Chronic cough: New guidelines, new approaches and new treatments

The end of 2023 brought with it updated national clinical statements on the management on chronic cough from both Australia and the United Kingdom.1, 2 Both were long in coming, being published 13 and 17 years since their predecessor documents, respectively. Much has changed in the intervening time in the understanding of cough, necessitating and informing the statement updates. Chronic cough in adults (lasting ≥8 weeks) is a common reason for visiting a respiratory physician, due not least to the associated significant detriment to quality of life.3 The 'causes' of such coughs however are not immediately obvious; medical assessment prior to that point should have included simple clinical questioning, examination, and a chest radiograph to rule out acute infection, ACE inhibitor usage, and classical presentations of asthma, gastroesophageal reflux and other contributory factors. Investigations should then include spirometry to help exclude airways disease, full blood count and fractional exhaled nitric oxide specifically for eosinophilic airway disease, and possibly computed tomography (according to 'red flags' and risks for cancer and other lung disease).1, 2 Beyond this, rapidly diminishing returns are encountered from further tests. There may be multiple medical consultations and treatment trials, many futile.4 Much of everyday practice in the management of chronic cough remains heavily influenced by an anatomic protocol, an attractive theory now >40 years old which posits that the majority of persistent cough reaching the respiratory specialist can be explained by and managed as either asthma, gastroesophageal reflux disease (GORD) or rhinosinusitis.5 This partly explains the frequent ongoing use of investigations such as oesophageal manometry or sinus imaging to investigate cough in the absence of classical features of GORD or sinus disease, respectively.4 With the passage of time, the establishment of specialist cough clinics, the accumulation of outcome data through specific clinical measurement tools for cough, and advances in basic science from preclinical studies, it is increasingly apparent that such a model of chronic cough is inadequate.2 Asthma and GORD are common conditions. Both certainly are associated with and aggravate cough, but cough is far from universal, and only the minority with either diagnosis present with cough as the sole symptom.6 Furthermore, empirical treatment of asthma, rhinosinusitis or GORD in isolated chronic cough with little to point specifically to those conditions probably has no effect other than acting as placebo.7 An alternative paradigm of chronic cough has been proposed and gained ground since the publication of previous versions of guidelines. Influenced by a long-established literature on chronic pain, a condition sharing many features with chronic cough, the latter may be considered a neuroinflammatory or neuropathic disorder.8 The substrate and crux of chronic cough is then hypersensitivity of the cough neural circuity. On this basis, chronic cough may in many cases be best considered a disease entity in its own right. Hitherto putative 'causes' of chronic cough, such as asthma and GORD, are then better considered aggravating factors or 'treatable traits' of the underlying disease process of cough hypersensitivity.2 This newer model is supported by observational and experimental evidence, including from pathological samples; an increased density of airway sensory nerve fibres in bronchial specimens of patients with chronic cough.9 Clinical questionnaires have documented consistent patient descriptions of triggers and sensations associated with chronic cough,10 and increased measured responses to inhaled tussogenic compounds on cough reflex testing is observed.11 Finally, functional magnetic resonance imaging has demonstrated changes in cortical centres in chronic cough which promote or fail to supress coughing.12, 13 A very similar phenomenon to refractory or unexplained cough is also common in CANVAS (cerebellar ataxia with neuropathy and vestibular areflexia syndrome), an inherited neurological disorder underpinned by repeat expansion sequences of the gene RFC1, giving further support for a neuropathic, although incompletely understood, basis for chronic cough in general.14 Developments in the treatment of chronic cough have subsequently focused more on controlling an exaggerated cough response than previously. Morphine, gabapentin, and pregabalin are repurposed old drugs with randomized controlled trial evidence as treatments for refractory or unexplained chronic cough, likely acting on higher centres within the nervous control of coughing.2 Most promising though is a pipeline of novel medications at various stages of development, culminating in a new era of clinical trials of specific antitussive agents.15 These medications largely target peripheral airway receptors which promote cough, a number of which are under investigation, and whose influence has only been fully appreciated in recent years. The furthest along this pipeline are P2X3 inhibitors, which through an adenosine triphosphate-mediated cough pathway are associated with reductions in cough frequency in refractory chronic cough.16 Gefapixant is now licensed for use in Japan, Switzerland and the European Union. Non-pharmacological approaches to treating cough have also been fruitful, again approaching cough as an entity on its own merit, employing behavioural techniques to improve dysfunctional physiological pathways contributing to cough hypersensitivity, best delivered by a specialist speech therapist or respiratory physiotherapist.17 Excluding serious causes might be management enough to provide reassurance for many seeking medical advice for cough. Beyond this, for those experiencing the common negative impacts of chronic cough, the use of investigations for secondary aggravants of cough should be judiciously tailored according to clinical context. This will not only save time and resources, but will reduce harms from a wider use of tests such as bronchoscopy and gastrointestinal studies which are not without risk, and may involve disparate disconnected specialists and clinics. The use of 'empirical' treatments for gastroesophageal reflux, rhinosinusitis and other conditions in the absence of specific features pointing to their presence should then be avoided, the common practice of doing so likely strengthened by frustration of the clinician who has traditionally had little else to offer the patient. Rather, treatments should be targeted at treatable traits (which also include smoking, obesity and obstructive sleep apnoea) only when they are evident, and at underlying cough hypersensitivity, of which earlier recognition is needed.2 With new guidelines will hopefully come improvements in the systematic and holistic clinical approach to cough, increased interest and recognition of chronic cough as disease, and better outcomes for patients, who often suffer for years from the wide-ranging impacts of a significant and, until now, neglected clinical problem. Open access publishing facilitated by Griffith University, as part of the Wiley - Griffith University agreement via the Council of Australian University Librarians. Stuart Mazzone is an author of the position statement on chronic cough in Australia; Surinder Birring is an author of the British Thoracic Society Clinical Statement on chronic cough. No other disclosures are made.