Dysregulation of airway and systemic interferon responses promotes asthma exacerbations in urban children

Background: Determining why some upper respiratory illnesses provoke asthma exacerbations remains an unmet need. Objective: We sought to identify transcriptome-wide gene expression changes associated with colds that progress to exacerbation. Methods: Two hundred eight urban children (6-17 years) with exacerbation-prone asthma were prospectively monitored for up to 2 cold illnesses. Exacerbation illnesses (Ex⁺), defined as colds leading to asthma exacerbations requiring systemic corticosteroids within 10 days, were compared to colds that resolved without exacerbation (Ex⁻). Peripheral blood and nasal lavage samples were collected at baseline and during colds for RNA sequencing. Interferon gene expression was compared between Ex⁺ and Ex⁻ illnesses. Generalized additive modeling revealed interferon response kinetics. Multiple linear regression models compared interferon expression to clinical variables. Results: One hundred six participants were evaluated during 154 colds. There was greater upregulation of differentially expressed interferon genes during Ex⁺ illnesses compared to Ex⁻. Ex⁺ illnesses had greater average and steeper rise in interferon expression. Within 3 days of illness, interferon expression was positively associated with nasal rhinovirus quantity (nasal: adjusted R² = 0.48, P = .015; blood: adjusted R² = 0.22, P = .013), and interferon expression was negatively associated with percentage predicted forced expiratory volume in 1 second (nasal: β = −0.010, P = .048; blood: β = −0.008, P = .023). Participants with lower baseline interferon expression had shorter time to exacerbation, higher risk for exacerbation with viral illnesses, and greater increase in interferon expression during viral colds (nasal: β = −0.80, P < .0001; blood: β = −0.75, P < .0001). Conclusion: Dysregulated interferon responses are important contributors to asthma exacerbation risk in children. Low baseline interferon expression followed by greater upregulation of interferon pathways in airway and blood during respiratory illnesses increased exacerbation risk. Targeting this pathway in at-risk individuals holds promise for the personalized prevention of asthma exacerbations.