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Air Pollutants in Urban Centers Trigger Non-Viral Asthma Exacerbations Through Activation of Coordinated Airway Inflammatory Responses

34 Pages Posted: 13 Jan 2022

See all articles by Matthew Charles Altman

Matthew Charles Altman

University of Washington

Meyer Kattan

Columbia University

George T. O’Connor

Boston University - Chobanian & Avedisian School of Medicine

Ryan C. Murphy

University of Washington

Elizabeth Whalen

Virginia Mason Medical Center - Benaroya Research Institute

Petra LeBeau

Rho Inc.

Agustin Calatroni

Rho Inc.

Michelle A. Gill

University of Texas at Dallas - Southwestern Medical Center

Rebecca S. Gruchalla

University of Texas at Dallas - Southwestern Medical Center

Andrew H. Liu

University of Colorado, Aurora - Children’s Hospital Colorado

Stephanie Lovinsky-Desir

Columbia University - Division of Pediatric Pulmonology

Jacqueline A. Pongracic

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

Carolyn M. Kercsmar

Cincinnati Children's Hospital Medical Center

Gurjit K. Khurana Hershey

Cincinnati Children's Hospital Medical Center

Edward M. Zoratti

Henry Ford Health System

Stephen J. Teach

Children's National Hospital

Leonard B. Bacharier

Vanderbilt University

Lisa M. Wheatley

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

Steve M. Sigelman

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

Peter J. Gergen

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

Alkis Togias

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

William W. Busse

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

James E. Gern

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

Daniel J. Jackson

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

NIAID Inner City Asthma Consortium

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Abstract

Background: Asthma prevalence and severity have markedly increased with urbanization, and children in low-income urban centers have among the greatest asthma morbidity. Outdoor air pollution has been associated with adverse respiratory effects in children with asthma. However, the mechanisms by which air pollution exposure exacerbates asthma, and how these mechanisms compare to respiratory virus induced exacerbations, are poorly understood.

Methods: We investigated the relationships among regional air pollutant levels, respiratory viral infections, lung function, and upper airway transcriptional signatures in a cohort of 208 urban children with exacerbation-prone asthma during reported respiratory illnesses, with particular focus on asthma exacerbations occurring in the absence of a respiratory virus. We then validated observed associations between regional air pollutant levels and non-viral exacerbations in an independent cohort of 189 urban children with persistent asthma.

Findings: We found that elevated air quality index (AQI) values, driven predominantly by elevated particulate matter less than 2.5µm (PM2.5) and ozone (O3), were significantly associated with asthma exacerbations and decreases in pulmonary function that occurred in the absence of a provoking viral infection. Moreover, individual pollutants were significantly associated with altered gene expression in coordinated inflammatory pathways, including PM2.5 with increased epithelial induction of tissue kallikreins, the IL-23/IL-17 axis, mucus hypersecretion, and barrier functions, and O3 with increased type-2 inflammation.

Interpretation: These results provide important mechanistic insights into the contributions of air pollution to the respiratory health and asthma exacerbation subtypes of urban children. Furthermore, they identify potential future targets for the prevention and management of asthma exacerbations.

Trial Registration: The MUPPITS1 study was registered on clinicaltrials.gov as NCT02502890. The ICATA study was registered on clinicaltrials.gov as NCT00377572.

Funding: Funded by the National Institutes of Health/ National Institute of Allergy and Infectious Diseases.

Declaration of Interest: All authors with the exception of L. Wheatley, S. Sigelman, P. Gergen, and A. Togias report grants from NIH/NIAID/DAIT during the conduct of study. M. Altman reports personal fees for consulting from Regeneron. M. Kattan reports consulting fees from Novartis. G. O’Connor reports consulting fees from AstraZeneca, and reports a grant from Janssen Pharmaceuticals paid to his employing institution. M. Gill reports consulting fees from the American Academy of Allergy, Asthma, and Immunology and the American Academy of Pediatrics. R. Gruchalla reports employment as a special government employee with the Center for Biologics Evaluation and Research, and consulting fees from the Consulting Massachusetts Medical Society. A. Liu is a Consultant for Phadia ThermoFisher, received non-monetary research support from Phadia Thermofisher and Propeller Health/ResMed, and research funding from Avillion; all funds paid to University of Colorado. S. Lovinsky-Desir reports funding from NIH/NHLBI and the Robert Wood Johnson Foundation. J. Pongracic reports provisions of study drug for other asthma studies from Glaxo SmithKline, Boehringer-Ingelheim, and Genentech/Novartis. C. Kercsmar reports personal fees from Glaxo SmithKline for service on a DSMB and royalties from UpToDate. G. K. Khurana Hershey reports advisory board fees from Hoth Therapeutics. E. Zoratti reports consulting fees from Wayne State University. S. Teach reports support from NIH/NHLBI and EJF Philanthropies and royalties from UpToDate. L. Bacharier reports grant support from the NIH/NHLBI, Sanofi, and Vectura, as well as personal fees from GlaxoSmithKline, Genentech, Novartis, Merck, DBV Technologies, Teva, Boehringer Ingelheim, AstraZeneca, WebMD/Medscape, Sanofi, Regeneron, Vectura, and Circassia. W. Busse reports grants from NIH/NHLBI, during the conduct of the study; personal fees from Novartis, Regeneron, AstraZeneca, GlaxoSmithKline, Genentech, Elsevier, Med Learning Group, Boston Scientific, Medscape. J. Gern reports grants from NIH, personal fees and stock options from Meissa Vaccines Inc., personal fees from AstraZeneca and Ena Therapeutics and a patent on methods for production of rhinoviruses. D. Jackson reports grants from NIH/NHLBI and GlaxoSmithKline, personal fees for DSMB from Pfizer and for consulting from Novartis, Sanofi-Regeneron, GlaxoSmithKline, Vifor Pharma and Astra Zeneca. R. Murphy, E. Whalen, P. LeBeau, A. Calatroni, L. Wheatley, S. Sigelman, P. Gergen, and A. Togias have nothing to disclose.

Ethical Approval: The MUPPITS1 and ICATA studies complied with all relevant ethical regulations. The MUPPITS1 study was approved by a central IRB (Western IRB), and a parent or legal guardian for each child signed written informed consent, and participants provided assent, before completing study procedures. The ICATA study was approved by the institutional review boards of all participating institutions and written informed consent was obtained from each participant or the participant's parent or legal guardian. Participants who were younger than 18 years of age provided assent.

Keywords: Asthma exacerbations, air pollutants, transcriptomics, network analysis

Suggested Citation

Altman, Matthew Charles and Kattan, Meyer and O’Connor, George T. and Murphy, Ryan C. and Whalen, Elizabeth and LeBeau, Petra and Calatroni, Agustin and Gill, Michelle A. and Gruchalla, Rebecca S. and Liu, Andrew H. and Lovinsky-Desir, Stephanie and Pongracic, Jacqueline A. and Kercsmar, Carolyn M. and Khurana Hershey, Gurjit K. and Zoratti, Edward M. and Teach, Stephen J. and Bacharier, Leonard B. and Wheatley, Lisa M. and Sigelman, Steve M. and Gergen, Peter J. and Togias, Alkis and Busse, William W. and Gern, James E. and Jackson, Daniel J. and Consortium, NIAID Inner City Asthma, Air Pollutants in Urban Centers Trigger Non-Viral Asthma Exacerbations Through Activation of Coordinated Airway Inflammatory Responses. Available at SSRN: https://ssrn.com/abstract=4000662 or http://dx.doi.org/10.2139/ssrn.4000662

Matthew Charles Altman (Contact Author)

University of Washington ( email )

Seattle, WA 98195
United States

Meyer Kattan

Columbia University ( email )

3022 Broadway
New York, NY 10027
United States

George T. O’Connor

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

771 Albany St
Boston, MA 02118
United States

Ryan C. Murphy

University of Washington ( email )

Seattle, WA 98195
United States

Elizabeth Whalen

Virginia Mason Medical Center - Benaroya Research Institute ( email )

United States

Petra LeBeau

Rho Inc. ( email )

Chapel Hill, NC
United States

Agustin Calatroni

Rho Inc. ( email )

Chapel Hill, NC
United States

Michelle A. Gill

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

5323 Harry Hines Blvd.
Dallas, TX 75390
United States

Rebecca S. Gruchalla

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

5323 Harry Hines Blvd.
Dallas, TX 75390
United States

Andrew H. Liu

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

Aurora, CO
United States

Stephanie Lovinsky-Desir

Columbia University - Division of Pediatric Pulmonology ( email )

3959 Broadway, CHC-701
New York, NY
United States
212-305-5122 (Phone)
718-305-6103 (Fax)

Jacqueline A. Pongracic

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

225 E Chicago Ave.
Chicago, IL 60611
United States

Carolyn M. Kercsmar

Cincinnati Children's Hospital Medical Center ( email )

3333 Burnet Avenue
Cincinnati, OH 45229
United States

Gurjit K. Khurana Hershey

Cincinnati Children's Hospital Medical Center ( email )

3333 Burnet Avenue
Cincinnati, OH 45229
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

Leonard B. Bacharier

Vanderbilt University ( email )

Lisa M. Wheatley

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

9000 Rockville Pike
Bethesda, MD 20892
United States

Steve M. Sigelman

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

9000 Rockville Pike
Bethesda, MD 20892
United States

Peter J. Gergen

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

9000 Rockville Pike
Bethesda, MD 20892
United States

Alkis Togias

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

9000 Rockville Pike
Bethesda, MD 20892
United States

William W. Busse

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

Madison, WI 53711
United States

James E. Gern

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

No contact information is available for NIAID Inner City Asthma Consortium

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