Chronic Cough Hypersensitivity as a Neuropathic Disorder: Implications for Management and New Treatments

Kian Fan Chung^1,2 and Stuart B. Mazzone³

¹National Heart and Lung Institute, Imperial College London, London, United Kingdom; email: f.chung@imperial.ac.uk
²Department of Respiratory Medicine, Royal Brompton and Harefield Hospital, Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom
³Department of Anatomy and Physiology, University of Melbourne, Parkville, Victoria, Australia

ABSTRACT

Chronic cough can coexist with or without pulmonary and extra- pulmonary conditions and can be refractory to therapies that improve these associated conditions. It is underlined by cough hypersensitivity, which is characterized by increased cough responses to stimuli that affect the airways and vagally innervated tissues as well as by excessive cough responses to innocuous stimuli, and it is caused by neuroinflammatory and neuropathic mechanisms at both peripheral and central levels. The management of chronic cough starts with exclusion of associated conditions, followed by use of neuromodulators and speech and language therapy. This is progressing toward personalized management, with new approaches to endotype to treat these patients with the introduction of novel antitussive therapies.

Keywords
refractory chronic cough, unexplained chronic cough, cough hypersensitivity syndrome, laryngeal hypersensitivity, urge to cough, antitussives

FROM CHRONIC COUGH TO COUGH HYPERSENSITIVITY

Cough is a common complaint that doctors in primary and secondary care have to deal with, which is not surprising when chronic cough affects ∼10% of adults, with the prevalence being higher in Europe and America ¹. The interest in chronic cough was ignited by the publication of an anatomical diagnostic protocol for its management by Irwin and colleagues in 1981², which emphasized excluding common conditions such as asthma, rhinosinusitis, and gastro-esophageal reflux that affect the structures within the anatomical distribution of the vagal afferent nerves.

This approach, which recognized that cough can be a defensive protective reflex mediated through the activation of cough receptors present in the upper and proximal intrapulmonary airways, became the cornerstone for managing chronic cough. The pathways regulating the cough reflex as a defensive mechanism had been described as involving various sensory receptors, known as cough receptors due to their conductive properties, with the afferent signals that they conduct carried via the vagus nerves to the nucleus tractus solitarius in the brainstem ³.

It was initially proposed that the cause of chronic cough can be determined 88–100% of the time, leading to successful treatment in 84–98% of patients ⁴. However, it became clear that there were chronic cough patients whose cough did not respond to treatment of any associated cause or who had no diagnosis or etiology associated with their cough⁵. This group, initially labeled as idiopathic chronic cough, ranged from 7% to 40% despite intensive investigations ⁵. With the definition of chronic cough being a cough that has lasted for more than 8 weeks, this subgroup of idiopathic cough came to be recognized as refractory chronic cough (RCC) or unexplained chronic cough (UCC) ⁶. Using patient-reported outcome tools to assess the impact of chronic cough, patients with chronic cough were found to have reduced quality of life, increased anxiety, exhaustion, and insomnia, which in turn impacted personal relationships, causing depression, self-isolation, and lower productivity at work ^{7, 8}.

The concept of cough hypersensitivity underlying chronic cough was proposed in 2010 ^9,10 and changed the way clinicians and researchers picture the condition. Cough hypersensitivity syndrome has been defined as troublesome coughing often triggered by low levels of thermal, mechanical, or chemical exposure. The concept of an overwhelmed repetitive protective cough reflex was quickly replaced with that of a hyperresponsive behavior underscored by neuropathic processes and neural damage caused by a range of inflammatory, infective, and allergic factors impacting peripheral and central nervous system pathways ¹¹ ( Figure 1 ).

COUGH HYPERSENSITIVITY AS A NEUROPATHIC COUGH

Peripheral Neural Mechanisms in Cough Hypersensitivity

Disordered neural function in chronic cough was initially presumed to occur at the level of the peripheral cough-evoking vagal sensory nerve fibers innervating the airways. Two types of vagal cough-evoking sensory nerve fibers exist (Aδ fibers and C fibers), enabling the detection of stimuli across broad physical, thermal, and chemical modalities ³. Cough may also be facilitated or inhibited by sensory inputs from other regions, including the nose, gut, ear, and skin, through convergent interactions with the central nervous system pathways involved in cough regulation ¹². In preclinical animal studies, vagal cough-evoking sensory neurons become sensitized in response to prostaglandins, cytokines, bradykinin, adenosine triphosphate (ATP) and other classical inflammatory chemicals released by resident or recruited immunological cells, inhaled environmental chemicals, changes in air temperature, and molecules produced and released directly by pathogens ³. Furthermore, vagal sensory fibers may also be modulated by inhaled environmental chemicals, changes in air temperature, and even molecules produced and released directly by pathogens ^13,14. When activated, vagal sensory neurons also contribute to the regulation of local airway inflammation via the release of neuroinflammatory peptides, such as substance P and calcitonin gene-related peptide ³ ( Figure 1 ).

It is not uncommon for chronic cough to occur in the absence of any identifiable airway pathology ⁶, which indicates that peripheral sensitization may not be a universal mechanism of cough hypersensitivity. Alternatively, the vagus nerve itself may develop an inflammatory response under some circumstances, contributing to altered vagal sensory function ( Figure 1 ). Persistent vagal neuroinflammation has been shown to be secondary to acute lung injury or infection, including in studies of lung fibrosis, influenza virus infection, and bacterial or allergen exposure ¹⁵. This neuroinflammation is associated with transcriptional, cellular, and structural vagal plasticity, which may contribute to hypersensitivity. Thus, airway biopsies from patients with chronic cough show signs of increased nerve fiber density and branching ¹⁶, which is expected in response to vagal neuroinflammation. Additionally, 10–20% of patients after COVID-19 infection and up to 43% of patients after H1N1 infection have persistent cough beyond the typical timeframe of infection pathogenesis ^17,18, suggesting that the mechanisms responsible for persistent cough are unrelated to the presence of an ongoing infectious airway pathology. Anecdotally, it is also not uncommon for chronic cough to start after experiencing cold or flu symptoms many years prior.

Central Neural Mechanisms in Cough Hypersensitivity

Alterations in brain processing also play an important role in cough hypersensitivity and chronic cough ¹⁹, resembling processes that occur in nociplastic pain syndromes characterized by augmented central sensory processing and altered sensorimotor modulation ²⁰ ( Figure 1 ). Vagal sensory fibers project to the brainstem, where inputs can reflexively regulate the respiratory neural circuits that generate breathing patterns ⁶. Ascending projections from the brainstem reach sensory, motor, prefrontal, and limbic cortices in the higher brain ¹⁹. The urge to cough is encoded at these higher brain levels, along with the accompanying affective (i.e., emotional) dimensions of coughing. Higher brain motor systems, in turn, provide a level of behavioral and cognitive control over cough, which can include pathways that both facilitate and inhibit coughing.

Longer chronic cough duration has been associated with a lower volume of brain gray matter in frontal lobe cortical regions ²¹, as well as with enhanced functional connectivity within the left frontoparietal cortical network associated with greater cough severity scores and a greater psychological and social impact of coughing ²¹. Functional imaging of the brain during experimentally induced urge to cough showed that patients with cough hypersensitivity have relatively normal lower brainstem processing responses (and therefore normal sensory nerve fiber inputs to the brainstem) during inhalation of cough stimuli, whereas higher brain circuit responses are increased ²², suggesting central amplification of cough signals. Thus, an amplifier of cough signals may exist in the brains of chronic cough patients, meaning that even low levels of sensory nerve activity are sufficient to evoke coughing. Patients also display reduced ability to volitionally suppress cough when challenged with an inhaled stimulus ²³, unlike individuals without chronic cough, who can volitionally suppress evoked cough through the activation of motor suppression brain networks ^19,24. Consequently, chronic cough could be considered a problem of increased central coupling of sensation to motor action, perhaps like that seen in patients with restless legs syndrome, where the urge-to-move sensation drives periodic limb movements ²⁵. These changes in central cough processing may manifest as part of a central neuroinflammatory state orchestrated by brain glial cells ²⁶. Interestingly, not all patients with chronic cough may have diminished central suppressive controls, as cough suppression appears to be unaffected in patients with chronic cough associated with chronic obstructive pulmonary disease ²⁷. This observation further supports the existence of distinct cough endotypes²⁸.

HETEROGENEITY OF COUGH HYPERSENSITIVITY–ASSOCIATED CONDITIONS

Clinical Aspects of Cough Hypersensitivity

Patients with chronic cough, particularly those with UCC or RCC, present with features of cough hypersensitivity and very often with features of laryngeal paresthesia, which is characterized by a persistent or intermittent tickling, irritating, or obstructive (i.e., globus) sensation in the pharynx or larynx ²⁹. This is described by patients as itching or choking sensations in the throat that precipitate bouts of often severe coughing, either spontaneously or in response to mild or otherwise innocuous stimuli ( Figure 1 ). There is an accompanying perception of an urge to cough, analogous to the need to scratch an itch ³⁰, which may not always be satiated by coughing, and this sensation can be more troubling to patients than the cough itself ²⁹. Other symptoms common in patients with chronic cough include repeated clearing of the throat in attempt to clear the globus sensation or abate the urge to cough, chest tightness, dysphonia (i.e., hoarse voice), vocal cord dysfunction, and dysphagia, many of which are the result of laryngeal hypersensitivity ^{6, 31}.

Refractory and Unexplained Chronic Cough

RCC and UCC patients are commonly recruited into clinical trials of new antitussives, if they score their cough severity as more than 40 mm on a 100 mm visual analog scale. In 2,044 such chronic cough patients, 75% were female, the mean age was 58 years, and 62% were diagnosed as RCC [with a diagnosis of asthma, gastroesophageal reflux disease (GERD), or upper airway cough syndrome (UACS)] and the rest as UCC; baseline cough characteristics were similar between RCC and UCC, with a mean duration of cough of 11.2 years and a cough frequency of 19.2/h ³². They had characteristics of cough hypersensitivity as determined by a high score on the Hull Airway Reflux Questionnaire.

Asthma and Eosinophilic Type 2 Inflammation

Asthma can present with cough as the sole or predominant symptom, with or without wheezing or dyspnea. Chronic cough in asthma has been associated with worse asthma severity and poorer outcomes, and cough worsening or onset has the highest prediction for progression to severe asthma ^33,34. Cough reflex hypersensitivity to capsaicin has been associated with greater exacerbation rates and poorer asthma control ³⁵ as well as with associated comorbidities in severe asthma ³⁶. Capsaicin cough hypersensitivity has been demonstrated in adults with asthma ³⁷, and laryngeal hypersensitivity is present in 87% of asthma patients presenting with laryngeal dysfunction ³⁸. Type 2 inflammation characterized by eosinophilic airway inflammation may underlie cough hypersensitivity in asthma through the interaction of eosinophils with airway nerves that could lead to increased airway nerve densities ³⁹. Products of activated eosinophils such as major basic protein can increase the sensitivity of C fibers to chemical and mechanical stimuli ⁴⁰. Airflow obstruction may underlie the cough of asthma potentially through the release of mediators such as ATP that may sensitize sensory nerves or through the activation of mechanosensitive afferent airway nerves ⁴¹.

Upper Airway Cough Syndrome

UACS, previously known as postnasal drip or nasal catarrh, is caused by upper respiratory disorders, including rhinosinusitis ⁴². It is diagnosed based on a chronic cough associated with rhinitis or rhinosinusitis and its response to an H1 receptor antagonist and/or nasal anti-inflammatory corticosteroid therapy. Postnasal drip is the term preferred by Europeans, who consider it a symptom of cough caused by upper airway disease ⁴³. The drip at the back of the nose can stimulate the afferent sensory nerves of the pharynx and larynx or even of the lower airways, although only 21% of subjects with postnasal drip report having chronic cough ⁴⁴. Airway remodeling that may have been caused by the drip has been reported in UACS patients ⁴⁵. Compared to healthy controls, increased cough sensitivity was noted in allergic rhinitis patients, a difference that became more prominent during the pollen season ⁴⁶, with the release of histamine in the nasal space sensitizing the nasal sensory nerves to capsaicin ⁴⁷.

Gastro-Esophageal Reflux Disease

GERD-associated cough is another common cause of chronic cough, accounting for 10–40% of chronic cough worldwide ⁴⁸. It is often triggered or made worse by a meal and may occur with or without acid regurgitation or heartburn, which may be accompanied by hoarseness and throat clearing, induced by the direct effect of GERD or by the accompanying postnasal drip (i.e., laryngopharyngeal reflux). Abnormal acid or nonacid reflux can be detected by esophageal reflux monitoring of acid exposure time.

The direct effect of acid or nonacid reflux from the stomach in the proximal esophagus and larynx, that is, activating cough receptors, is likely a mechanism for chronic cough. In addition, airway reflux consisting of a gaseous mist of nonacid contents, diagnosed by pH-impedance measurement, has been proposed. Alternatively, an esophageal afferent nerve mediated esophagus-tracheobronchial reflex has been associated with increased sensitivity of the cough reflex following the development of neurogenic airway inflammation ^49,50. In support of this, esophageal infusion of acid has led to increased cough sensitivity in patients with GERD and cough ^51,52. Esophageal motility may increase the duration of esophageal acid exposure with slower clearance of acid, leading to more severe mucosal damage and more frequent reflux episodes ⁵³. Finally, chronic cough can be an extraesophageal symptom of eosinophilic esophagitis, even without any gastrointestinal symptoms ⁵⁴.

Interstitial Lung Disease

Interstitial lung disease (ILD) consists of pulmonary conditions characterized by inflammation and/or fibrosis of the lung parenchyma leading to progressive dyspnea and frequently to respiratory failure. Cough is present in 50–90% of patients with interstitial pulmonary fibrosis (IPF), a common form of ILD ⁵⁵, and can be relentless, with one-third of patients indicating that cough is a worse symptom than dyspnea ⁵⁶. Subjective quality of life scores and objective cough counts indicate a moderate to severe cough ⁵⁷.

An increase in capsaicin and external percussion cough sensitivity in IPF has been reported ^58,59. The cough hypersensitivity may be related to abnormal epithelial repair with the release of growth factors such as transforming growth factor beta and nerve growth factor ⁶⁰. Mechanical distortion of the airways from fibrosis may lead to the activation of cough receptors, potentially mediated through TRPV4 receptors. Comorbid conditions such as GERD and UACS may also contribute ⁶¹.

Post-COVID Cough

Respiratory viral infections are typically accompanied by an acute cough that can persist for weeks or months in some patients. Cough reflex hypersensitivity to chemical and mechanical stimulation has been shown in experimental models of rhinovirus infections ^{62, 63}. Studies of the recent COVID-19 pandemic have focused on the post-viral complications of long-COVID or post-COVID syndrome, including a wide array of symptoms, such as brain fog, tiredness, arthralgia, headaches, fever, skin rashes, and emotional disturbances ⁶⁴. In the respiratory system, chest pain, breathlessness, and cough are common and may be associated with pulmonary dysfunction. The prevalence of post-COVID cough is reported to be ∼18% in patients who required hospitalization ¹⁷. Cough has been reported as the most common symptom, found in 92% of patients in the acute phase, with persistence of cough at 3 weeks or longer occurring in 13%, in whom the associated risk factors were diabetes, asthma, and chronic cough ⁶⁵. Post-COVID persistent cough is similar in clinical characteristics to chronic cough, with a higher proportion of those with post-COVID cough expressing high levels of exhaled nitric oxide ⁶⁴. The cough is characterized by both cough and laryngeal hypersensitivity ⁶⁶. While the mechanisms responsible for persistent cough are unrelated to the presence of an ongoing infectious airway pathology, one mechanism may involve the direct invasion of SARS-CoV-2 into sensory nerves to alter sensory neuronal function mediating cough and to induce central sensitization ¹⁷.

Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is a rare genetic disease caused by a multiple repeat expansion in the gene encoding replication factor complex subunit 1 (RFC1) ⁶⁷. Patients with CANVAS develop progressive peripheral sensory neuropathy, ataxia, and balance disorder. The neuropathy is characterized by peripheral nerve atrophy and loss of sensory nerve action potentials on nerve conduction studies.

A persistent, irritating, dry, spasmodic cough is an early presenting symptom, preceding walking difficulties by several decades ^68,69. Cough mainly occurs during the day and can be triggered by factors such as emotion, stress, speaking, or swallowing. It has a relentless clinical course with no seasonal fluctuations. Mechanical stimulation of the external ear canal innervated by the auricular branch of the vagus nerve triggers coughing via the Arnold nerve cough reflex, representing cough hypersensitivity along vagal sensory neural pathways ⁷⁰.

In 6–25% of patients with RCC, there is at least one monoallelic repeat expansion in the RFC1 gene ^71,72. The mechanisms leading to vagal hypersensitivity in CANVAS are unclear. Cough could occur with progressive neuronopathy, with a state of sensory hypersensitivity prior to sensory neuron destruction ^73,74. In later stages, the denervation of brainstem neurons receiving sensory inputs may lead to spontaneous activity of central cough-evoking pathways with deafferentation hypersensitivity ⁷⁵.

MANAGEMENT OF PATIENTS WITH CHRONIC COUGH HYPERSENSITIVITY

Excluding Treatable Causes of Chronic Cough

The first step in the evaluation of chronic cough is to exclude any underlying treatable cause using an anatomical diagnostic–therapeutic approach ^76,77. For asthma, use of fractional exhaled nitric oxide and blood eosinophil count may be useful to predict the response to inhaled cortico-steroids and anti-leukotrienes. A course of oral corticosteroids may be needed. For UACS, a trial of an anti-H1 histamine antagonist, which may include a first-generation anti-H1 antagonist, or topical corticosteroids, both with trial of a course of antibiotics, may be needed. For GERD, reflux preventive measures and anti-reflux therapies should be tried in those with a history of heartburn. Investigations regarding nonacid reflux could be considered in case of lack of effect of anti-reflux medications.

Treatment of Chronic Cough and Cough Hypersensitivity

Centrally acting neuromodulators as antitussives.

Slow-release morphine can be partially effective in controlling severe chronic cough ⁷⁸, although it is not universally recommended. Codeine, the methyl ether of morphine, was once common in cough syrups and previously the benchmark drug against which the efficacy of newer drugs was measured. Although codeine has little clinical efficacy in chronic cough, it is still used by some patients with variable effects ⁷⁹. At their effective doses, opiates cause a range of undesirable side effects, including physical dependence, sedation, respiratory depression, and constipation.

Other centrally acting neuro- modulators, including gabapentin, pregabalin, baclofen, and amitriptyline, represent important treatment options for chronic cough ⁸⁰, in line with their reported efficacy in neuropathic pain, because of their actions on the spinal and higher brain networks regulating pain processing ⁸¹. A systematic review of the clinical trial literature on gabapentin suggests that chronic cough patients commonly experience improvements in subjective cough severity and quality of life ⁸⁰. Gabapentin was effective in reducing cough frequency and severity and improving quality of life in patients with RCC but had no effect on capsaicin cough hypersensitivity ⁸². Gabapentin is usually started at a low dose of 100 mg three times daily and can be increased to a maximum dose of 600 mg three times daily. The other gabapentinoid, pregabalin, in combination with speech pathology also improved cough and quality of life compared to speech pathology therapy alone ⁸³.

Amitriptyline compared to a combination of codeine and guaifenesin for chronic cough after an upper respiratory tract infection caused greater subjective improvements in cough ⁸⁴. In another trial comparing gabapentin to tricyclic antidepressants (including amitriptyline) in patients with UCC, both neuromodulator classes demonstrated short-term benefit, but most patients in both treatment arms discontinued within 6 months due to tachyphylaxis in treatment effects ⁸⁵. Side effects are common for patients using neuromodulator therapies and include dizziness, confusion, nausea, dry mouth, and somnolence, often limiting long-term treatment compliance.

P2X3 blocker as a peripheral antitussive.

The purinergic receptors P2X3 and P2X2/3 are expressed by vagal sensory cough fibers and activated by ATP released from airway epithelial cells or inflammatory cells in response to airway injury, infection, or inflammation ⁸⁶. The first-in-class drug gefapixant displays activity at both P2X3 homomeric and P2X2/3 heteromeric receptors, and a meta-analysis of the clinical trials reported that gefapixant reduced cough frequency by 17.6%, lowered cough severity on a 100 mm visual analog scale by 6.2 mm, and improved Leicester Cough Questionnaire (LCQ) scores by 1.0 point 87. Taste-related events were reported by 69% of participants, with 12% discontinuing because of these side effects, which were due to P2X2/3 receptors that are also expressed by gustatory nerves involved in taste perception ⁸⁸. There were strikingly large placebo responses, reducing the efficacy of gefapixant. Licensing has been approved in Japan, the United Kingdom, and the European Union but not in the United States.

Camlipixant, a more selective P2X3 antagonist, demonstrated placebo-adjusted reductions in 24 h cough frequency of 34.4% and 34.3% in 50 mg and 200 mg twice daily doses, respectively, after 4 weeks and was accompanied by significant improvement in visual analog scale and LCQ scores, particularly at the 200 mg dose ⁸⁹. There was less impact on taste due to the selectivity at P2X3 homomeric receptors.

Speech and language therapy.

Behavioral cough suppression treatments have been developed by specialist speech therapists and respiratory physiotherapists. Such treatments involve a multifaceted approach, including educating patients about cough, identifying and managing cough triggers, improving laryngeal hygiene (e.g., avoiding cigarette smoke, excessive alcohol, dehydration, and vocal strain), and training with behavioral cough suppression techniques ⁹⁰. Randomized controlled studies show improvement in cough counts and quality of life measures ⁹¹. Speech and language therapy is now commonly used in parallel with medication in the management of chronic cough.

Potential new emerging antitussives for cough hypersensitivity.

Although preclinical studies have identified transient receptor potential (TRP) channels as targets for cough suppression ³, TRPV1, TRPA1, and TRPV4 antagonists have performed poorly in clinical trials of chronic cough. Agonists at the TRP cation channel subfamily M member 8 (TRPM8), a nonselective cation channel that controls Ca2+ homeostasis and that is responsive to cooling and menthol, are in early-phase trials and may prove useful for providing both short- and long-term relief of chronic cough due to the rapid-onset cooling sensation in the throat. Specific voltage-gated sodium channels that propagate action potentials along vagal sensory nerve fibers may lead to the development of a novel classes of antitussives ⁹². Selective inhibitors of specific sodium channel subunits, for example, NaV1.7, have shown antitussive activity in guinea pigs ⁹³, and a dry powder formulation of the charged sodium channel blocker NTX-1175 is in early-phase development. Centrally acting compounds such as the alpha-7 nicotinic acetylcholine receptor partial agonist (i.e., bradanicline), neurokinin 1 receptor antagonist (i.e., orvepitant), and the N-methyl-D-aspartic acid receptor allosteric modulator (i.e., ifenprodil) have been studied with no or marginal effects in RCC ^{94, 95}. In a randomized double-blind placebo-controlled crossover trial in patients with IPF, the mixed κ-opioid receptor agonist/μ-opioid receptor antagonist nalbuphine reduced cough severity more than placebo ⁹⁶.

COUGH HYPERSENSITIVITY NEUROPATHIC DISORDER AS A DISEASE

Significant progress has been made in our understanding of the mechanistic and clinical features of cough hypersensitivity and chronic cough ( Figure 1 ). By acknowledging that cough hypersensitivity represents a key feature of chronic cough, research and clinical efforts became focused on understanding and treating the causative under- lying neural hypersensitivity, advancing the field significantly. However, it has become clear that the causes of neural hypersensitivity are not simply explained by the existence of a known pathology impacting the airways. Thus, although some patients do have chronic cough as a symptom of an underlying disease impacting their airways, this view of cough is arguably too restricted and no longer adequate to manage all patients, especially those with RCC or UCC. The evidence for neuropathological causes of chronic cough in such patients suggests that an alternative perspective is needed, and this is further supported by the often-unsatisfactory clinical outcomes resulting from focusing cough management therapies on presumed peripheral disease causes ⁹⁷. The cough hypersensitivity neuropathic disorder underlying chronic cough should be considered as a distinct disease that requires different and dedicated approaches to clinical management.

A reassessment of RCC and UCC in specific respiratory conditions in terms of the heterogeneity of the hypersensitive pathways ⁹⁸, and in terms of understanding the mechanisms of hypersensitivity and new effective antitussive therapies ⁹⁹, is needed. Acknowledging that cough can be a neuropathic or nociplastic disease also reduces the risk of underestimating the physical, psychological, and social impact that chronic cough directly poses on patients. It encourages healthcare providers to consider these features of chronic cough more seriously as part of a spectrum of neurological complications. Chronic pain, another example of a sensory hypersensitivity, has been redefined as a disease with primary and secondary causes, resulting in improvements in clinical management, epidemiological investigations, policy, and research ¹⁰⁰. The imperative to consider chronic cough as a disease seems undeniable ¹⁰¹.

DISCLOSURE STATEMENT

K.F.C. has received research grants from GSK, Merck, and UK Research and Innovation, paid to his institution; personal honoraria for speaking engagements for AstraZeneca, GSK, and Novartis; and personal honoraria for participation on advisory board meetings of AstraZeneca, GSK, Merck, Nocion, Novartis, Reckitt Benckiser, Roche, Shionogi, and Trevi. He is also on the Scientific Advisory Board of The Clean Breathing Institute funded by Haleon. S.B.M. has received honoraria from Bellus Health, Chiesi, Merck, NeRRe Therapeutics, and Reckitt Benckiser, as well as grant support from Bellus Health, Merck, and Reckitt Benckiser, outside of the submitted work.

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Credits: Kian Fan Chung, Stuart B. Mazzone. 2026. Chronic Cough Hypersensitivity as a Neuropathic Disorder: Implications for Management and New Treatments. Annual Review Medicine. 77:449-462. https://doi.org/10.1146/annurev-med-050224-124414