Exploring the Relationship Between Respiratory Syncytial Virus and Asthma Using Calendar Time at Birth as a Source of Quasi‐Random Variation

BACKGROUND: Observational studies suggest an association between severe respiratory syncytial virus (RSV) and asthma, but it is unclear if this relationship is causal or confounded. OBJECTIVES: We investigated this relationship using calendar time at birth as a source of quasi-random variation with respect to individual-level risk factors for severe RSV infection. We similarly examined influenza (another respiratory virus) and rotavirus (a negative control exposure). METHODS: We analysed province-wide linked administrative data for 1,437,731 infants born in Ontario, Canada, from 2002-2013 (which facilitated 5 years of follow-up for asthma). We ascertained whether each infant experienced an RSV, influenza, and/or rotavirus hospitalisation (and the weekly incidences of RSV, influenza, and rotavirus hospitalisation among infants), and whether each child had asthma at 5 years of age. We used regression models to investigate the relationships between: (i) infant ages during the weeks with the highest incidences of RSV, influenza, and rotavirus hospitalisation and paediatric asthma; (ii) weekly incidences of RSV, influenza, and rotavirus hospitalisation and probability of paediatric asthma. RESULTS: We observed the highest odds of asthma among infants aged 13-16 weeks during the RSV peak, 11-13 weeks during the influenza peak, and 16-19 weeks during the rotavirus peak. The relationship between weekly incidence of RSV hospitalisation and probability of paediatric asthma was small in magnitude; we estimated a 3.15 (95% confidence interval -0.07, 6.36) percentage-point change in probability of paediatric asthma per 1 percentage-point change in weekly incidence of RSV hospitalisation among infants (offset by 13 weeks, which was the infant age at RSV peak that conferred maximum crude odds of paediatric asthma). Additionally, an unexpected relationship between rotavirus seasonal variation and asthma emerged. CONCLUSIONS: We found evidence supporting a limited causal role that did not fully explain the relationship between RSV and asthma. Other mechanisms, including seasonal factors, may contribute to previously reported associations.