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

305 Pages Posted: 22 May 2024

See all articles by Matthew Charles Altman

Matthew Charles Altman

University of Washington

Ryan C. Murphy

University of Washington

Tomasz Janczyk

Benaroya Research Institute

Naresh Doni Jayavelu

Benaroya Research Institute

Agustin Calatroni

Rho Inc.

Meyer Kattan

Columbia University

Michelle A. Gill

University of Texas at Dallas - Southwestern Medical Center

Jeffrey Stokes

Washington University in St. Louis

Andrew H. Liu

University of Colorado, Aurora - Children’s Hospital Colorado

Gurjit K. Khurana Hershey

Cincinnati Children's Hospital Medical Center

Michael Sherenian

Cincinnati Children's Hospital Medical Center

Rajesh Kumar

Ann & Robert H. Lurie Children’s Hospital of Chicago

Rachel G. Robison

Ann & Robert H. Lurie Children’s Hospital of Chicago

Rebecca S. Gruchalla

University of Texas at Dallas - Southwestern Medical Center

George T. O’Connor

Boston University - Chobanian & Avedisian School of Medicine

Edward M. Zoratti

Henry Ford Health System

Stephen J. Teach

Children's National Hospital

Susan V. Lynch

University of California, San Francisco - Division of Gastroenterology and Hepatology

Kimberly A. Dill-McFarland

University of Washington

Patrice M. Becker

Government of the United States of America - National Institute of Allergy and Infectious Diseases

Alkis Togias

Government of the United States of America - National Institutes of Health (NIH)

James E. Gern

University of Wisconsin-Madison - School of Medicine and Public Health

Leonard B. Bacharier

Vanderbilt University

William W. Busse

University of Wisconsin-Madison - School of Medicine and Public Health

Daniel J. Jackson

University of Wisconsin-Madison - School of Medicine and Public Health

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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

Suggested Citation

Altman, Matthew Charles and Murphy, Ryan C. and Janczyk, Tomasz and Doni Jayavelu, Naresh and Calatroni, Agustin and Kattan, Meyer and Gill, Michelle A. and Stokes, Jeffrey and Liu, Andrew H. and Khurana Hershey, Gurjit K. and Sherenian, Michael and Kumar, Rajesh and Robison, Rachel G. and Gruchalla, Rebecca S. and O’Connor, George T. and Zoratti, Edward M. and Teach, Stephen J. and Lynch, Susan V. and Dill-McFarland, Kimberly A. and Becker, Patrice M. and Togias, Alkis and Gern, James E. and Bacharier, Leonard B. and Busse, William W. and Jackson, Daniel J., Epithelial and Macrophage Associated Inflammatory Pathways Underlie Childhood Asthma Exacerbations:  Lessons from Blocking Il-5 Mediated T2-Inflammation. Available at SSRN: https://ssrn.com/abstract=4830495 or http://dx.doi.org/10.2139/ssrn.4830495

Matthew Charles Altman (Contact Author)

University of Washington ( email )

Seattle, WA 98195
United States

Ryan C. Murphy

University of Washington ( email )

Seattle, WA 98195
United States

Tomasz Janczyk

Benaroya Research Institute ( email )

Naresh Doni Jayavelu

Benaroya Research Institute ( email )

Agustin Calatroni

Rho Inc. ( email )

Chapel Hill, NC
United States

Meyer Kattan

Columbia University ( email )

3022 Broadway
New York, NY 10027
United States

Michelle A. Gill

University of Texas at Dallas - Southwestern Medical Center ( email )

5323 Harry Hines Blvd.
Dallas, TX 75390
United States

Jeffrey Stokes

Washington University in St. Louis ( email )

Andrew H. Liu

University of Colorado, Aurora - Children’s Hospital Colorado ( email )

Aurora, CO
United States

Gurjit K. Khurana Hershey

Cincinnati Children's Hospital Medical Center ( email )

3333 Burnet Avenue
Cincinnati, OH 45229
United States

Michael Sherenian

Cincinnati Children's Hospital Medical Center ( email )

Rajesh Kumar

Ann & Robert H. Lurie Children’s Hospital of Chicago ( email )

Rachel G. Robison

Ann & Robert H. Lurie Children’s Hospital of Chicago ( email )

Rebecca S. Gruchalla

University of Texas at Dallas - Southwestern Medical Center ( email )

5323 Harry Hines Blvd.
Dallas, TX 75390
United States

George T. O’Connor

Boston University - Chobanian & Avedisian School of Medicine ( email )

771 Albany St
Boston, MA 02118
United States

Edward M. Zoratti

Henry Ford Health System ( email )

Detroit, MI 48202-3450
United States

Stephen J. Teach

Children's National Hospital ( email )

Washington, DC
United States

Susan V. Lynch

University of California, San Francisco - Division of Gastroenterology and Hepatology ( email )

Third Avenue and Parnassus
San Francisco, CA CA 94143
United States

Kimberly A. Dill-McFarland

University of Washington ( email )

Seattle, WA 98195
United States

Patrice M. Becker

Government of the United States of America - National Institute of Allergy and Infectious Diseases ( email )

Alkis Togias

Government of the United States of America - National Institutes of Health (NIH) ( email )

9000 Rockville Pike
Bethesda, MD 20892
United States

James E. Gern

University of Wisconsin-Madison - School of Medicine and Public Health ( email )

Madison, WI 53711
United States

Leonard B. Bacharier

Vanderbilt University ( email )

William W. Busse

University of Wisconsin-Madison - School of Medicine and Public Health ( email )

Madison, WI 53711
United States

Daniel J. Jackson

University of Wisconsin-Madison - School of Medicine and Public Health ( email )

Madison, WI 53711
United States

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