viruses (Influenza, RSV and VZV) during the post NPIs period. Abbreviations: NPIs, non-pharmaceutical interventions; iGAS, invasive Group A streptococcus; SSTI, Skin and soft tissue infection.