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Clinical Trial
. 2025 Sep 1;179(9):957-970.
doi: 10.1001/jamapediatrics.2025.2044.

Inflammatory Pathways in Residual Asthma Exacerbations Among Mepolizumab-Treated Urban Children: A Secondary Analysis of a Randomized Clinical Trial

Matthew C Altman  1   2 , Tomasz Janczyk  2 , Ryan C Murphy  1 , Naresh Doni Jayavelu  2 , Agustin Calatroni  3 , Meyer Kattan  4 , Michelle A Gill  5 , Jeffrey Stokes  5 , Andrew H Liu  6 , Gurjit K Khurana Hershey  7 , Michael Sherenian  7 , Rajesh Kumar  8 , Rachel G Robison  8 , Rebecca S Gruchalla  9 , George T O'Connor  10 , Edward M Zoratti  11 , Stephen J Teach  12 , Susan V Lynch  13 , Kimberly A Dill-McFarland  1 , Patrice M Becker  14 , Alkis Togias  14 , James E Gern  15   16 , Leonard B Bacharier  17 , William W Busse  15   16 , Daniel J Jackson  15   16 ; Inner City Asthma Consortium and Childhood Asthma in Urban Settings Network
Affiliations
Clinical Trial

Inflammatory Pathways in Residual Asthma Exacerbations Among Mepolizumab-Treated Urban Children: A Secondary Analysis of a Randomized Clinical Trial

Matthew C Altman et al. 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Kattan reported personal fees from Regeneron outside the submitted work. Dr Gill reported grants and honoraria from the National Institute of Allergy and Infectious Diseases, National Institutes of Health during the conduct of the study; and honoraria from the American Academy of Pediatrics outside the submitted work. Dr Stokes reported grants from the National Institutes of Health during the conduct of the study; and grants from the National Heart, Lung, and Blood Institute and National Institutes of Health outside the submitted work. Dr Liu reported grants from the National Institutes of Health during the conduct of the study; and personal fees from ThermoFisher Scientific, Phadia, AstraZeneca, OM Pharma, Avillion, and Labcorp, grants from OM Pharma, ResMed/Propeller Health, and Avillion, and nonfinancial support from Revenio and ResMed/Propeller Health outside the submitted work. Dr Khurana Hershey reported grants from Adare during the conduct of the study. Dr Sherenian reported employment with AbbVie outside the submitted work. Dr Robison reported grants from Sanofi and AstraZeneca outside the submitted work. Dr Gruchalla reported employment with the Center for Biologics Evaluation and Research and personal fees from the Massachusetts Medical Society outside the submitted work. Dr O’Connor reported grants from the National Institutes of Health during the conduct of the study. Dr Zoratti reported grants from the National Institute of Allergy and Infectious Diseases, National Institutes of Health during the conduct of the study; and grants from the National Institute of Allergy and Infectious Diseases, National Institutes of Health outside the submitted work. Dr Teach reported grants from the National Institutes of Health during the conduct of the study; and grants from the National Heart, Lung, and Blood Institute, National Institutes of Health and personal fees from Medscape and UpToDate outside the submitted work. Dr Lynch reported grants from the National Institute of Allergy and Infectious Diseases, National Institutes of Health during the conduct of the study; and personal fees from Siolta Therapeutics Inc and Sanofi, a patent issued for reductive prodrug cancer chemothera (Stan449-PRV), patent WO 2010091189 A1 issued (combination antibiotic and antibody therapy for the treatment of Pseudomonas aeruginosa infection) with royalties paid to KaloBios Inc, a patent for therapeutic microbial consortium for induction of immune tolerance licensed to Siolta Therapeutics, patent WO 2012027302 A3 issued (systems and methods for detecting antibiotic resistance), a patent US 7687474 B2 issued (nitroreductase enzymes), patent WO 2013155370 A1 issued (sinusitis diagnostics and treatments), patent US 20120264637 A1 issued (methods and systems for phylogenetic analysis), a patent for methods and compositions relating to epoxide hydrolase genes issued to Siolta Therapeutics, and being a cofounder of Siolta Therapeutics outside the submitted work. Dr Dill-McFarland reported personal fees from EuropaDX and Seattle BioSoftware outside the submitted work. Dr Togias reported employment with the National Institute of Allergy and Infectious Diseases, National Institutes of Health outside the submitted work. Dr Gern reported personal fees from Meissa Vaccines Inc, Arrowhead Pharmaceuticals, Via Nova Therapeutics Inc, and AstraZeneca, stock options with Meissa Vaccines Inc, and 2 patents for methods to enhance the production of rhinoviruses outside the submitted work. Dr Bacharier reported personal fees from GlaxoSmithKline, Sanofi/Regeneron, AstraZeneca, and Novartis during the conduct of the study; and personal fees from Vertex, DBV Technologies, Aravax, Sanofi, Regeneron, Genentech, GlaxoSmithKline, DBV Technologies, Teva, Medscape, Kinaset, OM Pharma, and AstraZeneca, book royalties from Elsevier, honoraria from Sanofi, Regeneron, and GlaxoSmithKline, advisory board participation for DBV Technologies, AstraZeneca and Vertex, leadership roles for the American Academy of Allergy, Asthma, and Immunology and the American Board of Allergy and Immunology, and medical writing services for Sanofi/Regeneron. outside the submitted work. Dr Busse reported personal fees from Sanofi, Regeneron, GlaxoSmithKline, Novartis, Genentech, and AstraZeneca and royalties from Elsevier outside the submitted work. Dr Jackson reported grants from the National Institute of Allergy and Infectious Diseases, National Institutes of Health and GlaxoSmithKline during the conduct of the study; personal fees from Avillion, AstraZeneca, Areteia, Genentech, GlaxoSmithKline, Regeneron, Sanofi, Upstream Bio, Pfizer, Novartis, and Vifor Pharma and grants from Regeneron, GlaxoSmithKline, and the National Heart, Lung, and Blood Institute, National Institutes of Health outside the submitted work. No other disclosures were reported.

Comment on

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