Epithelial-Associated Inflammatory Pathways Underlie Residual Asthma Exacerbations in Urban Children Treated with Mepolizumab Therapy
Patel S, Altman M, Cox M, Bacharier L, Calatroni A, Gill M, Stokes J, Liu A, Cohen R, Makhija M, Hershey GK, O'Connor G, Zoratti E, Teach S, Kattan M, Becker P, Togias A, Busse W, and Jackson D. Epithelial-Associated Inflammatory Pathways Underlie Residual Asthma Exacerbations in Urban Children Treated with Mepolizumab Therapy. J Allergy Clin Immunol 2023; 151(2):AB222.
J Allergy Clin Immunol
Rationale: Identification of airway inflammatory pathways in asthma has proven essential to understanding mechanisms of disease and has led to effective personalized treatment with biologic therapies. However, relatively little is known about patterns of airway inflammation at the time of respiratory illnesses and how such patterns relate to responsiveness to biologic therapies.
Methods: The MUPPITS-1 (n=106) and MUPPITS-2 (n=290) studies investigated asthma exacerbations in urban children with exacerbation-prone asthma and ≥150/microliter blood eosinophils. Children in both studies received guidelines-based asthma care; in MUPPITS-2, participants were additionally randomized (1:1) to placebo or mepolizumab. Nasal lavage samples were collected during respiratory illnesses for RNA-sequencing and analyzed by modular analysis to assess genome-wide expression patterns associated with exacerbation illnesses.
Results: Among 284 illnesses, exacerbations that occurred in the absence of mepolizumab therapy showed significantly higher upregulation of eosinophil associated inflammatory pathways (fold change values [FC]=1.27-1.43, p-values<0.05), including a Type-2 inflammation module composed of eosinophil, mast cell, and IL-13 response genes. In contrast, exacerbations that occurred while on mepolizumab therapy showed significantly higher upregulation of several epithelial inflammatory pathways (FC=1.36-1.64, p-values<0.05) including TGF-β/Smad3 signaling, extracellular matrix production, and epidermal growth factor receptor signaling.
Conclusions: These results indicate that novel inflammatory pathways, likely originating from the airway epithelium and distinct from Type-2 or eosinophilic inflammation, drive residual exacerbations that occur in children treated with mepolizumab therapy added to guideline-based care. These findings identify likely mechanisms of persistent disease expression in these children despite significant depletion of eosinophils and can identify novel treatment targets for future studies.