Integrated associations of nasopharyngeal and serum metabolome with bronchiolitis severity and asthma: A multicenter prospective cohort study.

Fujiogi, Michimasa; Camargo, Carlos A; Raita, Yoshihiko; Zhu, Zhaozong; Celedón, Juan C; Mansbach, Jonathan M; Spergel, Jonathan M; Hasegawa, Kohei

BACKGROUND While infant bronchiolitis contributes to substantial acute (e.g., severity) and chronic (e.g., asthma development) morbidities, its pathobiology remains uncertain. We examined the integrated relationships of local (nasopharyngeal) and systemic (serum) responses with bronchiolitis morbidities. METHODS In a multicenter prospective cohort study of infants hospitalized for bronchiolitis, we applied a network analysis approach to identify distinct networks (modules)-clusters of densely interconnected metabolites-of the nasopharyngeal and serum metabolome. We examined their individual and integrated relationships with acute severity (defined by positive pressure ventilation [PPV] use) and asthma development by age 5 years. RESULTS In 140 infants, we identified 285 nasopharyngeal and 639 serum metabolites. Network analysis revealed 7 nasopharyngeal and 8 serum modules. At the individual module-level, nasopharyngeal-amino acid, tricarboxylic acid (TCA) cycle, and carnitine modules were associated with higher risk of PPV use (r>0.20; P<0.001), while serum-carnitine, amino acid and glycerophosphorylcholine (GPC)/glycerophosphorylethanolamine (GPE) modules were associated with lower risk (all r<- 0.20; P<0.05). The integrated analysis for PPV use revealed consistent findings-e.g., nasopharyngeal-TCA (adjOR 2.87, 95%CI 1.68-12.2) and serum-GPC/GPE (adjOR 0.54, 95%CI 0.38-0.80) modules-and an additional module-serum-glucose-alanine cycle module (adjOR 0.69, 95%CI 0.56-0.86). With asthma risk, there were no individual associations but there were integrated associations (e.g., nasopharyngeal-carnitine module; adjOR 1.48, 95%CI 1.11-1.99). CONCLUSION In infants with bronchiolitis, we found integrated relationships of local and systemic metabolome networks with acute and chronic morbidity. Our findings advance research into the complex interplay among respiratory viruses, local and systemic response, and disease pathobiology in infants with bronchiolitis.