A PROSPECTIVE LONGITUDINAL-STUDY OF METHACHOLINE AIRWAY RESPONSIVENESS AS A PREDICTOR OF PULMONARY-FUNCTION DECLINE - THE NORMATIVE AGING STUDY

It has been hypothesized that nonspecific airway hyperresponsiveness is a risk factor for accelerated pulmonary-function decline during aging and the development of chronic airflow obstruction. We tested this hypothesis in a prospective, longitudinal study of 912 middle-aged and older men (median age, 60 yr; range, 41 to 86 yr) participating in the Normative Aging Study (NAS). Subjects underwent methacholine challenge testing and spirometry at the time of a regularly scheduled NAS examination, and follow-up spirometry was performed after a median interval of 3.3 yr. Allergy skin testing with a panel of four aeroallergens (mixed grasses, mixed trees, ragweed, and house dust) was also performed at the initial examination. Methacholine responsiveness was expressed as the dose-response slope (DRS) (i.e., the slope of a line connecting the origin with the last point of the methacholine dose-response plot) in units of percent decline FEV(1)/mu mol methacholine. The relationship of the methacholine DRS to the subsequent rate of annual decline in lung function (FEV(1), FVC, and FEV(1)/FVC) was examined using multiple linear-regression models with the rates of pulmonary-function decline as the outcome variables. After adjusting for age, height, smoking status, and initial level of lung function, the log(10) DRS was a significant predictor of the rate of decline of FEV(1) (regression coefficient beta = 12.8, p = 0.03) and FEV(1)/FVC x 100 (beta = 0.506, p = 0.0001), and a borderline significant predictor of FVC (beta = 15.3, p = 0.05). The regression model for FEV(1) predicted an excess decline of 8.4 ml/yr in association with a 2 SD increase in log(10) DRS, compared with an excess decline of 17.2 ml/yr in association with current cigarette smoking in the same model. After adjusting for atopic status in the regression models, the relationship of log(10) DRS to pulmonary-function decline remained significant for FEV(1)/FVC x 100 (beta = 0.507, p = 0.0001) and of borderline significance for FEV(1)(P = 11.8, p = 0.05) and NC (P = 15.7, p 0.05). Restricting the analysis to men who denied any history of asthma weakened this relationship for FEV(1) decline, but log(10) DRS remained a significant predictor of annual decline in FEV(1)/FVC. We conclude that airway responsiveness to methacholine was a significant predictor of subsequent accelerated pulmonary decline in pulmonary function in this cohort of middle-aged and older men. This finding suggests the need for intervention trials to determine whether therapies that reduce nonspecific airway responsiveness, such as inhaled corticosteroids, can slow the progression of chronic airflow obstruction and prevent the development of disabling ventilatory impairment.