Dysregulation of Airway and Systemic Interferon Responses Promotes Asthma Exacerbations in Urban Children

To identify gene expression changes associated with respiratory infections that progress to asthma exacerbation and those that do not. Researchers hypothesized that impaired interferon signaling during periods of wellness may facilitate early viral replication and, with increasing viral load, lead to immune dysregulation that ultimately drives asthma exacerbation.The study included 208 children (aged 6-17 years) with exacerbation-prone asthma (defined as ≥2 exacerbations requiring systemic corticosteroids in the last year, blood eosinophil count of ≥150/mL, and requirement of a minimum of twice-daily inhaled corticosteroid treatment) across 9 urban medical centers in the United States.Participants were followed prospectively for up to 2 “cold” events or approximately 6 months after enrollment, whichever occurred first. Participants who reported cold symptoms returned to clinic for a visit within 3 days of symptom onset and again 4 to 6 days after onset. Exacerbation positive (Ex+) illnesses were defined by treatment with systemic corticosteroids within 10 days after cold symptom onset. Nasal lavage and peripheral blood samples, as well as spirometry, were collected at baseline and during cold visits. Complex gene set enrichment analyses were performed and used to calculate a composite interferon score for modeling.Of the 208 enrolled participants, 106 were evaluated during 154 cold events. Viral positivity was noted in 33 of 47 patients (70%) in the exacerbation group and 69 of 107 patients (64%) in the nonexacerbation group. Ex+ illnesses were found to have a steeper rise and greater average composite interferon score during cold symptoms, as evidenced by reaching significance thresholds in P values for shape of curve trajectory and average composite scores for both nasal and blood samples. Additionally, a lower baseline composite interferon expression was associated with more exaggerated interferon response during viral illnesses and independently predicted a shorter time to exacerbation. There was no evidence of inhaled corticosteroid–dependent suppression on baseline composite interferon score.This prospective study evaluated interferon kinetics in pediatric patients with severe asthma by sampling interferon response at multiple time points during upper respiratory illness. Patients with lower baseline interferon expression had both higher risk for exacerbation and shorter time to exacerbation, suggesting that lower baseline interferon composite scores may identify those who are at higher risk of exacerbation with colds. Dysregulated interferon responses were found to be important contributors to exacerbation risk in this cohort of children with severe persistent asthma.Determining why some patients have more severe exacerbations with upper respiratory illnesses remains an area of active interest. This study illuminated the interplay of interferon pathways in patients with severe asthma experiencing exacerbations. Additional studies would be helpful to determine whether baseline interferon expression may be a useful method of risk stratification for patients with asthma. Similar studies of patients with mild to moderate asthma may also be helpful. Overall, this study highlights important clinical correlates of the immune dysregulation present in asthma, and further studies targeting the interferon pathway may create more options for personalized treatment in the future.