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

Background: Infants with bronchiolitis are at increased risk of 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 multicentre prospective cohort study of infants with severe bronchiolitis (i.e. bronchiolitis requiring hospitalisation), we profiled nasopharyngeal airway metagenome and virus at hospitalisation, and calculated the polygenic risk score of asthma. Using similarity network fusion clustering approach, we identified integrated metagenome-asthma genetic risk endotypes. In addition, we examined their longitudinal association with the risk of developing asthma by the age of 6 years.

Results: Out of 450 infants with bronchiolitis (median age 3 months), we identified five distinct endotypes, characterised by their nasopharyngeal metagenome, virus and asthma genetic risk profiles. Compared with endotype A infants (who clinically resembled "classic" bronchiolitis), endotype E infants (characterised by a high abundance of Haemophilus influenzae, high proportion of rhinovirus (RV)-A and RV-C infections and high asthma genetic risk) had a significantly higher risk of developing asthma (16.7% versus 35.9%; adjusted OR 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. interferons, interleukin-6/Janus kinase/signal transducers and activators of transcription-3, fatty acids, major histocompatibility complex and immunoglobin-related) (false discovery rate (FDR)<0.05). Additionally, endotype E had a significantly higher proportion of neutrophils (FDR<0.05).

Conclusion: In this multicentre prospective cohort study of infant bronchiolitis, the clustering analysis of integrated-omics data identified biologically distinct endotypes with differential risks of developing asthma.