Integrated nasopharyngeal airway metagenome and asthma genetic risk endotyping of severe bronchiolitis in infancy and risk of childhood asthma

Abstract

The severe bronchiolitis endotype characterized by a high abundance of H. influenzae, high proportion of RV-A and RV-C infections, and high asthma genetic risk had a significantly higher risk for developing asthma. Background Infants with bronchiolitis are at increased risk for developing asthma. Growing evidence suggests bronchiolitis is a heterogeneous condition. However, little is known about its biologically distinct subgroups based on the integrated metagenome and asthma genetic risk signature and their longitudinal relationships with asthma development. Methods In a multi-center prospective cohort study of infants with severe bronchiolitis ( i.e. , bronchiolitis requiring hospitalization), we profiled nasopharyngeal airway metagenome and virus at hospitalization, and calculated the polygenic risk score of asthma. Using similarity network fusion clustering approach, we identified integrated metagenome-asthma genetic risk endotypes. We also examined their longitudinal association with the risk of developing asthma by age six years. Results Of 450 infants with bronchiolitis (median age, 3 months), we identified five distinct endotypes—characterized by their nasopharyngeal metagenome, virus, and asthma genetic risk profiles. Compared with endotype A infants (who clinically resembled “classic” bronchiolitis), endotype E infants (characterized by a high abundance of H. influenzae , high proportion of RV-A and RV-C infections, and high asthma genetic risk) had a significantly higher risk for developing asthma (35.9% versus 16.7%; OR adj , 2.24; 95%CI, 1.02–4.97; p=0.046). The pathway analysis showed that endotype E had enriched microbial pathways ( e.g. , glycolysis, L-lysine, arginine metabolism) and host pathways ( e.g. , IFNs, IL-6/JAK/STAT3, fatty acids, MHC, and immunoglobin-related) (FDR<0.05). Additionally, endotype E had a significantly higher proportion of neutrophils (FDR<0.05). Conclusion In this multi-center prospective cohort study of infant bronchiolitis, the clustering analysis of integrated-omics data identified biologically distinct endotypes with differential risks for developing asthma.