Airway hyperresponsiveness in chronic obstructive pulmonary disease: A marker of asthma-chronic obstructive pulmonary disease overlap syndrome?

Ruzena Tkacova, Darlene L Y Dai, Judith M. Vonk, Janice M. Leung, Pieter S. Hiemstra, Maarten van den Berge, Lisette Kunz, Zsuzsanna Hollander, Donald Tashkin, Robert Wise, John Connett, Raymond Ng, Bruce McManus, S. F. Paul Man, Dirkje S. Postma, Don D. Sin

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24 Scopus citations

Abstract

Background The impact of airway hyperreactivity (AHR) on respiratory mortality and systemic inflammation among patients with chronic obstructive pulmonary disease (COPD) is largely unknown. We used data from 2 large studies to determine the relationship between AHR and FEV1 decline, respiratory mortality, and systemic inflammation. Objectives We sought to determine the relationship of AHR with FEV1 decline, respiratory mortality, and systemic inflammatory burden in patients with COPD in the Lung Health Study (LHS) and the Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease (GLUCOLD) study. Methods The LHS enrolled current smokers with mild-to-moderate COPD (n = 5887), and the GLUCOLD study enrolled former and current smokers with moderate-to-severe COPD (n = 51). For the primary analysis, we defined AHR by a methacholine provocation concentration of 4 mg/mL or less, which led to a 20% reduction in FEV1 (PC20). Results The primary outcomes were FEV1 decline, respiratory mortality, and biomarkers of systemic inflammation. Approximately 24% of LHS participants had AHR. Compared with patients without AHR, patients with AHR had a 2-fold increased risk of respiratory mortality (hazard ratio, 2.38; 95% CI, 1.38-4.11; P = .002) and experienced an accelerated FEV1 decline by 13.2 mL/y in the LHS (P = .007) and by 12.4 mL/y in the much smaller GLUCOLD study (P = .079). Patients with AHR had generally reduced burden of systemic inflammatory biomarkers than did those without AHR. Conclusions AHR is common in patients with mild-to-moderate COPD, affecting 1 in 4 patients and identifies a distinct subset of patients who have increased risk of disease progression and mortality. AHR may represent a spectrum of the asthma-COPD overlap phenotype that urgently requires disease modification.

Original languageEnglish (US)
Pages (from-to)1571-1579.e10
JournalJournal of Allergy and Clinical Immunology
Volume138
Issue number6
DOIs
StatePublished - Dec 1 2016

Bibliographical note

Funding Information:
Disclosure of potential conflict of interest: R. Tkacova was supported by the project MediPark, Kosice, ITMS:26220220185, Operational Programme Research and Development (OPVaV-2012/2.2/08-RO) (contract no. OPVaV/12/2013) and has received payment for developing educational presentations from Novartis, Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline. J. M. Leung is a fellow with the Michael Smith Foundation for Health Research. P. S. Hiemstra has received research support from the Netherlands Organization for Scientific Research, Netherlands Asthma Foundation and GlaxoSmithKline, Galapagos NV, and Boehringer Ingelheim. M. van den Berge has received research support from GlaxoSmithKline, Chiesi, and Teva. L. Kunz has received lecture fees from AstraZeneca. D. Tashkin has received research support from the National Heart, Lung, and Blood Institute (NHLBI), AstraZeneca, Boehringer Ingelheim, and Novartis; is on the boards for AstraZeneca, Novartis, and Sunovion; has received consultancy fees from AstraZeneca, Novartis, Theravance, and Sunovion; and has received lecture fees from AstraZeneca, Boehringer Ingelheim, and Sunovion. R. Wise has received research support from GlaxoSmithKline; is on the GlaxoSmithKline Clinical Endpoint Committee and Data Monitoring Committee (GlaxoSmithKline supplied drugs for support of a clinical trial); has received research support from AstraZeneca; is on the AstraZeneca Data Monitoring Committee, Clinical Endpoint Committee, and Steering Committee; has received research support from and is on the Data Monitoring Committee for Boehringer Ingelheim; has received advisory fees from Novartis, Sunovoin, Takeda, Vertex, Verona, Theravance, Sarepta, Grifols, and Sunovoin; is on the Mylan and Pfizer Clinical Endpoint Committees; has received research support and advisory fees from Teva; is on the Data Monitoring Committees for Roche, Merck, Pulmonx, Bristol Myers Squibb, and Janssen; and is on the Spiration Steering Committee. J. Connett has received research support from the NHLBI, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute of Allergy and Infectious Diseases. D. S. Postma has received consultancy fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Takeda, and Teva and has received research support from AstraZeneca, Chiesi, Genentech, GlaxoSmithKline, and Roche. D. D. Sin is a Tier 1 Canada Research Chair in COPD; is on the Novartis and Boehringer Ingelheim Canadian COPD Advisory Committees; is on the AstraZeneca International COPD Advisory Committee; has received research support from Merck, AstraZeneca, and Boehringer Ingelheim; has received lecture fees from Novartis, Boehringer Ingelheim, and AstraZeneca; and has received travel support from Boehringer Ingelheim. The rest of the authors declare that they have no relevant conflicts of interest.

Funding Information:
The Lung Health Study (LHS) Biomarker Study was funded by the Canadian Institutes of Health Research (CIHR) & Genome Canada (grant no. 144COP) and the Canadian Respiratory Research Network. The original LHS was funded by the US National Heart, Lung, and Blood Institute (NHLBI-1U10-HL59275). The Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease study was originally funded by the Netherlands Organization for Scientific Research , the Netherlands Asthma Foundation , GlaxoSmithKline , University Medical Center Groningen , and Leiden University Medical Center . D.D.S. is supported by a Tier 1 Canada Research Chair in chronic obstructive pulmonary disease.

Publisher Copyright:
© 2016 American Academy of Allergy, Asthma & Immunology

Keywords

  • Respiratory hypersensitivity
  • airway obstruction
  • death rate
  • lung function tests

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