Alternative Epithelial and Macrophage Inflammation Linked to Asthma Exacerbations in Children on Mepolizumab: JAMA

The study analyzed data from the MUPPITS-2 clinical trial, which included children with exacerbation-prone asthma from underserved urban communities across nine U.S. cities. Participants aged 6–17 years received either mepolizumab or placebo through subcutaneous injections every four weeks for one year. The team collected nasal samples during acute respiratory illnesses to investigate gene expression patterns linked to asthma exacerbations.

The key findings of the study were as follows:

• Out of 290 children enrolled in the study, 108 provided nasal samples during 176 illness episodes.
• Children treated with mepolizumab during asthma flare-ups showed a significant reduction in eosinophil-driven type 2 (T2) inflammation.
• Despite the decrease in T2 inflammation, these children displayed increased activity in alternative inflammatory pathways involving airway epithelial cells and macrophages.
• Both the mepolizumab and placebo groups exhibited heightened mucus secretion and cellular stress responses during exacerbations.
• In children receiving mepolizumab, epithelial inflammatory pathways were upregulated even without the presence of viral infections.
• Macrophage-driven pathways were particularly associated with virus-induced exacerbations.
• The findings revealed three distinct inflammatory axes contributing to asthma flare-ups, underscoring the heterogeneity of disease mechanisms.

The study suggests that by suppressing eosinophilic inflammation, mepolizumab may unmask other inflammatory processes that can still trigger asthma attacks. This has important implications for clinical care, as it shows the limitations of focusing solely on T2 inflammation and underscores the need for more personalized approaches.

While the researchers acknowledge limitations—such as relying on upper airway samples as a proxy for lung inflammation—the use of transcriptomic analysis helped reveal shifts in cell activity and composition during illness episodes. The data also suggest distinct inflammatory "endotypes" depending on viral involvement, which could inform future treatment strategies.

Ultimately, the study highlights the need for broader therapeutic targets in managing asthma and supports incorporating molecular-level data into clinical trials. By mapping these alternative pathways, the research opens doors for new treatments tailored to individual patient profiles, especially for children who continue to experience flare-ups despite biologic therapy.

Reference:

Altman MC, Janczyk T, Murphy RC, et al. Inflammatory Pathways in Residual Asthma Exacerbations Among Mepolizumab-Treated Urban Children: A Secondary Analysis of a Randomized Clinical Trial. JAMA Pediatr. Published online July 14, 2025. doi:10.1001/jamapediatrics.2025.2044