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

J Allergy Clin Immunol. 2016 Dec;138(6):1571-1579.e10. doi: 10.1016/j.jaci.2016.04.022. Epub 2016 May 24.


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.

Keywords: Respiratory hypersensitivity; airway obstruction; death rate; lung function tests.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Asthma / diagnosis
  • Asthma / epidemiology*
  • Asthma / mortality
  • Biomarkers / metabolism
  • Humans
  • Inflammation Mediators / metabolism
  • Middle Aged
  • Netherlands
  • Pulmonary Disease, Chronic Obstructive / diagnosis
  • Pulmonary Disease, Chronic Obstructive / epidemiology*
  • Pulmonary Disease, Chronic Obstructive / mortality
  • Respiratory Hypersensitivity / diagnosis
  • Respiratory Hypersensitivity / epidemiology*
  • Respiratory Hypersensitivity / mortality
  • Risk
  • Smoking / adverse effects
  • Spirometry
  • Survival Analysis
  • Syndrome


  • Biomarkers
  • Inflammation Mediators