Exploring the Varied Clinical Presentation of Pediatric Asthma through the Metabolome

<b>Rationale:</b> Pediatric asthma is heterogeneous, with varied clinical presentations and treatment responses. Metabolomic profiling may uncover shared and unique biological mechanisms across clinical traits that characterize pediatric asthma. <b>Objectives:</b> To characterize the varied clinical presentation of pediatric asthma by examining the metabolome's relationship with 22 clinical traits, categorized into five phenotypic domains: airway hyperresponsiveness, atopy, lung function, blood eosinophils, and blood neutrophils. <b>Methods:</b> Metabolomic profiling was conducted on plasma samples from children in the Childhood Asthma Management Program study (<i>n</i> = 953) and the Genetic Epidemiology of Asthma in Costa Rica Study (<i>n</i> = 1,155). We identified domain-specific and multidomain metabolites using a fixed-effect meta-analysis of generalized linear models between metabolites and 22 clinical traits. Metabolomic risk scores (MRSs) were developed to summarize the metabolic processes for each domain at the patient level. <b>Measurements and Main Results:</b> There were 154 unique metabolites significantly associated with at least one of 22 clinical traits (<i>q</i> < 0.05). Histamine and kynurenine were significant across four domains, whereas seven metabolites-12,13-diHOME, azelate, sebacate, PC(P-36:0)/PC(O-36:1), taurine, nudifloramide, and niacinamide-were significant across three. Notable domain-specific metabolites include <i>n</i>-oleoyl dopamine for airway hyperresponsiveness, 9-<i>cis</i>-retinoic acid for lung function, phosphatidylcholines for blood eosinophils, and 2-hydroxybutyric acid for blood neutrophils. Domain specific MRS exhibited distinct patterns across the metaboendotypes, highlighting the ability of this approach to refine asthma subtypes. <b>Conclusions:</b> This study demonstrated the power of the metabolome to capture the heterogeneity in the clinical presentation of pediatric asthma and to develop clinically relevant MRSs that inform our understanding of specific metabotypes to guide targeted treatment approaches.