Ventilation heterogeneity is a major determinant of airway hyperresponsiveness in asthma, independent of airway inflammation

Abstract

Background: Airway hyperresponsiveness is the ability of airways to narrow excessively in response to inhaled stimuli and is a key feature of asthma. Airway inflammation and ventilation heterogeneity have been separately shown to be associated with airway hyperresponsiveness. Objective: To establish if ventilation heterogeneity was associated with airway hyperresponsiveness, independently of airway inflammation in asthmatics, and to determine the effect of inhaled corticosteroids on this relationship. Methods: In 40 asthmatic subjects, airway inflammation was measured by exhaled nitric oxide, ventilation heterogeneity by multiple breath nitrogen washout and airway hyperresponsiveness by methacholine challenge. In 18 of these subjects with uncontrolled symptoms, measurements were repeated after three months treatment with inhaled beclomethasone dipropionate. Results: At baseline, airway hyperresponsiveness was independently predicted by airway inflammation (partial r² = 0.20, p<0.001) and ventilation heterogeneity (partial r² = 0.39, p<0.001). Inhaled corticosteroid treatment decreased airway inflammation (p = 0.002), ventilation heterogeneity (p = 0.009), and airway hyperresponsiveness (p<0.001). After treatment, ventilation heterogeneity was the sole predictor of airway hyperresponsiveness (r² = 0.64, p<0.001). Conclusion: Baseline ventilation heterogeneity is a strong predictor of airway hyperresponsiveness, independent of airway inflammation in asthmatic subjects. Its persistent relationship with airway hyperresponsiveness following anti-inflammatory treatment suggests that it is an important independent determinant of airway hyperresponsiveness. Clinical implication: The strength of the association between ventilation heterogeneity and airway hyperresponsiveness elucidates a possible mechanism of airway hyperresponsiveness in asthma. Consequently, the normalisation of ventilation heterogeneity is a potential goal of therapy that may lead to improved long term outcomes.