An Exaggerated Type I Interferon Antiviral Response is Associated with Exacerbations in Pediatric Asthma

Type-I interferon responses are critical to controlling viral upper respiratory tract infections (URIs), but excessive antiviral responses can have detrimental effects on the airway. We investigated the peripheral blood and upper airway gene expression responses to URIs in children with difficult-to-control asthma to determine differences in type-I interferon responses associated with exacerbations in vivo. 106 children with exacerbation prone asthma and peripheral blood eosinophils ≥150 /mm3 were enrolled. Peripheral blood and nasal samples were collected at baseline and within 72 hours of URI onset (prior to any systemic corticosteroid use). Gene expression was determined by RNA-sequencing and virus infection by PCR. Differential gene expression was assessed by modular analysis coupled with multivariable linear modeling. URIs for which a virus was detected had significantly elevated expression of multiple interferon-associated modules in both the upper airway and peripheral blood compared to baseline samples and compared to URIs without a detectable virus (fold changes 1.3-2.1, p<0.05). Children who had an asthma exacerbation requiring systemic corticosteroids within 72 hours of the start of a viral URI had the highest expression of an inflammatory interferon-associated module in the airway, 1.5x higher than children without exacerbation (p<0.05). Significant correlation was observed between the expression of this module in the airway and the magnitude of decline in lung function during exacerbation. An exaggerated type-I interferon response may contribute to viral URI induced exacerbations in severe pediatric asthma. Continued understanding of the cause of altered interferon responses in asthma can lead into new insights into exacerbation pathogenesis.