The role of nerves in asthma: insights from the study of cough

Abstract

Introduction: Cough in asthma predicts disease severity, poor prognosis, and is a common troublesome symptom, yet remarkably, little is understood about the underlying neuronal mechanisms. Current dogma suggests asthma symptoms arise as a consequence of bronchial hyper-responsiveness and airway inflammation. Yet despite effective treatments targeting these pathologies, many patients have substantial residual disease and symptoms. Symptoms such as wheeze, cough, chest tightness and breathlessness occur as a consequence of neuronal input from the airways and chest wall. However, there is a paucity of data investigating whether sensory nerve function is heightened in patients with asthma. Many symptoms are challenging to study as they can only be reported subjectively. In contrast, cough is more readily accessible to objective quantification and hence has the most potential for providing insights into the role of nerves in asthma.Methods: We performed capsaicin cough challenges to experimentally evoke the cough reflex via activation of the transient receptor potential vanilloid type-1 (TRPV1) receptor found characteristically on airway c-fibres. Evoked and spontaneous coughs were objectively quantified and verified using a semi-automated cough recorder (VitaloJAK). We first performed an observational cross-sectional study comparing full dose capsaicin cough responses in patients with mild to moderate stable asthma with healthy volunteers. We performed non-linear pharmacodynamic modelling (NONMEM) to compare differences in the maximum evoked coughs (Emax) and the dose of capsaicin that evoked at least half the responses (ED50). This was followed by two separate randomised, single-blind, placebo controlled cross-over studies investigating the effects of methacholine induced bronchoconstriction and inhaled allergen challenge on capsaicin ED50 evoked coughs. Generalised estimating equations (GEE) were used to model the effects of bronchoconstriction on cough responses.Results:i. Compared with healthy volunteers (HV), patients with asthma (A) displayed higher Emax and lower ED50 on full dose capsaicin evoked cough challenge. Emax was influenced by disease group (HV or A), gender, atopic status and objective cough rates, whilst ED50 was influenced by disease group, gender, asthma control (ACQ), and total serum IgE.ii. Methacholine induced bronchoconstriction was associated with an increase in capsaicin evoked cough response, but capsaicin evoked coughs had no influence on bronchial hyper-responsiveness to methacholine.iii. Inhaled allergen challenge induced an acute early asthmatic response (EAR) and a late asthmatic response (LAR). There was an increase in capsaicin evoked coughs in the EAR and 24 hours after the start of inhaled allergen challenge.Conclusions: Patients with asthma exhibited heightened cough responses to capsaicin at baseline, which increased further after inducing bronchoconstriction and allergen exposure. The exaggerated cough reflex observed could be due to peripheral sensitisation and/or central sensitisation. The exact mechanism of how bronchoconstriction and airway inflammation influences the cough reflex to capsaicin requires further evaluation.

Date of Award	18 May 2017
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Stephen Fowler (Co Supervisor), Jacky Smith (Main Supervisor) & Paul O'Byrne (Co Supervisor)