Epithelial and Macrophage Associated Inflammatory Pathways Underlie Childhood Asthma Exacerbations:  Lessons from Blocking Il-5 Mediated T2-Inflammation

Abstract

Background: 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. We aimed to identify the multiple distinct molecular mechanisms implicated in asthma exacerbations in children by contrasting exacerbations among urban children with eosinophilic asthma enrolled in a clinical trial comparing treatment with mepolizumab versus placebo.

Methods: We performed transcriptomic modular analysis of nasal samples obtained during acute respiratory illnesses from urban children with exacerbation-prone eosinophilic asthma enrolled in the MUPPITS-2 clinical trial, which compared treatment with mepolizumab versus placebo. We investigated associations among upper airway transcriptional signatures, respiratory illnesses that resulted in exacerbations, pulmonary function, and biomarkers of T2 inflammation.

Findings: Of the 290 participants enrolled in the MUPPITS-2 trial, 108 participants 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 related to T2 inflammation but increased expression of gene modules associated with epithelial and macrophage inflammatory pathways relative to children receiving placebo. Both groups showed higher expression of mucus secretion and cellular stress response pathways during exacerbations relative to non-exacerbation illnesses. The mepolizumab group demonstrated upregulation of epithelial inflammatory pathways in exacerbations irrespective of a respiratory virus while macrophage pathways occurred specifically in viral exacerbations.

Interpretation: Our findings implicate multiple alternative inflammatory pathways related to the epithelium and macrophages, as well as mucus hypersecretion, as probable mechanisms responsible for residual acute exacerbations in children receiving mepolizumab. Further, they indicate that multiple distinct inflammatory axes contribute to asthma exacerbations.

Funding: The research reported in this publication was supported by NIH-NIAID award numbers 5UM1AI114271, UM1AI160040, and UM2AI117870, with additional support provided through award numbers UL1TRG01422, UL1RR025741, UL1TR000150, UL1TR001422, UL1 TR002535, UL1TR001876, and 5UL1TR001425–03. Additional support was also provided through an unrestricted grant from GlaxoSmithKline.

Declaration of Interest: All authors except A. Togias and P. Becker report grants from NIH/NIAID during the conduct of study. W. Busse reports consulting fees from Novartis, GlaxoSmithKline, Genentech, Sanofi, AstraZeneca and Regeneron, royalties from Elsevier outside the submitted work. M. Gill reports an honorarium for and support for travel to the 2017 AAAAI meeting during the conduct of study and monetary compensation from the American Academy of Pediatrics for her work teaching the biannual Pediatrics board review course, PREP The Course. K. Hershey reports grants from Adare, during the conduct of the study. D. Jackson reports personal fees from Novartis, Pfizer, Regeneron, AstraZeneca, Sanofi and Vifor Pharma, grants and personal fees from GlaxoSmithKline and grants from NIH/NHLBI, outside the submitted work. M. Kattan reports personal fees from Regeneron, outside the submitted work. R. Gruchalla reports government employment from Center for Biologics Evaluation and Research as well as personal fees from Consulting Massachusetts Medical Society, outside the submitted work. A. Liu reports personal fees from Phadia ThermoFisher as consulting honoraria, grants and non-financial support from ResMed/Propeller Health, non-financial support from Revenio, grants and personal fees from Avillion and personal fees from Labcorp, outside the submitted work. L. Bacharier reports book royalties from Elsevier, consulting fees from Sanofi, Regeneron, Genentech, GlaxoSmithKline, DBV technologies, Teva, Medscape, Kinaset, OM Pharma and AstraZeneca, honoraria from Sanofi, Regeneron and GlaxoSmithKline, participation in advisory board for DBV Technologies, AstraZeneca and Vertex, leadership role in American Academy of Allergy Asthma & Immunology and American Board of Allergy and Immunology and medical writing services for Sanofi/Regeneron. J. Gern reports consulting fees from AstraZeneca and Meissa Vaccines, two patents related to the methods to enhance the production of rhinoviruses and stock options with Meissa Vaccines. S. Teach reports grants from NIH–NHLBI, payment from Medscape and personal fees from Uptodate. S. Lynch reports personal fees from Siolta Therapeutics, personal fees from Sanofi, a patent Reductive prodrug cancer chemothera (Stan449-PRV) issued, a patent Combination antibiotic and antibody therapy for the treatment of Pseudomonas aeruginosa infection; WO 2010091189 A1 with royalties paid to KaloBios Inc., a patent Therapeutic microbial consortium for induction of immune tolerance licensed to Siolta Therapeutics, a patent Systems and methods for detecting antibiotic resistance (WO 2012027302 A3) issued, a patent Nitroreductase enzymes. US 7687474 B2 issued, a patent Sinusitis diagnostics and treatments WO 2013155370 A1 issued, a patent Methods and systems for phylogenetic analysis US 20120264637 A1 issued, and a patent methods and compositions relating to epoxide hydrolase genes issued to Siolta Therapeutics and reports that she is a co-founder of Siolta Therapeutics, a start up company that is developing a mixed-species microbial oral therapeutic for induction of immune tolerance. All other authors declare no competing interests.

Ethical Approval: The protocol was approved by a central IRB. The legal guardians of all study participants provided written informed consent and children provided assent.

Keywords: Pediatric Asthma, Transcriptomics, Mepolizumab