Physiology of Cough in Asthma: Comparison of Mechanical Responses to Mannitol and High-Dose Methacholine Challenges

Abstract

Rationale: Methacholine and mannitol challenges are used clinically to assess airway hyperresponsiveness (AHR). Cough during (a) high-dose methacholine challenge in individuals with methacholine-induced cough and normal airway sensitivity and (b) mannitol challenge in some individuals with asthma both occur in the absence of significant declines in forced expiratory volume in one second (FEV1). We hypothesized mechanical responses to these challenges would reflect a continuum amongst subjects with: (i) asthma; (ii) cough variant asthma (CVA) and (iii) methacholine-induced cough and normal airway sensitivity due to varying degrees of impairment/preservation of the beneficial effects of deep inspirations. Purpose: To compare cough and airway responses to mannitol and high-dose methacholine challenges between these groups. Methods: Individuals with asthma or suspected CVA were invited to participate. Subjects were challenged with mannitol and high-dose methacholine in random order 2-14 days apart. Cough frequency, spirometry and esophageal-pressure were recorded at baseline and after each dose of mannitol and methacholine to a maximal decline in FEV1 of 15% and 50% respectively. Plethysmography was used to measure lung volumes at baseline, the dose nearest to a 15% decline in FEV1 during mannitol challenge (PD15) and 20% decline in FEV1 during methacholine challenge (PC20), and at the highest dose of methacholine. Measurements were compared: (a) between groups at PD15, PC20 and the highest dose of methacholine; and (b) within groups at PD15 and PC20, and the highest equivalent level of bronchoconstriction. Results: 22 subjects (17 female; 48.0±12.7 (mean±SD years)) who completed both challenges were included. All subjects coughed during both challenges. Mechanical responses to mannitol and high-dose methacholine challenges reflected a continuum amongst groups. Six of 8 subjects with asthma were mannitol postitive (PD15=115.2±100.0 mg) and were significantly more sensitive to mannitol compared to 3 of 5 mannitol positive subjects with CVA (PD15=533.6±88.3 mg; p=0.020) and 3 of 9 mannitol positive subjects with methacholine-induced cough and normal airway sensitivity (PD15=472.8±203.0 mg; p=0.037). At the highest equivalent level of bronchoconstriction, methacholine induced significant declines in FEF50% and FEF25-75% in all subjects groups while mannitol did not. Conclusion: Mechanical responses to mannitol and high-dose methacholine challenges reflected a continuum amongst groups.