Nasal airway microRNA profiling of infants with severe bronchiolitis and risk of childhood asthma: A multicenter prospective study.

Abstract

Severe bronchiolitis (i.e., bronchiolitis requiring hospitalization) during infancy is a major risk factor for childhood asthma. However, the exact mechanism linking these common conditions remains unclear. We examined the longitudinal relationship between nasal airway miRNAs during severe bronchiolitis and the risk of developing asthma. In a 17-center prospective cohort study of infants with severe bronchiolitis, we sequenced their nasal miRNA at hospitalization. First, we identified differentially expressed miRNAs (DEmiRNAs) associated with the risk of developing asthma by age 6 years. Second, we characterized the DEmiRNAs based on their association with asthma-related clinical features, and expression level by tissue and cell types. Third, we conducted pathway and network analyses by integrating DEmiRNAs and their mRNA targets. Finally, we investigated the association of DEmiRNAs and nasal cytokines. In 575 infants (median age=3 months), we identified 23 DEmiRNAs associated with asthma development (e.g., hsa-miR-29a-3p, FDR<0.10), particularly in infants with respiratory syncytial virus infection (FDRinteraction<0.05). These DEmiRNAs were associated with 16 asthma-related clinical features (FDR<0.05)-e.g., infant eczema and corticosteroid use during hospitalization. These DEmiRNAs were also highly expressed in lung tissue and immune cells (e.g., TH cells, neutrophils). Third, DEmiRNAs were negatively correlated with their mRNA targets (e.g., hsa-miR-324-3p/IL13), which were enriched in asthma-related pathways (FDR<0.05)-e.g., toll-like receptor, PI3K-Akt, and FcɛR signaling pathways, and validated by cytokine data. In a multicenter cohort of infants with severe bronchiolitis, we identified nasal miRNAs during illness that were associated with major asthma-related clinical features, immune response, and risk of asthma development.