title: Airway hyperresponsiveness in chronic obstructive pulmonary disease: A marker of asthma-chronic obstructive pulmonary disease overlap syndrome?
abstract: 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 FEV1decline, respiratory mortality, and systemic inflammation.
  
  
  
  We sought to determine the relationship of AHR with FEV1decline, 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.
  
  
  
  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).
  
  
  
  The primary outcomes were FEV1decline, 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 FEV1decline 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.
  
  
  
  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.
authors.affiliation: UBC James Hogg Research Center & the Institute for Heart and Lung Health, St Paul's Hospital, Vancouver, British Columbia, Canada; Faculty of Medicine, Department of Respiratory Medicine and Tuberculosis, P.J. Safarik University, Kosice, Slovakia.
authors.forename: Ruzena
authors.initials: R
authors.lastname: Tkacova
authors.affiliation: UBC James Hogg Research Center & the Institute for Heart and Lung Health, St Paul's Hospital, Vancouver, British Columbia, Canada; PROOF Center of Excellence, St Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Darlene L Y
authors.initials: DLY
authors.lastname: Dai
authors.affiliation: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Vonk
authors.affiliation: UBC James Hogg Research Center & the Institute for Heart and Lung Health, St Paul's Hospital, Vancouver, British Columbia, Canada; Department of Medicine (Pulmonary Division), University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Janice M
authors.initials: JM
authors.lastname: Leung
authors.affiliation: Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Pieter S
authors.initials: PS
authors.lastname: Hiemstra
authors.affiliation: University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands; Department of Pulmonary Diseases University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: van den Berge
authors.affiliation: Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Lisette
authors.initials: L
authors.lastname: Kunz
authors.affiliation: UBC James Hogg Research Center & the Institute for Heart and Lung Health, St Paul's Hospital, Vancouver, British Columbia, Canada; PROOF Center of Excellence, St Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Hollander
authors.affiliation: David Geffen School of Medicine at UCLA, Los Angeles, Calif.
authors.forename: Donald
authors.initials: D
authors.lastname: Tashkin
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Md.
authors.forename: Robert
authors.initials: R
authors.lastname: Wise
authors.affiliation: University of Minnesota School of Public Health, Minneapolis, Minn.
authors.forename: John
authors.initials: J
authors.lastname: Connett
authors.affiliation: UBC James Hogg Research Center & the Institute for Heart and Lung Health, St Paul's Hospital, Vancouver, British Columbia, Canada; PROOF Center of Excellence, St Paul's Hospital, Vancouver, British Columbia, Canada; Department of Computer Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Raymond
authors.initials: R
authors.lastname: Ng
authors.affiliation: UBC James Hogg Research Center & the Institute for Heart and Lung Health, St Paul's Hospital, Vancouver, British Columbia, Canada; PROOF Center of Excellence, St Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Bruce
authors.initials: B
authors.lastname: McManus
authors.affiliation: UBC James Hogg Research Center & the Institute for Heart and Lung Health, St Paul's Hospital, Vancouver, British Columbia, Canada; Department of Medicine (Pulmonary Division), University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: S F
authors.initials: SF
authors.lastname: Paul Man
authors.affiliation: University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands; Department of Pulmonary Diseases University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: UBC James Hogg Research Center & the Institute for Heart and Lung Health, St Paul's Hospital, Vancouver, British Columbia, Canada; Department of Medicine (Pulmonary Division), University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: don.sin@hli.ubc.ca.
authors.forename: Don D
authors.initials: DD
authors.lastname: Sin
mesh_terms: D000328:Adult; D000368:Aged; D001249:Asthma / Q000175:diagnosis / Q000453:epidemiology* / Q000401:mortality; D015415:Biomarkers / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008875:Middle Aged; D009426:Netherlands; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000453:epidemiology* / Q000401:mortality; D012130:Respiratory Hypersensitivity / Q000175:diagnosis / Q000453:epidemiology* / Q000401:mortality; D012306:Risk; D012907:Smoking / Q000009:adverse effects; D013147:Spirometry; D016019:Survival Analysis; D013577:Syndrome
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators
keywords: Respiratory hypersensitivity; airway obstruction; death rate; lung function tests