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

Background Smoking and airway lability, which is expressed by histamine air way hyper-responsiveness, are known risk factors for development of respira tory symptoms. Smoking is also associated with increased mortality risks. W e studied whether airway hyper-responsiveness is associated with increased mortality, and whether this risk was independent of smoking and reduced lun g function. Methods We followed up 2008 inhabitants of the communities of Vlagtwedde, V laardingen, 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 c ardiovascular disease, 54 from lung cancer, and 21 from chronic obstructive pulmonary disease [COPD]). Findings Mortality from COPD increased with more severe hyper-responsivenes s; 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 histamin e thresholds of 32 g/L, 16 g/L, 8 g/L, 4 g/L, and 1 g/L, respectively, comp ared 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 hyperresponsiveness predicts mort ality from COPD. Although this trend was more pronounced in smokers, an inc reasing proportion of COPD deaths with increasing hyperresponsiveness was a lso present among individuals who had never smoked.