Abstract
The term “cough hypersensitivity syndrome” describes exaggerated cough but not necessarily the mechanisms involved http://ow.ly/Wk0n30bWmAy
To the Editor:
The term “cough hypersensitivity syndrome” (CHS) has been proposed by a European Respiratory Society Task Force as a clinical syndrome characterised by troublesome coughing often triggered by low levels of thermal, mechanical or chemical exposure, in patients presenting with chronic cough [1]. There are no agreed clinical criteria defining this syndrome or diagnostic tests to confirm its presence. However, it is often assumed that this syndrome must be linked to a hypersensitivity of the vagal afferent nerves and an intrinsic defect in the nerves themselves, which may not be the case [2]. The paper by Fowles et al. [3] describes a tussive challenge study with ATP and AMP in healthy volunteers and unselected patients attending a cough clinic, demonstrating the greater potency of ATP versus AMP, and that chronic cough patients had a greater cough response at lower concentrations of ATP. The degree of hypersensitivity demonstrated in chronic cough patients did not appear to be greater in magnitude than seen previously with capsaicin challenge (the only other example where an intervention against a specific challenge agent has been tested) [4–6]. However, a TRPV1 receptor antagonist did not impact on cough in this patient group despite a greater sensitivity to capsaicin challenge [6]. The authors have concluded, therefore, that 1) a similar shift in sensitivity in the ATP challenge does not explain the efficacy of the P2X3 antagonist (AF-219/MK-7264) and that 2) it is not a peripheral response to ATP that underlies the increased coughing in these patients.
This is an important and interesting study, but we would not agree with the conclusions proffered by the authors or in the accompanying commentary [7] and would suggest that the shift in response cannot be compared to any other tussive agents. Firstly, it is notable that this study did not investigate well-phenotyped patients with refractory (idiopathic) chronic cough, the specific group shown to be highly responsive to P2X3 antagonism [8]. Furthermore, whether a shift in the coughing to ATP challenge predicts clinical efficacy of AF-219/MK-7264 can only be established when the cough challenge and the compound are tested in follow-up studies in refractory chronic cough, unselected chronic cough and other patient groups that exhibit chronic cough. If efficacy is established in more than one group with a similar shift in the ATP challenge response, then an ATP challenge may well predict clinical efficacy of AF-219/MK-7264 or other P2X3 antagonists.
Secondly, even if the sensitivity of the nerve to exogenous challenge agents does not turn out to predict clinical efficacy, this does not rule out that it is a peripheral response to ATP that underlies the enhanced cough in these patients. Increased coughing may be due to 1) phenotypic change of the nerve and increased expression of the relevant target (e.g. P2X3 ion channel), 2) peripheral or central sensitisation of the nerve so that it responds at lower thresholds (the hypothesis suggested by the authors), or 3) elevated levels of the endogenous activating mediator produced by the diseased lung (e.g. ATP). In the latter case, there would be no requirement for an increase in the nerve sensitivity to exogenous agents. We suggest that at least in patients with chronic idiopathic cough that respond to AF-219/MK-7264, this may be the case. Our hypothesis is based on two pieces of evidence: 1) AF-219/MK-7264 is a peripherally restricted drug [8] and 2) capsaicin challenge in refractory chronic cough patients is not blocked by AF-219/MK-7264 [9], suggesting that the enhanced responses to other tussive agents are not necessarily driven by ATP. All this evidence points to the conclusion that enhanced cough in patients who are treatment sensitive is due to increased levels of ATP produced in the lung, perhaps by upregulation of ATP releasing mechanisms such as the TRPV4/pannexin axis [10], providing an increased sensory afferent drive to evoke cough. We would suggest that the term “CHS” is used only to describe the exaggerated cough seen in patients, rather than confused with the terminology used to describe the underlying mechanisms.
Disclosures
Footnotes
Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com
- Received March 20, 2017.
- Accepted April 4, 2017.
- Copyright ©ERS 2017