Inflammatory Pathways in Residual Asthma Exacerbations Among Mepolizumab-Treated Urban Children: A Secondary Analysis of a Randomized Clinical Trial
Recommended Citation
Altman MC, Janczyk T, Murphy RC, Jayavelu ND, Calatroni A, Kattan M, Gill MA, Stokes J, Liu AH, Khurana Hershey GK, Sherenian M, Kumar R, Robison RG, Gruchalla RS, O'Connor GT, Zoratti EM, Teach SJ, Lynch SV, Dill-McFarland KA, Becker PM, Togias A, Gern JE, Bacharier LB, Busse WW, and Jackson DJ. Inflammatory Pathways in Residual Asthma Exacerbations Among Mepolizumab-Treated Urban Children: A Secondary Analysis of a Randomized Clinical Trial. JAMA Pediatr 2025.
Document Type
Article
Publication Date
7-14-2025
Publication Title
JAMA Pediatr
Abstract
IMPORTANCE: While biologic therapies targeting type 2 (T2) inflammation reduce acute exacerbation rates in children with asthma and T2 inflammation, exacerbations still occur, and the underlying molecular mechanisms are poorly defined.
OBJECTIVE: To identify multiple distinct molecular mechanisms implicated in asthma exacerbations by characterizing respiratory illnesses among urban children with eosinophilic asthma enrolled in a clinical trial comparing treatment with mepolizumab vs placebo.
DESIGN, SETTING, AND PARTICIPANTS: This is a secondary analysis of the Mechanisms Underlying Asthma Exacerbations Prevented and Persistent With Immune-Based Therapy: A Systems Approach Phase 2 (MUPPITS-2) double-blind, placebo-controlled, parallel-group, randomized clinical trial comparing treatment with mepolizumab vs placebo among children with exacerbation-prone asthma in low-income urban centers in 9 US cities. Data analysis was performed from September 2022 to April 2025.
INTERVENTION: Participants were randomized to receive either mepolizumab (aged 6-11 years: 40 mg; aged 12-17 years: 100 mg) or matching placebo by subcutaneous injection once every 4 weeks for 52 weeks.
MAIN OUTCOMES AND MEASURES: The primary measurement was a transcriptomic modular analysis by RNA sequencing of nasal samples obtained during acute respiratory illnesses. Associations among upper airway transcriptional signatures, the clinical outcome of respiratory illnesses, and pulmonary functions were investigated.
RESULTS: Of the 290 participants enrolled in the MUPPITS-2 trial, 108 participants (median [IQR] age, 10.0 [9.0-13.0] years; 48 [44%] female) were sampled during 176 acute respiratory illness events. During illness events resulting in asthma exacerbations, children receiving mepolizumab demonstrated decreased expression of an eosinophil-associated module associated with T2 inflammation (log2 fold change [FC] estimate, -0.60; false discovery rate [FDR] < .05) but increased expression of gene modules associated with epithelial and macrophage inflammatory pathways relative to children receiving placebo (log2 FC estimates, 0.22-0.85; FDR < .05). Both groups showed higher expression of mucus secretion and cellular stress response pathways during exacerbations relative to nonexacerbation illnesses. The mepolizumab group demonstrated upregulation of epithelial inflammatory pathways in exacerbations irrespective of a respiratory virus, while macrophage pathways contributed specifically to viral exacerbations. Three distinct, semiorthogonal inflammatory axes were shown to underlie the majority of the heterogeneity among exacerbations in the 2 groups.
CONCLUSIONS AND RELEVANCE: The study's findings implicate multiple alternative inflammatory pathways associated with the epithelium and macrophages, as well as mucus hypersecretion, as mechanisms of residual acute exacerbations in children receiving mepolizumab. Further, they indicate that multiple distinct inflammatory axes can independently contribute to asthma exacerbations.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03292588.
PubMed ID
40658400
ePublication
ePub ahead of print
