Exacerbation-prone pediatric asthma is associated with arginine, lysine, methionine pathway alterations

• Authors: Kirsten A Cottrill, Emory University; Susan T Stephenson, Emory University; Ahmad F Mohammad, Emory University; Susan O Kim, Emory University; Nael McCarty, Emory University; Rishikesan Kamaleswaran, Emory University; Anne Fitzpatrick, Emory University; Joshua Chandler, Emory University
• Journal Title: Journal of Allergy and Clinical Immunology
• Volume: Volume 151, Number 1
• Publisher: Elsevier | 2022-09-08, Pages 118.E10-127.E10
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.jaci.2022.07.027
• Subjects: Health Sciences, Immunology; Health Sciences, General
• Keywords: Pediatric asthma; asthma exacerbations; arginine metabolism; lysine metabolism; methionine metabolism; metabolomics

Abstract

Background: Some children with asthma remain poorly controlled and have recurrent exacerbations despite treatment with inhaled corticosteroids. Aside from prior exacerbations, there are currently no reliable predictors of exacerbation-prone asthma in these children and limited understanding of potential underlying mechanisms. Objective: We sought to quantify small molecules in the plasma of children with exacerbation-prone asthma through mass spectrometry-based metabolomics. We hypothesized that the plasma metabolome of these children would differ from that of children with non-exacerbation-prone asthma. Methods: Plasma metabolites were extracted from four pediatric asthma cohorts (n=215 total, n=41 with exacerbation-prone asthma) and detected using a ZIC-HILIC column coupled to a Q Exactive HF mass spectrometer. High-confidence annotations were retained for univariate analysis and were confirmed by a sensitivity analysis in subjects on high-dose inhaled corticosteroids. Metabolites that varied by cohort were excluded. Metaboanalyst was used to identify pathways of interest. Concentrations were calculated by reference standardization to NIST SRM 1950. Results: We identified 32 unique, cohort-independent metabolites that differed in children with exacerbation-prone asthma compared to children with non-exacerbation-prone asthma. Comparison of metabolite concentrations to literature-reported values for healthy children revealed that most metabolites were decreased in both asthma groups, but more so in exacerbation-prone asthma. Pathway analysis identified arginine, lysine, and methionine pathways as most impacted. Conclusions: Several plasma metabolites are perturbed in children with exacerbation-prone asthma and are largely related to arginine, lysine, and methionine pathways. While validation is needed, plasma metabolites may be potential biomarkers for exacerbation-prone asthma in children.