Sensory-Mechanical Responses to High-Dose Methacholine Bronchoprovocation: The Modulating Effects of Deep Inspirations

Abstract

Rationale: The physiologic variables distinguishing classic asthma (CA), cough variant asthma (CVA), and methacholine (MCh)-induced cough with normal airway sensitivity (COUGH) are incompletely understood. Defining the range of normal responses associated with deep inspirations (DIs) during high-dose MCh is key to understand the clinical relevance of COUGH. Purpose: To characterize responses to DI in healthy normal individuals (without asthma, chronic cough or asymptomatic airway hyperresponsiveness) during high-dose MCh and compare with responses in CA, CVA and COUGH. Methods: Individuals aged 18-65 years with no history of asthma and/or chronic cough attended 2 visits. On visit 1, after baseline spirometry and body plethysmography, participants were randomized to perform either: (i) modified high-dose MCh challenge using partial and maximal expiratory flow-volume curves (PEFV/MEFV) and impulse oscillometry (IOS) or (ii) traditional high-dose MCh challenge using MEFV, at each dose to a maximum change (∆) in FEV1 of 50% from baseline (MAX). Previously published data (Wasilewski et al., 2016) was used to compare the responses of healthy individuals to individuals with CA (n=11), CVA (n=10) and COUGH (n=7). Results: 15 participants (31.4±7.3years) (Mean±SD) completed the protocol. At MAX, participants developed minor but significant cough (3.2±4.7; p=0.022), dyspnea (Borg: 0.4±0.7; p=0.016), bronchoconstriction (%∆FEV1 -14.7±7.9%; p<0.001) and gas trapping (∆IC -0.20±0.36; p=0.001), compared to baseline. At MAX, the bronchodilation effect of DIs was preserved (DI index: 0.67±0.44 and -0.14 ± 0.15 at MAX and baseline, respectively; p<0.001). Compared to healthy individuals, the COUGH group developed more cough (p=0.006), dyspnea (p=0.029) but comparable bronchoconstriction and gas trapping in response to high-dose MCh. At MAX, the bronchodilating effect was preserved in CA, CVA and healthy participants but impaired in COUGH (DI Index: 0.67±0.97 (CA); 0.51±0.73 (CVA); 0.01±0.36 (COUGH); 0.68±0.45 (healthy participants); p=0.009). Conclusion: The responses to high-dose MCh in healthy participants and participants with COUGH, CVA and CA lie on a continuum, which may reflect fundamental pathophysiological differences in terms of impairment versus preservation of the bronchodilating effect of DIs. COUGH appears to be a clinically relevant phenotype, distinct from healthy normal and CVA.