Airways hyper-responsiveness to bradykinin and methacholine: Effects of inhaled fluticasone

Background: Although inhaled corticosteroids are the most effective anti-inflammatory agents available for the treatment of asthma, they have, at best, only modest effects on airways responsiveness to methacholine. Thus, hyper-responsiveness to methacholine is a relatively insensitive monitor of the effectiveness of glucocorticoids in asthmatic subjects. Objective: The study aimed to determine if airways hyper-responsiveness to bradykinin provides a more sensitive index of glucocorticoid responsiveness in asthmatic subjects than does hyper-responsiveness to methacholine. Methods: A double-blind, placebo-controlled, parallel group study comparing the effects of inhaled fluticasone (220 μg twice daily) on responsiveness to the two stimuli in asthmatic subjects who had never previously received corticosteroid therapy. Drug (n = 13) or placebo (n = 12) were administered for 16 weeks. Responsiveness to bradykinin and methacholine was determined at baseline and at 4 week intervals. Results: Placebo did not alter responsiveness to either stimulus compared to baseline. Fluticasone treatment significantly reduced responsiveness to bradykinin (P < 0.001 by Friedman ANOVA) and methacholine (P = 0.02), but changes in responsiveness to bradykinin were significantly greater than those in methacholine responsiveness (P = 0.002). Bradykinin responsiveness was decreased at all treatment times compared to baseline, while methacholine responsiveness was not decreased until 8 weeks of therapy. When data were analyzed as changes from baseline (ΔLog PD₂₀), ΔLog PD₂₀ for methacholine was not different at any time-point between the two treatment groups. By contrast, ΔLog PD₂₀ for bradykinin was significantly greater in patients receiving fluticasone compared to those on placebo at all but the 16-week treatment time. Ten of 13 subjects receiving fluticasone failed, on at least one post-treatment visit, to show a 20% fall in forced expiratory volume (FEV₁), even at the highest dose of bradykinin. Conclusions: Airways responsiveness to bradykinin is more profoundly, and more rapidly, reduced by inhaled glucocorticoids than is responsiveness to methacholine. Airways hyper-responsiveness to bradykinin provides a convenient and sensitive monitor of glucocorticoid responsiveness in asthma.