Histamine airway hyper-responsiveness and mortality from chronic obstructive pulmonary disease: a cohort study

Lancet. 2000 Oct 14;356(9238):1313-7. doi: 10.1016/S0140-6736(00)02815-4.


Background: Smoking and airway lability, which is expressed by histamine airway hyper-responsiveness, are known risk factors for development of respiratory symptoms. Smoking is also associated with increased mortality risks. We studied whether airway hyper-responsiveness is associated with increased mortality, and whether this risk was independent of smoking and reduced lung function.

Methods: We followed up 2008 inhabitants of the communities of Vlagtwedde, Vlaardingen, and Meppel (Netherlands), who had histamine challenge test data, from 1964-72 for 30 years. Follow-up was 99% successful (29 patients lost to follow-up) with 1453 participants alive and 526 deaths (246 died from cardiovascular disease, 54 from lung cancer, and 21 from chronic obstructive pulmonary disease [COPD]).

Findings: Mortality from COPD increased with more severe hyper-responsiveness; relative risks of 3.83 (95% CI 0.97-15.1), 4.40 (1.16-16.7), 4.78 (1.27-18.0), 6.69 (1.71-26.1), and 15.8 (3.72-67.1) were associated with histamine thresholds of 32 g/L, 16 g/L, 8 g/L, 4 g/L, and 1 g/L, respectively, compared with no hyper-responsiveness. These risks were adjusted for sex, age, smoking, lung function, body-mass index, positive skin tests, eosinophilia, asthma, and city of residence.

Interpretation: Increased histamine airway hyper-responsiveness predicts mortality from COPD. Although this trend was more pronounced in smokers, an increasing proportion of COPD deaths with increasing hyper-responsiveness was also present among individuals who had never smoked.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Age Distribution
  • Aged
  • Body Mass Index
  • Bronchial Hyperreactivity / complications
  • Bronchial Hyperreactivity / diagnosis*
  • Bronchial Provocation Tests
  • Cohort Studies
  • Female
  • Histamine*
  • Humans
  • Lung Diseases, Obstructive / etiology*
  • Lung Diseases, Obstructive / mortality
  • Male
  • Middle Aged
  • Netherlands
  • Predictive Value of Tests
  • Proportional Hazards Models
  • Risk
  • Sex Distribution
  • Smoking / adverse effects*
  • Vital Capacity


  • Histamine