Establishing critical time windows of infant RSV infection in the causal relationship of RSV and childhood asthma

Project Summary Sixty years of observational studies have consistently demonstrated an association between respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) and asthma, the two most common respiratory diseases of infancy and childhood, resulting in significant morbidity and mortality in the US and worldwide. However, we have demonstrated the problem with this approach, given confounding due to shared heredity. To overcome this, we have demonstrated in both retrospective and prospective studies that RSV infection, not only severe infection, during a susceptible age window increases the risk of asthma development, and that delayed primary RSV infection until after infancy is associated with a significantly decreased risk of developing childhood asthma. Our results along with human and experimental findings, provide the preliminary data to support that there is an age-dependent causal relationship between infant RSV infection and asthma. Key remaining unanswered questions include determining the critical susceptibility period/timing of RSV infection during which infection results in increased childhood asthma, establishing causality between RSV infection and asthma, and determining if new RSV prevention products impact long-term respiratory morbidity. We hypothesize that there is an identifiable age-dependent window during which RSV infection results in an enhanced risk of childhood asthma, and that prevention or delay in initial infection protects from asthma development. To test the hypotheses, we will assemble a population of over 4 million infants who were born and enrolled in a state Medicaid program and the Department of Defense Military Healthcare System from 2003-2028. We will address the questions using 1) an instrumental variable (IV) approach and 2) the "natural experiment" of the SARS-CoV-2 pandemic time period which resulted in more than a year during which there was almost no RSV circulation followed by an off-season summer RSV peak and an extremely early RSV season. The IV approach, designed to address causal questions using observational data, is a novel statistical method that has been successfully implemented in many health outcome studies. We will also address this question by taking advantage of the soon-to-be available RSV protection product(s) during the 2023-2028 RSV seasons to assess if they have an impact on long-term childhood respiratory morbidities including asthma. Establishment of an age-dependent causal relationship between RSV and asthma will be of enormous public health importance for asthma prevention, as there is currently no effective primary prevention strategy for asthma. Further, results of this study will be important in understanding required duration of protection during infancy to inform RSV prevention product recommendations. Lastly, demonstrating value added long-term benefit of RSV prevention strategies will certainly enhance the cost-benefit for uptake of RSV prevention products in low- and middle-income countries (LMICs), as well as individual acceptability and adherence to recommendations for RSV vaccines and monoclonal antibodies.