Immunity to Streptococcus pyogenes and Common Respiratory Viruses at Age 0-4 Years after COVID-19 restrictions: A Cross-Sectional Study

ImportanceThe upsurge in invasive disease caused by Streptococcus pyogenes among children reported in several European countries during 2022-2023 has not been fully explained. ObjectiveTo test the hypothesis that changes in circulation of common respiratory pathogens associated with the introduction of non-pharmaceutical interventions (NPIs) during the COVID-19 pandemic altered acquisition of immunity to S. pyogenes and common respiratory viruses. DesignCross-sectional study recruiting before (September 2016 to March 2020) and after (April 2020 to July 2023) introduction of NPIs. SettingEuropean hospitals in 10 countries. ParticipantsChildren with suspected infection and afebrile controls, aged 0-4 years. Main OutcomesMolecular detection of bacterial and viral pathogens on throat swabs and age-stratified total serum IgG reactivity to S. pyogenes cell wall extract from two strains (measured by ELISA), and respiratory syncytial virus (RSV), five influenza viruses and four common cold coronaviruses and SARS-CoV-2 measured by Mesoscale immunoassay. ResultsThroat swabs from 1942 children under 5-years of age were tested for respiratory pathogens (1449 recruited before introduction of NPIs; 493 recruited after). A decrease in detection of S. pyogenes, RSV, common cold coronaviruses, and influenza viruses was observed between March 2020 to July 2021, corresponding to the maximal period of NPIs. Antibodies to S. pyogenes were measured in 252 children recruited before NPIs and 200 thereafter. Antibodies to viral antigens were measured in 230 before NPIs and 92 thereafter. Total IgG to S. pyogenes and RSV was significantly lower in children aged 3-4 years recruited after NPI introduction compared with before (S. pyogenes emm1: after, n=67, median 0.13 vs before, n=87, 0.35 IVIG relative-units, p=0.007. RSV: after, n=30, median 49604 vs before, n=76, 141782 mesoscale-units p<0.001). No such differences were observed for children aged 0-2 years, or for individual influenza viruses, common cold coronaviruses or SARS-CoV-2. Conclusions and RelevanceWe found a significant reduction in serum antibodies to S. pyogenes and RSV in children aged 3-4 years after introduction of NPIs. Equivalent to approximately a year delay in acquisition of immunity, these data provide a biological basis for the 2022-2023 upsurge in severe S. pyogenes infections in this age group.