Background: Acute chest syndrome (ACS) is a life-threatening complication of sickle-cell disease (SCD). Although respiratory pathogens are frequently detected in children with ACS, their respective role in triggering the disease is still unclear. We hypothesized that ACS incidence followed the unprecedented population-level changes in respiratory pathogens dynamics following the COVID-19-related non-pharmaceutical interventions (NPIs). Research question: What is the respective role of respiratory pathogens in ACS epidemiology? Study design: AND METHODS. We performed an interrupted time-series analysis of patient records from a national hospital-based surveillance system. All children < 18 years of age with SCD hospitalized for ACS in France between January 2015 and May 2022 were included. The monthly incidence of ACS per 1000 children with SCD over time was analyzed using a quasi-Poisson regression model. The circulation of 12 respiratory pathogens in the general pediatric population over the same period was included in the model to assess the fraction of ACS potentially attributable to each respiratory pathogen. Results: Among the 55,941 hospitalizations of children with SCD, 2306 episodes of ACS were included (median [IQR] age, 9 [5-13] years). We observed a significant decrease in ACS incidence after NPI implementation in March 2020 (-29.5%; 95% CI, -46.8% to -12.2%; P = .001) and a significant increase after lifting of the NPIs in April 2021 (24.4%; 95% CI, 7.2% to 41.6%; P = .007). Using population-level incidence of several respiratory pathogens, we found that Streptococcus pneumoniae accounted for 30.9% (95% CI, 4.9% to 56.9%; P = .02) of ACS incidence over the study period and influenza 6.8% (95% CI, 2.3% to 11.3%; P = .004), whereas other respiratory pathogens had only a minor role. Interpretation: NPIs were associated with significant changes in ACS incidence concomitantly with major changes in the circulation of several respiratory pathogens in the general population. This unique epidemiological situation allowed to unravel the contribution of these respiratory pathogens, in particular S. pneumoniae and influenza, to the burden of childhood ACS, highlighting the potential benefit of vaccine prevention in this vulnerable population.