D2.142 - Longitudinal Airway Immune Responses to Respiratory Viruses in Asthmatic and Atopic Children

As part of the NIAID HIPC consortium, we enrolled 108 children aged 6–17 years with and without asthma and atopy to test the hypothesis that asthma and/or atopy independently drive maladaptive innate and adaptive immune responses to respiratory viruses, influencing acute respiratory viral infection (ARVI) severity, viral clearance, and immunologic memory. The goal was to define airway and systemic immune responses to naturally occurring ARVIs in high-risk versus healthy children.

Participants from two U.S. clinical sites were classified as asthma or non-asthma based on clinician diagnosis and current medication use, and further stratified by atopic status using aeroallergen skin-prick testing, yielding four groups: atopic asthma, non-atopic asthma, atopic non-asthma, and non-atopic non-asthma. Participants were followed for up to 24 months with active symptom reporting, clinic-based illness evaluations, and home nasal sampling. Each participant could contribute up to three respiratory illness episodes, with up to three time points per illness and a post-illness convalescent sample. Illnesses were molecularly characterized using longitudinal upper-airway bulk RNA sequencing from nasal swabs and lavage, along with peripheral blood sampling.

Gene module–based kinetic generalized additive mixed models identified over 40 gene-set pathways with dynamic expression across acute illness and convalescence. Antiviral interferon response modules were robustly induced across illnesses but showed higher and more persistent expression in asthma groups. The atopic asthma group exhibited sustained elevation of inflammatory modules enriched for eosinophilic and type 2 (T2) inflammatory genes, alongside broader innate immune activation throughout illness. In contrast, non-asthmatic, non-atopic controls showed transient pathway induction, largely

These data define distinct airway transcriptional programs during pediatric ARVIs and support the hypothesis that asthma and atopy are associated with maladaptive immune responses to viral infection. Group- and module-specific coordination of antiviral, epithelial, granulocyte, and immune pathways correlates with asthma status and clinical severity, providing a molecular framework for identifying therapeutic targets to reduce ARVI-associated morbidity in children.