Current Opinion in Refractory and/or Unexplained Chronic Cough

Abstract

Purpose of Review:

Otolaryngologists are vital to successfully managing chronic cough in adults. This review presents updates regarding rapidly evolving concepts in chronic cough.

Recent Findings:

Significant growth is occurring in chronic cough research, strengthening the evidence of its major psychosocial impacts. Elucidation of the neural underpinnings of normal and abnormal cough within both the peripheral and central nervous systems highlight the previously underappreciated complexity of cough. Recent clinical practice recommendations emphasize personalized treatment approaches through addressing treatable traits of chronic cough. Investigations are ongoing to better distinguish chronic cough subgroups, and multiple types of important clinical outcome measures are being characterized. Newer research about chronic cough treatment encompasses pharmacologic and nonpharmacologic interventions, including oral and inhaled medications, superior laryngeal nerve blocks, and behavioral therapy.

Summary:

As knowledge about chronic cough in adults continues to expand in both research and clinical practice, otolaryngologists can continue to raise awareness of the role of the larynx in cough and promote ongoing multidisciplinary collaborations. In the coming years, more pharmacologic options and personalized treatment approaches will likely emerge for chronic cough.

Introduction

Chronic cough in adults refers to a cough lasting longer than 8 weeks and leads to significant morbidity.¹ Multiple mechanisms cause or contribute to chronic cough, leading to wider consensus that chronic cough is a heterogeneous condition.^2,3 Across etiologies, otolaryngologists are recognized as key contributors in the management of chronic cough^4–6 and integral to a successful multidisciplinary approach alongside other specialists.^7–9 However, discrepancies are observed between chronic cough practice guidelines and implementation among otolaryngologists.¹⁰ Chronic cough frequently persists despite thorough workup and empirical therapy,¹¹ which we subsequently term refractory chronic cough and/or unexplained chronic cough (RCC/UCC). The purpose of this review is to highlight research advancements and evolving clinical knowledge about RCC/UCC for otolaryngologists.

Public Health Burden

RCC/UCC is unequivocally a major public health challenge. The sharpened focus surrounding the unmet needs in RCC/UCC spans recent studies in epidemiology,^12–19 health care utilization and costs,^20–22 physical and mental health comorbidities,^23–26 and qualitative methods to elucidate the lived experience of those suffering from RCC/UCC.^27–29 With a pooled overall prevalence of 11.8% across 34 countries,³⁰ several of the most common consequences of UCC/RCC are insomnia, vomiting, and urinary incontinence.³¹ Other repetitive stress injuries associated with UCC/RCC include rib fractures³² and benign vocal fold lesions.³³ Moreover, the stigma associated with UCC/RCC presents major psychosocial obstacles such as receiving unwanted attention³⁴ and disrupting daily activities (e.g., eating).³⁵

Additional signs substantiate the growing recognition of the importance of RCC/UCC. The World Health Organization launched an International Classification of Diseases (10th revision) diagnosis code ‘R05.3’ for chronic cough in 2022.^36,37 Similarly, the U.S. National Library of Medicine introduced ‘chronic cough’ as a Medical Subject Heading for health-related literature databases in 2024.³⁸ Ongoing momentum in RCC/UCC demands that otolaryngologists lead continued endeavors in advocating for patient needs, earlier referrals, and multidisciplinary chronic cough clinics, and collaborating with funding agencies to conduct clinical research in RCC/UCC. Recent efforts are not limited to public health research, as we next highlight exciting basic science advancements in RCC/UCC.

Pathophysiology

Some excellent recent reviews discuss cough and vagal hypersensitivity.^1,39 RCC/UCC is now conceptualized as a disorder with a neurophysiologic basis^40,41 involving structural or functional changes in peripheral and/or associated central nervous system pathways. From a peripheral standpoint, neurophenotypes in airway diseases have been proposed based on differential reactivity to substances,⁴² as numerous types of airway sensory neurons exist.⁴³ A combination of structural remodeling (e.g., hyperinnervation) and eosinophil interactions leads to dysregulated airway neural function.⁴⁴ Some peripheral sensitization studies also focused on inhibition of P2X3, which is expressed in the airways (also see “Established and Emerging Treatments” below). Another peripherally located and relevant region is the esophagus, given the observation of abnormal esophageal motility in two-thirds of patients with RCC/UCC.⁴⁵ An unanswered question remains regarding the extent to which cellular damage, mechanical forces, and/or neural receptor stimulation contribute to extraesophageal and non-acidic reflux.³⁹

From a central perspective, mechanistic insights into RCC/UCC are also increasing. The sensation of the urge to cough is associated with activation of multiple cortical areas as well as the cerebellum and midbrain.³⁹ A brain morphometry study revealed that the lower anterior cingulate cortex, an area involved in cough suppression, had reduced volume in individuals with RCC/UCC compared to non-coughing adults.⁴⁶ Another study identified a lower volume of gray matter in the left frontal cluster, including the left middle frontal gyrus, which was associated with a longer history of RCC/UCC.⁴⁷ Finally, a third study noted that typical brain activity suppression during vocalization, a non-cough laryngeal motor activity, was reduced in people with RCC/UCC, suggesting that differences observed in people with RCC/UCC extend beyond the act of coughing.⁴⁸ Figure 1 depicts an anatomical representation of the neural pathways of cough.

Figure 1.

Anatomical Representation of the Neural Pathways of Cough.

Potential genetic contributions to RCC/UCC are also being acknowledged. The Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS), characterized by gait ataxia, peripheral neuropathy, and autonomic dysfunction, often includes chronic cough that can precede neurological symptoms by decades.⁴⁹ Patients with CANVAS, identified by a RFC1 (replication factor complex subunit 1) mutation, presented with chronic cough onset younger than people with RCC/UCC who did not have the mutation.⁴⁹ Among people with RCC/UCC but no neurological concerns, 25% had RFC1 gene expansions compared to a population rate of 0.7%.⁵⁰ It has also been observed that specific single nucleotide polymorphisms in the transient receptor potential vanilloid 1 (TRPV1) genes are associated with capsaicin cough sensitivity in healthy subjects.⁵¹ Collectively, these findings highlight the complexity of cough mechanisms and potential genetic contributions to RCC/UCC. As expected with the ongoing explosion of basic research, the concept of RCC/UCC is simultaneously evolving⁵² and influencing clinical practice recommendations for otolaryngologists and other specialists.^53–56

Clinical Evaluation

RCC/UCC can be caused by a myriad of underlying etiologies, making assessment and treatment challenging. Following various prior guidelines on the evaluation and management of RCC/UCC, the British Thoracic Society published a Clinical Statement on Chronic Cough in 2023.⁵⁵ Recommended workup includes chest X-ray, blood count, formal spirometry, and fractional exhaled nitric oxide testing.⁵⁵ Previously viewed as a secondary symptom of lung disease (e.g., asthma) and other underlying etiologies (e.g., sinonasal disease),⁵⁷ RCC/UCC is increasingly thought to represent a related but distinct syndrome based on a central, treatable trait of cough hypersensitivity, or an upregulated cough reflex.^58,59 This perspective is shifting practice away from treating RCC/UCC in a broad standardized protocol. Rather, current recommendations suggest focusing on management of the confirmed symptoms and/or signs associated with the cough.⁶⁰ These updated recommendations are based on goals of improving efficiency and reducing polypharmacy risks of prior algorithmic approaches to treating RCC/UCC.⁵⁵ Personalized approaches to “treatable traits” of RCC/UCC target smoking, angiotensin-converting enzyme (ACE) inhibitors, productive cough, eosinophilic airway disease, gastroesophageal reflux disease (GERD), and upper airway symptoms including chronic rhinosinusitis, obstructive sleep apnea, and obesity.⁵⁵ Further, a systematic screening protocol may reduce the number of appointments to accurately diagnose RCC/UCC,⁶¹ thereby reducing health care expenditures.

The coronavirus disease 2019 (COVID-19) pandemic resulted in a newer group of patients with RCC/UCC. Approximately one-third of individuals with post-acute sequelae of COVID-19 report chronic cough.⁶² Among patients with post-COVID cough for ≥12 weeks, more than half presented with dysphonia and 32% showed findings suggestive of hypesthesia (e.g., deficient cough reflex to supraglottic contact). Laryngeal electromyography was abnormal in the thyroarytenoid and cricothyroid muscles in 76% of patients, of whom 83% had signs of chronic denervation.⁶³ Fortunately, most patients with post-COVID chronic cough reported improvement over time.⁶⁴ The cohort observations of RCC/UCC associated with post-viral upper respiratory infections such as COVID-19 underscore the need for improved clinical subgroup classifications.

Classifying Clinical Subgroups

The recognized heterogeneity of RCC/UCC has led to efforts to classify patient subgroups based on symptomatology and other clinical characteristics. A recent large population-based Austrian study quantified several potential cough phenotypes, such as asthmatic cough, GERD-related cough, and RCC/UCC.⁶⁵ Most of the cohort had ≥ 1 phenotype(s). Fifteen percent of the cohort had RCC/UCC, among which 45% were former smokers, tended to be younger and female, and less likely to report dyspnea, wheezing, and sputum compared to the general chronic cough population. Cluster analysis of Finnish working-age adults with chronic cough were defined according to two clusters, differentiated by the number of (1) cough triggers, especially paints/fumes/scents and poor indoor air quality; and (2) related background disorders, especially asthma, reflux, and chronic rhinosinusitis.⁶⁶ In this second cluster (37% of the sample), nearly half were still coughing one year later. Cough duration did not determine clustering.

Researchers in Korea used cluster analysis to identify four chronic cough phenotypes, incorporating factors including cough characteristics, sleep disturbance, fatigue, and sociodemographics: (1) elderly people with mild cough in whom reflux was common; (2) middle aged people with moderate cough, in whom asthma was uncommon; (3) younger people, predominantly male, with severe cough; and (4) female-predominant elderly people with severe cough, in whom asthma was relatively more common and reflux less common.⁶⁷ Cough duration was not associated with phenotype. In a related study,⁶⁸ cough severity was noted to decrease with age. Collectively, research is progressing toward more precision in defining clinical phenotypes or clusters, with the goal of leading ultimately to better treatment approaches for RCC/UCC.

Outcome Measurements

An ongoing challenge in RCC/UCC is ambiguity regarding optimal selection of clinical outcome measures.⁶⁹ Outcomes are generally collected using subjective (e.g., cough-specific quality of life questionnaires, cough severity scales) and objective assessment procedures (e.g., cough frequency monitoring, cough airflow metrics, cough reflex sensitivity).⁷⁰ It can be challenging to balance the rigor of established cough research methodologies with feasibility of implementing these measurements in clinical settings. Due to the quality-of-life impact of RCC/UCC, collecting patient-reported outcomes is recommended (e.g., Leicester Cough Questionnaire^71,72). Validated instruments should ideally offer established psychometric properties, normative data, and information on clinically meaningful changes. Among the available objective outcomes, ambulatory monitors can provide cough counts over time.⁷³ Because patient-reported outcomes and objective cough counts likely measure separate domains of RCC/UCC, it may be beneficial to implement both in treatment decision-making.⁷⁴

A continued focus area in cough research is chemical sensing, or chemosensation. Traditional tussive agents to test cough reflex sensitivity are capsaicin and citric acid.⁷⁵ A recent review also provided guidance on the use of alternative standardized chemosensory stimuli and psychophysical methodologies.⁷⁶ One example is an inhaled volatile ester, ethyl butyrate, which elicits reflexive cough in healthy adults.⁷⁷ This experimental approach allows systematic assessment of other interventions such as breath control techniques. Additional research has revealed that capsaicin cough sensitivity in healthy subjects was associated with a lower pain threshold and higher intrinsic functional connectivity of the saliency network, enhancing stimulus perception.⁷⁸ Moreover, newly developed capsaicin sensitivity measures can discriminate between people with RCC/UCC from healthy controls.⁷⁹ Chemosensation methods, although predominantly applied in the research domain, might offer future clinically relevant cough-related measurements. Capsaicin is also emerging as a way to manage RCC/UCC, along with other treatment options discussed below.

Established and Emerging Treatments

Oral medications.

Steady progress is being made in pharmacological treatments for RCC/UCC and more in-depth information is available in referenced studies.^58,80 Some recent studies further investigated the off-label use of neuromodulating drugs on clinical outcomes in RCC/UCC.^81,82 However, real-world data reveal that a considerable number of patients do not improve with these currently available treatments.^83–85 Beyond neuromodulating drugs, concerted efforts have been underway for years in pharmaceutical drug discovery and development to target RCC/UCC. Perhaps the most prominent drug target to date is the P2X3 receptor. P2X3 antagonists such as gefapixant, camlipixant, sivopixant, and eliapixant reduce cough symptoms in about two-thirds of participants.^39,86 At the time of this review, the U.S. Food and Drug Administration (FDA) twice rejected gefapixant, further underscoring the challenges associated with evaluating clinically meaningful endpoints for novel antitussives.

Superior laryngeal nerve blocks.

There is increasing literature on superior laryngeal nerve blocks for reducing RCC/UCC.^87,88 Injections include corticosteroid +/− local anesthetic, and may be unilateral or bilateral. Across studies, 70–80% of patients reported improvement, with no major adverse events. The mean duration of effect in one study was 8 weeks,⁸⁷ and in another study, responsiveness was not predicted by localizing symptoms, specific cough features, or medical history.⁸⁸ In a small randomized trial, 80% in the treatment (corticosteroid with local anesthetic) group reported subjective improvement compared to 14% in the saline placebo group, associated with Leicester Cough Questionnaire improvement in the treatment group only.⁸⁹ Relatedly, a recent paper described laryngeal adductor botulinum toxin injections for RCC/UCC.⁹⁰ Approximately 70% reported subjective improvement accompanied by a Cough Severity Index score reduction, and injections were well tolerated with 8% reporting temporary dysphagia.

Nonpharmacological cough management.

As an adjunct to medical interventions for RCC/UCC, there are observed benefits of nonpharmacological, behavioral treatments offered by speech-language pathologists.⁹¹ Recent systematic reviews have evaluated these behavioral interventions for RCC/UCC.^92–94 Common therapeutic elements offered in speech therapy include patient education, cough control techniques, laryngeal hygiene, and psychoeducational counseling.⁹⁵ Although it is still unclear which patients with RCC/UCC are ideal candidates for nonpharmacological management via speech therapy, Demirjian et al.¹⁰ suggested that otolaryngologists underutilize speech therapy referrals for RCC/UCC. Some components of these nonpharmacological treatments, such as patient education and psychoeducational counseling, may be suited for earlier implementation in the workup for RCC/UCC.

Capsaicin.

Another focus area is therapeutic capsaicin for RCC/UCC. Oral capsaicin can reduce cough symptom scores and increase cough sensory thresholds.⁹⁶ Topical capsaicin via pharyngeal spray was also associated with self-reported reduction of cough in 64%, and 22% reported minor adverse effects.⁹⁷ Aerosolized capsaicin was tested in a small randomized controlled trial to evaluate its effect on behavioral cough suppression (BCS), based on the premise that aerosolized capsaicin would increase the urge to cough and thus facilitate learning of BCS techniques.⁹⁸ While both groups showed improved cough-related quality of life, improvement was greater in the capsaicin group, accompanied by a greater reduction in the urge to cough. These findings offer insight into the potential benefits of combining nonpharmacological and pharmacological treatment options. Additional noninvasive therapeutic strategies for RCC/UCC are being explored, including vibrotactile stimulation of the larynx.⁹⁹

Future Directions

Given the major strides made in RCC/UCC research, the unmet needs of patients necessitate further work dedicated to differential diagnosis of clinical subgroups and personalized treatment. Moreover, there is a significant need for improved risk-benefit assessment of currently available and emerging RCC/UCC treatments. This will help addresses how to measure the impacts of these treatments with the goal to determine which patients are candidates for pharmacological (medical, procedural) versus nonpharmacological (behavioral) treatments, as well as combined interventions.⁹¹ Lastly, RCC/UCC is a complex condition requiring multidisciplinary workup and management. As such, an interdisciplinary and collaborative approach is essential to more widely disseminate findings across disciplines with an interest in treating RCC/UCC.

Conclusion

The psychosocial challenges of patients with RCC/UCC are receiving increasing formal recognition. Accumulating research reveals the complexity of RCC/UCC neurophysiology and begins to explain why patients do not uniformly respond to treatments. Clinical practice recommendations from multiple fields can inform the workup and treatment of RCC/UCC. As knowledge about chronic cough in adults continues to expand in both research and clinical practice, otolaryngologists can continue to raise awareness of the role of the larynx in cough and promote ongoing multidisciplinary collaborations. In the coming years, more pharmacologic options and personalized treatment approaches are anticipated for chronic cough.

Key Points.

• Otolaryngologists, among other specialists, are essential in managing chronic cough in adults, which imposes major individual and societal burdens.

• The neurophysiology of chronic cough implicates both central and peripheral pathways.

• Chronic cough is increasingly recognized as a heterogeneous disease, so workup should preferably include chest radiograph, blood count, formal spirometry, and fractional exhaled nitric oxide testing, along with focusing on “treatable traits” or contributors to allow a personalized approach to care.

• Potential treatment avenues for refractory and/or unexplained chronic cough include oral and inhaled medications, superior laryngeal nerve blocks, and behavioral therapy.

• The complexity and heterogeneity of chronic cough warrant ongoing multidisciplinary collaborative research and care.