Unexplained or refractory chronic cough causes significant impairments in quality of life, and effective assessment, use of practice guidelines, and appropriate treatment approaches are crucial. This certified ECHO activity reviews the anatomy and neurophysiology of protective and pathologic cough, shares diagnostic options available to clinicians, and takes a look at targeted therapies currently under investigation.
Diagnosis and Management of Unexplained or Refractory
Diagnosis and Management of Unexplained or Refractory Chronic Cough
Cough is the most common symptom in patients seeking medical advice from primary care providers (PCPs).1 Chronic cough is defined as a cough that persists for 8 weeks or more.2 It can be associated with very common conditions, such as asthma, gastroesophageal reflux disease (GERD), and upper airway infection.1, 3, 4 In a subset of patients, however, chronic cough is refractory. That is, it fails to respond to aggressive, targeted therapy after a thorough workup for underlying etiologies and reversible causes.
Epidemiology and Physiology
Patients with chronic cough usually present in the sixth or seventh decade of life. Approximately 60% to 70% of cases of refractory cough are in women; the typical patient is perimenopausal.3, 4 Most cases of chronic cough are in individuals who are lifetime nonsmokers, yet they may cough literally hundreds of times a day or have episodes so severe that they vomit, become dizzy or faint, or experience urinary incontinence (see Table 1).1, 5 Chronic cough has a significant negative effect on quality of life, and many patients see a host of healthcare providers—PCPs and specialists in pulmonology, allergy, and gastroenterology, as well as ear, nose, and throat specialists—before they receive effective treatment.
An abundance of research has been done on the anatomy and physiology of cough, which is complex. Cough is a vagal reflex that results from the activation of sensory nerves that innervate the airway’s mucosa. It is a defensive reflex that protects the airways from inhaled irritants, accumulated secretions, or stimuli such as cold air or strong smells.
Two types of sensory nerves play a primary role in inducing cough: A-delta fibers and unmyelinated C-fibers. A-delta fibers are thinly myelinated and conduct action potentials at 5 m/s. They are very sensitive to mechanical stimuli, such as accumulated secretions or aspiration of food, and have a defensive function. C-fibers are relatively insensitive to mechanical stimuli but respond to many of the inflammatory mediators associated with chronic airway diseases. They are believed to regulate coughing that manifests as chronic and refractory (see Table 2).
Central Regulation of Cough and Cough Hypersensitivity Syndrome
Cough is a primitive reflex that involves integration of sensory input in the central nervous system (CNS) and coding of an appropriate response. Vagal sensory nerves, which regulate coughing, terminate in the brain stem. Neurotransmitters such as glutamate and neuropeptides such as substance P and neurokinin A are relayed by neurons from the CNS to the respiratory muscles. In chronic refractory cough, the central regulatory mechanisms promoting or inhibiting cough may be altered, such that given a particular tussive stimulus, a patient will cough excessively, whereas an otherwise healthy individual will have little or no cough (see Figure 1).
One concept that has emerged recently in cough research is cough hypersensitivity syndrome.7 The two main peripheral mechanisms for it are: (1) excessive production of stimuli for initiating coughing, such as bradykinin or adenosine triphosphate; and (2) hyperexcitability of sensory nerves caused by receptors and ion channels on their peripheral terminals (see Figure 2). Insights about the pathophysiology of cough and cough hypersensitivity syndrome have led to the identification of rational therapeutic targets expressed on the peripheral terminals of sensory nerves, particularly the bronchopulmonary C-fibers.
The current treatment landscape for refractory cough includes two categories of drugs—opiates and neuromodulators—and speech pathology.10 Opiates are used more commonly for this indication in the UK than in the United States. A systematic review showed that codeine was more effective than placebo in reducing cough severity and frequency.10 Of patients with refractory cough, 15% to 20% respond to the neuromodulators amitriptyline and gabapentin. The latter drug is recommended in the CHEST guidelines but is associated with nausea and fatigue.8, 11 In the past decade, randomized controlled trials have shown that the involvement of a speech-language pathologist as part of the chronic cough treatment team can be a very valuable component of treatment (see Table 3).12
New research about the neurophysiology of cough has led to the discovery of drugs that are antagonists to the receptors and ion channels involved in the process. P2X3 antagonists under investigation include BLU-5937, BAY 1817080, and S-600918; the neurokinin-1 receptor antagonist orvepitant is also being studied. Much earlier in the drug development pipeline is GSK2339345, a voltage-gated sodium channel blocker (see Table 4).
The P2X3 antagonist gefapixant has been studied in two phase 3 trials at dosages of 45 mg or 15 mg twice daily.13 The results show that the drug significantly reduced the primary endpoint of 24-hour coughs per hour versus placebo, but only at the higher dosage (see Table 5).
Phase 2 trials are underway of the P2X3 antagonists BLU-5937 and BAY 1817080 for refractory chronic cough.14, 15 A phase 2 trial of S-600918 is active but not recruiting.16 A phase 2 trial of orvepitant has been completed, but no results have been published yet.17 Results of a phase 2 UK trial of GSK2339345 showed that while the sodium channel blocker was well tolerated, it had no antitussive effect despite reaching airway sensory nerves as evidence by the evoked transient cough.18
In the past decade, advances in research have led to an increased understanding of chronic cough as a condition and a disease in and of itself that can significantly impair patient quality of life when it is unexplained or refractory. Before making the diagnosis, a thorough evaluation must be undertaken to exclude any reversible or treatable underlying causes. For chronic cough that persists despite aggressive medical therapy, a rational management strategy is possible, based on the latest sound science performed at the nerve ending and molecular level.
- Irwin RS, Baumann MH, Bolser DC, et al. Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest. Jan 2006;129(1 Suppl):1S-23S. doi:10.1378/chest.129.1_suppl.1S
- Kawai S, Baba K. A case of refractory chronic cough that resolved completely with long-term low-dose gabapentin. J Respir Med Lung Dis. 2020;5(1):1052.
- Irwin RS, Corrao WM, Pratter MR. Chronic persistent cough in the adult: the spectrum and frequency of causes and successful outcome of specific therapy. Am Rev Respir Dis. 1981;123(4 Pt 1):413-417. doi:10.1164/arrd.19184.108.40.2063
- Irwin RS, Curley FJ, French CL. Chronic cough. The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Am Rev Respir Dis. 1990;141(3):640-647. doi:10.1164/ajrccm/141.3.640
- Smyrnios NA, Irwin RS, Curley FJ, French CL. From a prospective study of chronic cough: diagnostic and therapeutic aspects in older adults. Arch Intern Med. 1998;158(11):1222-1228. doi:10.1001/archinte.158.11.1222
- Canning BJ, Chang AB, Bolser DC, et al. Anatomy and neurophysiology of cough: CHEST Guideline and Expert Panel report. Chest. 2014;146(6):1633-1648. doi:10.1378/chest.14-1481
- Song WJ, Morice AH. Cough hypersensitivity syndrome: a few more steps forward. Allergy Asthma Immunol Res. 2017;9(5):394-402. doi:10.4168/aair.2017.9.5.394
- Gibson P, Wang G, McGarvey L, et al. Treatment of unexplained chronic cough: CHEST Guideline and Expert Panel report. Chest. 2016;149(1):27-44. doi:10.1378/chest.15-1496
- Morice AH, Millqvist E, Bieksiene K, et al. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J. 2020;55(1):1901136. doi:10.1183/13993003.01136-2019
- Yancy WS Jr, McCrory DC, Coeytaux RR, et al. Efficacy and tolerability of treatments for chronic cough: a systematic review and meta-analysis. Chest. 2013;144(6):1827-1838. doi:10.1378/chest.13-0490
- Ryan NM, Birring SS, Gibson PG. Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial. Lancet. 2012;380(9853):1583-1589. doi:10.1016/S0140-6736(12)60776-4
- Vertigan AE, Kapela SL, Ryan NM, Birring SS, McElduff P, Gibson PG. Pregabalin and speech pathology combination therapy for refractory chronic cough: a randomized controlled trial. Chest. 2016;149(3):639-648. doi:10.1378/chest.15-1271
- McGarvey L. Late breaking abstract – Two phase 3 randomized clinical trials of gefapixant, a P2X3 receptor antagonist, in refractory or unexplained chronic cough (COUGH-1 and COUGH-2). Eur Respir J. 2020;56(suppl 64):3800. doi:10.1183/13993003.congress-2020.3800
- Evaluation of the efficacy and safety of BLU-5937 in adults with refractory chronic cough (SOOTHE). ClinicalTrials.Gov identifier: NCT04678206. Updated December 21, 2020. https://clinicaltrials.gov/ct2/show/NCT04678206
- Clinical study to evaluate the efficacy and safety of three different doses of BAY1817080 compared to placebo in patients with chronic cough (PAGANINI). ClinicalTrials.gov identifier: NCT04562155. Updated January 8, 2021. https://clinicaltrials.gov/ct2/show/NCT04562155
- Evaluation of S-600918 in adults with refractory chronic cough. ClinicalTrials.gov identifier: NCT04110054. Updated November 13, 2020. https://clinicaltrials.gov/ct2/show/NCT04110054
- A dose-ranging study of orvepitant in patients with chronic refractory cough. ClinicalTrials.gov identifier: NCT02993822. Updated March 13, 2020. https://clinicaltrials.gov/ct2/show/NCT02993822
- Smith JA, McGarvey LPA, Badri H, et al. Effects of a novel sodium channel blocker, GSK2339345, in patients with refractory chronic cough. Int J Clin Pharmacol Ther. 2017;55(9):712-719. doi:10.5414/CP202804
In accordance with the ACCME Standards for Commercial Support, Global Learning Collaborative (GLC) requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. GLC resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational programs.
Brendan J. Canning, PhD
Professor of Medicine
Johns Hopkins Asthma and Allergy Center
Consulting Fees: Merck, Nocion
Peter Dicpinigaitis, MD
Professor of Medicine
Albert Einstein College of Medicine
Consulting Fees: Bayer, BELLUS Health, Merck, Shionogi
- Sean T. Barrett has nothing to disclose.
- Amanda Hilferty has nothing to disclose.
- Libby Lurwick has nothing to disclose.
- Brian P. McDonough, MD, FAAFP, has nothing to disclose.
- Robert Schneider, MSW, has nothing to disclose.
After participating in this educational activity, participants should be better able to:
- Demonstrate competency in defining the anatomy and neurophysiology of protective and pathologic cough.
- Define the rationale and clinical evidence for several targeted therapies currently under clinical investigation for the management of unexplained chronic cough (UCC).
- Explain the extensive assessment process underlying the diagnosis of UCC per published best practice guidelines, protocols, and guidance.
This activity is designed to meet the educational needs of otolaryngologists, pulmonologists, allergists/immunologists, gastroenterologists, primary care physicians, nurse practitioners, and physician assistants.
Global Learning Collaborative is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
Global Learning Collaborative designates this enduring material for a maximum of .25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
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This activity is supported by an independent educational grant from Merck.
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Jeffrey S. Weber, MD, PhDPeer