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An Investigation Into the Mechanism of Inhalational Cough Challenge’

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An Investigation Into the Mechanism of Inhalational Cough Challenge’ ‘An Investigation into the Mechanism of Inhalational Cough Challenge’ Dr Helen Elizabeth Fowles MBBCh MRCP(UK) (Respiratory Medicine) Degree Title: MD The University of Hull and the University of York Hull York Medical School January 2018 1 Abstract Chronic cough is a common problem. Historically treatments have focussed on treating underlying physiological causes. More recently an overarching theory of cough hypersensitivity syndrome has developed. In-vitro models of cough have not successfully translated into human studies. Testing the cough reflex in humans via inhalational cough challenge has been utilised since the 1950s. The mechanisms of cough challenge are poorly understood. This thesis sets out to investigate these mechanisms further in three different experiments. By altering pH in a citric acid challenge and measuring cough response, I show that cough hypersensitivity is not due purely to a shift in the dose response curve to pH, but also an alteration in the pattern of response to a given stimulus. Designing a cough challenge with a novel agent (ATP) revealed that the cough response to ATP is clearly delineated from that of AMP. The response to ATP in chronic cough is heightened, but not to such a degree as to implicate the acute response to inhalation of ATP in the pathophysiology of cough hypersensitivity syndrome. Comparing four cough challenges – the commonly used citric acid and capsaicin; the slightly less utilised distilled water fog challenge; and the new ATP challenge – proved that all challenges show less intra-patient reproducibility in chronic cough patients. Inhaled ATP cough challenge responses correlated with citric acid and capsaicin challenge suggesting overlap in mode of action. All experiments explore the cough challenge further in a group who have had little previous cough challenge investigation: the patient with chronic cough. They reveal that patients with cough hypersensitivity syndrome have not only a heightened but an unpredictable cough reflex, and that this is not due solely to upregulation of the cough receptors at peripheral nerve endings. Inhalational cough challenge plays an important role in further elucidating the mechanisms of chronic cough. 2 List of Contents 1 List of Tables and Illustrations ........................................................................... 8 2 Acknowledgements ......................................................................................... 11 3 Dedication ...................................................................................................... 12 4 Author’s Declaration ....................................................................................... 13 5 List of Publications Arising from this Thesis ...................................................... 14 5.1 Presentations and Abstracts ................................................................................. 14 5.2 Publications .......................................................................................................... 14 6 Introduction .................................................................................................... 15 6.1 Cough – clinical aspects ........................................................................................ 15 6.1.1 Causes of chronic cough ........................................................................................ 17 6.1.1.1 Reflux ...............................................................................................................................17 6.1.1.2 Eosinophilic cough syndromes ......................................................................................18 6.1.1.3 Post nasal drip ................................................................................................................19 6.1.1.4 ACE-inhibitor induced cough .........................................................................................19 6.1.1.5 Auricular nerve stimulation ...........................................................................................19 6.1.1.6 Other clinical conditions associated with isolated chronic cough ..............................19 6.1.1.7 Linking these Phenotypes together ..............................................................................20 6.1.1.8 Hypersensitivity cough ...................................................................................................20 6.2 The cough reflex ................................................................................................... 21 6.3 Receptors involved in cough ................................................................................. 22 6.3.1 TRPV1 .................................................................................................................... 22 6.3.2 TRPA1 .................................................................................................................... 22 6.3.3 Acid Sensing Ion Channels (ASICs)......................................................................... 23 6.3.4 Other TRP receptors .............................................................................................. 23 6.3.5 Purinergic receptors and ATP ................................................................................ 23 6.4 Inhalational challenges ......................................................................................... 24 6.4.1 Citric acid challenge .............................................................................................. 24 6.4.2 Capsaicin challenge ............................................................................................... 24 6.4.3 Fog challenge......................................................................................................... 25 6.4.4 ATP challenge ........................................................................................................ 26 6.5 Designing an inhalational cough challenge ........................................................... 27 6.5.1 Diurnal variation .................................................................................................... 27 3 6.5.2 Substrate factors ................................................................................................... 27 6.5.3 Patient factors ....................................................................................................... 28 6.5.4 Safety and tolerance ............................................................................................. 29 6.5.5 Nebuliser factors ................................................................................................... 29 6.5.6 Measuring coughing .............................................................................................. 29 6.5.7 End points for Inhalational Cough Challenges ...................................................... 30 6.5.8 Designing a fog challenge ...................................................................................... 31 6.5.9 Cough challenges in chronic cough patients ......................................................... 31 6.5.10 Gender and the citric acid cough challenge...................................................... 32 6.5.11 Summary ........................................................................................................... 33 7 Summary of Aims, Objectives and Hypotheses ................................................. 34 8 Investigating the effect of pH on the citric acid challenge in healthy volunteers and chronic cough patients ..................................................................................... 35 8.1 Introduction .......................................................................................................... 35 8.1.1 Citric acid challenge .............................................................................................. 35 8.1.2 Gender and the citric acid cough challenge .......................................................... 35 8.1.3 Smoking status and the citric acid cough challenge ............................................. 37 8.1.4 Citric acid challenge in respiratory disease ........................................................... 37 8.1.5 Citric acid challenge in chronic cough patients ..................................................... 38 8.1.6 Safety of citric acid challenge ................................................................................ 38 8.1.7 Why does citric acid produce a tussive response? ............................................... 39 8.1.8 Rationale behind choice of pH values used .......................................................... 39 8.2 Hypothesis ............................................................................................................ 40 8.3 Methods ............................................................................................................... 41 8.3.1 Recruitment........................................................................................................... 41 8.3.2 Inclusion and exclusion criteria ............................................................................. 41 8.3.3 The challenge agents ............................................................................................. 41 8.3.4 Delivery of the challenges ..................................................................................... 43 8.3.5 Statistical analysis. ................................................................................................ 44 8.3.6 Approvals..............................................................................................................
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