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

Abstract

Background While infant bronchiolitis contributes to substantial acute (eg, severity) and chronic (eg, 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 > .20; P < .001), while serum‐carnitine, amino acid, and glycerophosphorylcholine (GPC)/glycerophosphorylethanolamine (GPE) modules were associated with lower risk (all r < −.20; P < .05). The integrated analysis for PPV use revealed consistent findings—for example, 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 (eg, 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.

Association of Nasopharyngeal and Serum Glutathione Metabolism with Bronchiolitis Severity and Asthma Risk: A Prospective Multicenter Cohort Study

“…Second, to investigate the associations of nasopharyngeal and serum glutathione-related metabolites with the outcomes of interest, we fit unadjusted and multivariable logistic regression models. In the multivariable models, we adjusted for potential confounders (age, sex, and RSV infection) that were selected based on a priori knowledge [ 35 , 49 , 50 ]. In the sensitivity analysis, we also stratified the analysis by RSV infection.…”

“…Then, we fit unadjusted and multivariable logistic regression models to examine the association of the signatures with the risk of asthma development. In the multivariable models, we adjusted for potential confounders (age, sex, race/ethnicity, prematurity, daycare use, cigarette smoke exposure at home, maternal smoking during pregnancy, parent history of eczema, RSV infection, RV infection, and immunoglobulin E sensitization) that were selected based on a priori knowledge [ 30 , 49 , 50 , 52 , 53 ]. Statistical analyses were conducted using R version 4.1.0 (R Foundation, Vienna, Austria).…”

Metabolomics in pediatric lower respiratory tract infections and sepsis: a literature review

“…We direct the reader to the original article for in-depth descriptions of the complex integrated analyses. 40 To our knowledge, this study was the first to investigate the relationship between the serum and nasopharyngeal metabolome in regards to infant bronchiolitis; a step in the right direction toward designing optimal metabolomics studies for diagnosing and prognosing bronchiolitis.…”

“…Two of the most recent multicenter metabolomic studies on bronchiolitis have focused on multiple outcomes using both serum and nasopharyngeal metabolomes. 39,40 In 2020, Fujiogi et al analyzed the serum metabolomes of 113 infants with bronchiolitis. Their first outcome was to distinguish RSV bronchiolitis from both RV-A and RV-C bronchiolitis.…”

“…42,43 The second recent study analyzed both the nasopharyngeal and serum metabolomes of infants with bronchiolitis and looked for subsequent associations with bronchiolitis severity and development of asthma. 40 The group clustered the metabolites into modules based on their respective biological pathways, and then looked for correlations of entire modules with clinical outcomes. Several identified pathways from both the serum and nasopharyngeal samples were associated with the use of PPV, but no pathways from either group were associated with asthma development.…”