Updates in Treatment of Adults With Chronic Cough - AJMC.com Managed Markets Network

Posted: 15 Oct 2020 08:05 AM PDT

Am J Manag Care. 2020;26:S239-S245. https://doi.org/10.37765/ajmc.2020.88515

Introduction

Chronic cough is a severely debilitating condition that can result from multiple different etiologies. Historically, most treatments available to patients have been effective for the resolution of acute cough. Patients can purchase antitussives without a prescription and self-treat when needed. If self-treatment with over-the-counter therapy fails, patients may seek prescription medications for acute cough from their primary care physician, such as benzonatate or cough syrups with codeine.

However, patients whose cough persists beyond 8 weeks (refractory chronic cough [RCC] or unexplained chronic cough [UCC]) experience great irritation as they often cough in excess of hundreds to thousands of times daily.¹ Pharmacologic treatment for chronic cough has limited efficacy, resulting in decreased quality of life (QOL) for many patients affected. Recent advances over the past decade have improved the understanding of the pathophysiology of chronic cough and the suspected neurobiological role leading to the development of novel therapeutic agents to help address this debilitating condition.

Chronic Cough Guidelines for Adult Patients

Currently, 2 major treatment guidelines address the medical management of RCC and UCC: those of the American College of Chest Physicians (ACCP or CHEST) and the European Respiratory Society (ERS).^2,3 Both guidelines recommend a thorough history and physical when evaluating patients who present with chronic cough.^2,3 A CHEST guideline and expert panel also recommend focusing on the identification of red-flag symptoms (see Table 14) and ruling out other conditions that either commonly or more rarely result in chronic cough.⁴

CHEST guidelines recommend that individuals with a known cause of their chronic cough have their therapy optimized for each diagnosis.^2,3 Patients need to be assessed for adherence regularly, with frequent follow-up to monitor for barriers, efficacy of treatment, cough severity, and QOL. Education to avoid exposure to known environmental and occupational triggers should also be provided. A referral to a cough clinic should be considered in patients with RCC.^2,3

A comparison of CHEST and ERS guideline recommendations for the nonpharmacologic and pharmacologic treatment of chronic cough is outlined in Table 2.^2,3 Both guidelines recommend a trial of speech pathology and gabapentin in patients with UCC and recommend against the use of proton pump inhibitors (PPIs) in the absence of gastroesophageal reflux disease (GERD). The guidelines differ in their recommendations of inhaled corticosteroids (ICS) and morphine.^2,3 Current options for the management of RCC and UCC will be discussed in further detail in subsequent sections. Chronic cough management is often complex, requiring an individualized treatment plan. Therefore, treatment options discussed below include a summary of efficacy and tolerability data to guide clinical decision making.

Nonpharmacologic Treatment of Chronic Cough

Current CHEST guidelines recommend a trial of multimodality speech pathology therapy in patients with UCC.² This recommendation was based on positive cough severity, randomized control trial data.^5,6 Results of a systematic review by Chamberlain et al found 2 to 4 sessions of speech pathology that included education, cough suppression techniques, breathing exercises, laryngeal hygiene, and counseling resulted in decreased cough frequency, improved cough severity, and positive benefits on cough-related QOL.⁶

Speech pathology typically begins with measuring symptoms, assessing laryngeal physiology, and determining whether the individual is a good candidate for speech pathology treatment for chronic cough (SPTCC).⁷ The exact mechanism for chronic cough improvement after SPTCC is not fully elucidated. Individuals who present with a nonproductive cough; abnormal laryngeal sensations, such as tickle, itch, tightness, dryness, or globus; coughs triggered by nontussive stimuli, including perfumes, cold air, or talking; and low doses of tussive stimuli, such as chemical fumes or smoke, seem to improve the most from SPTCC. The desired outcomes for SPTCC include a reduced urge to cough, improved coping skills, decreased anxiety and depression, and reduced laryngeal constriction.⁷

Treatment of the Most Common Causes of Chronic Cough

Upper Airway Cough Syndrome (UACS)

Previously called postnasal drip syndrome, UACS is the most common cause of chronic cough in adults and should be addressed first when managing this condition.^8,9 Patients may require further workups, such as allergy testing (allergic rhinitis) and computed tomography of the sinuses (sinusitis), as indicated on an individual patient basis.^8,9

The etiology of UACS will dictate the selection of treatment for affected patients. Managing exposure to environmental irritants, such as perfumes or pollution, and any other offending agents, including pollen, dust, or mites, is a standard first-line nonpharmacologic therapy approach.^8,9 Sinusitis can be managed via saline lavage, nasal corticosteroids, antihistamines, and antibiotics as needed.^8,9 If the cause of chronic cough is unknown, then initiation of a decongestant (eg, pseudoephedrine, phenylephrine) plus a first-generation antihistamine (eg, chlorpheniramine) may be started initially.¹⁰ Other therapies, such as intranasal corticosteroids (eg, fluticasone), saline lavage, nasal anticholinergics (eg, ipratropium), and antihistamines (eg, cetirizine, fexofenadine, loratadine), may also be considered. Typically, clinical improvement is expected within days to weeks, with a maximum of 2 months for resolution of UACS.^9,10

Angiotensin-Converting Enzyme (ACE) Inhibitor-Induced Cough

ACE inhibitor-induced cough is a common cause among individuals on ACE inhibitor therapy.¹⁰ Upon discontinuation, the ACE inhibitor-induced cough typically resolves within 1 week to 3 months. Angiotensin receptor blockers (ARBs) are commonly prescribed as a replacement for patients who experience ACE inhibitor-induced coughs. Depending on the clinical circumstance, providers may choose to restart ACE inhibitor therapy, and the reoccurrence of cough may not occur in some patients.^10,11

Asthma

Asthma is another common cause of chronic cough, and treatment should begin with patient education on smoking cessation and the avoidance of potential triggers.^9,10 Asthma treatment should then follow guidelines from the Global Initiative for Asthma (GINA) cycle of asthma care.^12,13 The GINA control-based cycle of asthma care starts with the assessment of a patient's symptom control and risk factors, inhaler technique and adherence, and patient preferences. Treatment should be adjusted, taking into consideration modifiable risk factors, current asthma medications, and any nonpharmacologic strategies being employed. Then, the patient's response to the treatment plan is reviewed, addressing aspects including symptoms, exacerbations, adverse effects (AEs), patient satisfaction, and lung function, and the process continues with assessment.^10,12

Pharmacologic treatment usually consists of a bronchodilator (eg, albuterol) and an ICS (eg, budesonide). Leukotriene receptor antagonists (eg, montelukast, zafirlukast) are also sometimes added. Severe or refractory cough usually will require an oral corticosteroid (eg, prednisone, methylprednisolone) for 5 to 10 days.¹⁰

Chronic Obstructive Pulmonary Disease (COPD)

COPD frequently causes a chronic cough, but, unlike asthma, patients typically do not have undiagnosed COPD. Because symptoms of asthma and COPD can overlap, it is important to use spirometry to aid in the diagnosis, so proper treatment can be administered.

Treatment of COPD should follow the stepwise approach recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines.¹⁴ Pharmacologic agents usually include an inhaled bronchodilator, inhaled anticholinergic, and ICS. A short course (5-7 days) of an oral corticosteroid (plus or minus antibiotics) may be used for acute management of exacerbations.¹⁴

Gastroesophageal Reflux Disease (GERD)

GERD has been associated with chronic cough in research, but treatment is considered controversial as the pathophysiology of cough related to GERD is highly complex.^10,15 The 2016 CHEST and expert panel guideline recommend individuals suspected to have reflux-cough syndrome first begin with diet modification to lose weight in patients who are overweight or obese, elevating the head of the bed, and avoiding meals within 3 hours of bedtime.¹⁵

Among individuals with reported acid reflux and regurgitation, antacid agents, such as histamine-2 receptor antagonists (H2 RAs), PPIs, alginate, and calcium carbonate, are recommended to alleviate symptoms.¹⁵ PPI therapy is not recommended by CHEST among those who have chronic cough without acid reflux or regurgitation, as treatment is considered unlikely to be effective. Gastroesophageal symptoms typically respond within 4 to 8 weeks but may take up to 3 months. Chronic cough that persists beyond the 3-month antacid therapy trial should be further evaluated; additional diagnostic tests, such as esophageal manometry and/or pH-metry, should be conducted as indicated.¹⁵

Nonasthmatic Eosinophilic Bronchitis (NAEB)

NAEB is another common cause of chronic cough that is characterized by unresponsiveness to bronchodilators.¹⁰ Avoidance of inhaled allergens due to occupational exposure should be considered first when there is a known cause. ICS are usually effective for NAEB, and oral corticosteroids can be considered after failure of high-dose ICS.^10,16

Traditional Pharmacologic Agents for Chronic Cough

Nonprescription Products

The majority of products sold without a prescription for cough relief (eg, dextromethorphan, guaifenesin, diphenhydramine, and, in some states, low-dose codeine) are not considered more effective than placebo when studied in randomized clinical trials for cough suppression.^17,18 These agents are readily available, inexpensive, and typically safe when used appropriately per nonprescription product labeling. Therefore, they are commonly used to address acute and chronic cough among patients who self-treat. However, none of these agents is indicated for chronic cough, so patients should be referred to their provider for further workup.

Opiates

Codeine and morphine are the most used opiate antitussives.¹⁹ Codeine has been used for more than 200 years to treat cough, including tuberculosis-induced cough. It has a rapid onset of action, and responders are easily identified from nonresponders within 1 to 2 weeks of initiation. Approximately 50% of patients with chronic cough will have a suboptimal cough suppression. Further, additional limitations, such as individual variability with codeine metabolism (CYP2D6) and potential safety concerns, are important considerations. Patients who are poor metabolizers (little to no CYP2D6 activity) will have a decreased response to codeine. AEs, such as constipation and nausea, are common with codeine treatment.¹⁹ The efficacy of codeine is not well supported in clinical trials. Results of a trial by Smith and colleagues that investigated the use of 60 mg codeine phosphate daily did not find it to be more effective than placebo for reducing objective or subjective cough frequency or severity in individuals with COPD and cough.²⁰ Additional studies are needed to fully ascertain the utility of codeine in patients with chronic cough.

Morphine is an alternative opiate to codeine that is typically reserved for the most severe intractable coughs and is not recommended in current CHEST guidelines.^2,19 In contrast with codeine, morphine does not exhibit the CYP2D6 variability in metabolism and is approximately 10 times more potent.¹⁹ Due to safety risks including respiratory depression, drowsiness, addiction, and accidental overdose, patients should be closely monitored. The efficacy and tolerability of morphine (5-10 mg) extended-release was evaluated in a 4-week randomized, placebo-controlled, crossover study (N = 27) in patients with chronic cough.²¹ Those who were treated with morphine reported a significant difference in the Leicester Cough Questionnaire (LCQ) score compared with placebo (mean difference, 2; P <.02) and daily cough severity score (range, 0; mean difference, –3.4 ± 1.8; P <.01). Although treatment was generally well tolerated and most effects were observed within the first week, 18 of 27 enrolled patients continued on to the extension study, and two-thirds opted to double their dose due to inadequate control of their cough during the core study.^19,21

Neuromodulator Agents

Gabapentin inhibits α2δ subunits on voltage-gated calcium channels and is approved for the treatment of seizures and neuropathic pain within the United States.²² It is now also considered a possible therapeutic option in patients with chronic cough based on improved understanding of chronic cough pathophysiology.^23,24 The efficacy of gabapentin was evaluated in a 10-week randomized controlled trial (N = 62) in patients with RCC, and results indicated that gabapentin (1800 mg/day) significantly improved LCQ scores compared with placebo (P = .004). It also decreased cough severity scores (P = .029) and objective cough frequency (P = .028) by week 8. Once treatment was discontinued, the antitussive effects were not sustained.23 Current CHEST guidelines recommend a trial of gabapentin as long as patients are educated on the potential for AEs and the risk−benefit profile along with a reassessment of risk−benefit at 6 months before continuing therapy.²

Pregabalin is a structural derivative of γ-aminobutyric acid and binds α2δ subunits on voltage-gated calcium channels.²⁵ Like gabapentin, pregabalin has also been evaluated for efficacy in RCC. A 14-week study evaluated pregabalin as adjunctive treatment to speech pathology therapy and demonstrated a significant improvement in LCQ scores (P = .024) and decreased cough severity (P = .002) compared with just speech pathology alone.²⁶

Both gabapentin and pregabalin are associated with AEs, such as drowsiness, confusion, fatigue, and blurred vision, which have led to discontinuation.^23,26 It has also been proposed that both gabapentin and pregabalin may just alter the perception of cough versus controlling cough.^23,26 Therefore, additional randomized controlled trials are required to fully ascertain the utility of these agents in the treatment of chronic cough.

The tricyclic antidepressant amitriptyline is FDA approved for depression and is also frequently used for the treatment of anxiety, neuropathic pain, and potentially for chronic cough.^27,28 At the time of this writing, no placebo-controlled randomized clinical trials are evaluating the efficacy of amitriptyline in the treatment of chronic cough. A small randomized trial (N = 28) evaluated the efficacy of amitriptyline 10 mg in patients with post-viral vagal neuropathy cough.²⁹ Amitriptyline was shown to be significantly more effective compared with the combination of codeine/guaifenesin in complete cough response and cough-specific QOL at 10 days.²⁹ A major limitation of this study was that neither objective cough frequency nor any safety outcomes were measured. Additional research is required to fully elucidate the role of amitriptyline in the treatment of chronic cough.

Novel Emerging Agents for Chronic Cough

The lack of efficacy of traditional antitussive agents combined with an improved understanding of the neurobiology of the cough reflex has led to an increased focus on the development of new agents to address this treatment gap.^30,31 The new chronic cough agents target specific receptors or channels in the peripheral sensory neurons with the goal of reduced central nervous system AEs and control of hypersensitivity while reserving the protective cough response.³²

Transient Receptor Potential Receptor Vanilloid-1 (TRPV1) Antagonists

The TRPV1 channel was the first therapeutic target evaluated for chronic cough.³² TRPV1 channels are present in both peripheral neurons and nonneuronal cells.¹⁹ They are activated by hot temperatures (>43 °C), acidic pH, or inflammatory mediators and recognize capsaicin.³³ Two subsequent clinical trials in patients with chronic cough did not demonstrate that TRPV1 antagonists were clinically beneficial in the treatment of chronic cough.^34,35 SB-705498, a highly selective and potent competitive antagonist for TRPV1 receptors, has shown to significantly affect the capsaicin cough reflex but had almost no effect on objective cough frequency, cough severity scores, or CQLQ scores.³⁵ XEN-D0501, which is significantly more potent than SB-705498 in vivo, exhibited similar results and failed to significantly reduce cough frequency in patients with chronic cough compared with placebo (P = .41).³⁴

Transient Receptor Potential Ankyrin-1 (TRPA1) Antagonist

TRPA1 is an environmental-sensing member of the transient receptor potential channel family.¹⁹ This channel family is activated by cold temperature (<17 °C), cigarette smoke, cinnamaldehyde, acrolein, and other various cough irritants.³⁶ Cold air is a common trigger observed clinically among patients with chronic cough, leading to optimism for this potential therapeutic target.^37-39 An early-phase clinical trial investigating the potent TRPA1 antagonist GRC 17536 did not demonstrate a clinical benefit compared with placebo in patients with RCC.⁴⁰ At the current time of writing, there are no other TRPA1 antagonist clinical trials underway within the United States.

P2X3 Antagonists

P2X3 receptors play an important role in the activation of sensory neurons integral to the cough reflex (Aδ-fibres and C-fibres).⁴¹ Combined with an increased understanding of afferent sensitization in airway dysfunction among patients with chronic cough, P2X3 receptor antagonists are being investigated as a potential therapeutic option.¹

Gefapixant

Gefapixant (MK-7264/AF-219) is a novel, first-in-class, nonnarcotic, selective antagonist of the P2X3 receptor currently in clinical trials evaluating its safety and efficacy for treatment of chronic cough.⁴¹ Phase 1 and 2 clinical trials evaluated more than 300 patients and demonstrated positive results for decreased mean daytime cough frequency, 24-hour cough frequency, and awake cough frequency.^42-44 Phase 1 trials used a significantly higher dose of gefapixant (600 mg), resulting in major taste disturbances due to inhibition of the P2X2/3 channels.⁴³ Subsequent dose-finding studies found an optimal dose of 30 mg to 50 mg twice daily.⁴³ Gefapixant was generally well tolerated in all phase 2 trials with no major safety concerns. Dose-dependent dysgeusia was the most common AE and should subside with discontinuation of gefapixant.⁴¹

Following the positive results from phase 1 and 2 trials, investigation of the utility of gefapixant was continued into phase 3 clinical trials. Two parallel, double-blind, randomized, placebo-controlled trials (ClinicalTrial.gov Identifiers: NCT03449134 [COUGH-1], NCT03449147 [COUGH-2]) were conducted to assess the efficacy and safety of gefapixant (15 mg or 45 mg twice daily) in patients with chronic cough.^41,45-47 The primary efficacy outcomes included 24-hour cough frequency (at week 24), percentage of at least 1 AE during treatment and follow-up (up to 54 weeks), and percentage of participants who discontinued due to an AE (up to 52 weeks). The results of COUGH-1 and COUGH-2 were presented virtually at the European Respiratory Society International Congress in August 2020. Reported results found a statistically significant reduction in 24-hour cough frequency versus placebo at 12 weeks (COUGH-1) (18.45%, P = .041) and 24 weeks (COUGH-2) (14.64%, P = .031) in patients treated with gefapixant 45 mg twice daily.⁴⁷ Gefapixant 15 mg twice daily treatment arms did not meet the primary efficacy end point in either study. AEs reported were consistent with previous trials (dysgeusia occurring at a higher incidence with gefapixant 45 mg twice daily), and discontinuations of study drugs due to AEs were more frequent in the gefapixant 45 mg treatment arms compared to the gefapixant 15 mg and placebo arms.

BAY1817080, BLU-5937, and S-600918

Three additional P2X3 antagonists, BAY1817080, BLU-5937, and S-600918, are newer agents under investigation that are highly selective and may cause less dysgeusia compared with gefapixant. Each is discussed further in the following paragraphs (ClinicialTrials.gov identifiers NCT03310645, NCT03979638, and NCT04110054, respectively).^48-50

The results from the BAY1817080 phase 1/2a double-blind, placebo-controlled, randomized, 2-way crossover trial (NCT03310645) was presented at the American Thoracic Society International conference virtually in August 2020.51 Reported results found BAY1817080 caused AEs in 41% to 49% of patients, with the majority being mild. Taste-disturbance AEs were dose dependent and occurred in 5% to 21% of patients. The 24-hour cough frequency counts were decreased with higher BAY1817080 doses compared with placebo (50 mg, P = .054; 200 mg, P = .004; 750 mg, P = .002). Cough frequency counts also decreased from baseline by 17% (P = .025) and patient-reported cough severity was significantly improved compared with placebo.⁵¹

The BLUE-5937 (RELIEF) trial was a phase 2, randomized, double-blind, placebo-controlled, crossover, dose-escalation study.⁴⁹ Individuals received two 16-day treatment periods with 4 escalating doses or matching placebo at 4-day intervals. The two 16-day treatment periods were separated by a 10- to 14-day washout period, with a 14-day follow-up period. The trial was terminated early in June 2020 due to the impact of the novel coronavirus 2019 (COVID-19) pandemic on clinical trial activities. There were 68 patients enrolled in the trial, and 52 completed the dosing trial.⁴⁹ Topline results from the RELIEF trial are expected to be released sometime in 2020.⁵²

The trial evaluating S-600918 is a phase 2b trial that is actively recruiting patients to determine the optimal dose of S-600918 in patients with RCC via a change in baseline in 24-hour cough frequency compared with placebo. The investigators expect to enroll 372 participants who will receive 50 mg, 150 mg, or 300 mg of S-600918, or placebo for 28 days. The anticipated study completion date is May 25, 2021.⁵⁰

Neurokinin-1 Receptor (NK-1) Antagonists

NK-1 and substance P (SP) are suspected of playing an important role in the induction and maintenance of cough reflex hypersensitivity.^53,54 This is evidenced by the increased SP concentrations in biological fluids and an increased cough response with inhaled SP in patients with idiopathic pulmonary fibrosis and acute cough.^55-60

Evidence for the utility of NK-1 receptor antagonists first came from a randomized, double-blind, placebo-controlled, crossover pilot study (N = 20) evaluating aprepitant in patients with lung cancer-associated cough. Statistically significant improvements in cough frequency, cough severity, and QOL were observed.⁶¹

Recently, a phase 2, open-label, pilot study (VOLCANO-1) was conducted to evaluate efficacy and safety of orvepitant, a selective, centrally acting NK-1 receptor antagonist, in 13 patients with RCC.^61-63 Orvepitant demonstrated a statistically significant decrease in objective daytime cough frequency at week 4 (P <.001). The decreased cough frequency occurred early with a measurable improvement by week 1 (P = .001) and was sustained after discontinuation of orvepitant at week 8 (P = .020). Orvepitant also significantly improved severity scores and QOL, with a favorable safety profile.⁶³

VOLCANO-2 was a phase 2b, placebo-controlled trial (N = 275) conducted over 12 weeks in patients with RCC and a baseline awake cough frequency of at least 10 coughs/hour (ClinicalTrials.gov identifier NCT02993822).^64,65 The primary cough frequency end point was not significant; however, an improved efficacy trend was observed among patients taking 30 mg orvepitant and a higher cough frequency (≈66.7 coughs/hour) compared with placebo (P = .066). The most common AEs included headache, dizziness, fatigue, and somnolence.^65,66

Other Agents Considered for Chronic Cough Treatment

Several other agents, such as esomeprazole, erythromycin, and ipratropium bromide, have been evaluated by CHEST guidelines for patients with chronic cough.² However, due to various factors including small sample size, lack of results replication, and lack of efficacy, among others, they are not currently recommended for the treatment of chronic cough.² Multiple other therapies are in various stages of investigation for their utility in the treatment of chronic cough, including TRPV4 antagonists, voltage-gated sodium channel blockers, γ-aminobutyric acid (GABA) B receptor agonists, nicotinic acetylcholine receptor α7-subunit agonists, and inhaled sodium cromoglycate.¹⁹

Conclusions

In summary, RCC and UCC are disabling conditions that historically lacked effective treatment options. Any patient who presents with RCC or UCC must be thoroughly worked up (including a detailed medical and medication history), evaluated for any red-flag symptoms, and asssessed by a differential diagnosis for common and uncommon causes of chronic cough before a treatment approach is developed. If a specific etiology is discovered, that condition should be optimally treated first before treating the chronic cough. Current guidelines recommend nonpharmacologic and pharmacologic treatments based on individual patient circumstances and should follow a guideline/protocol process. Traditional treatments, such as speech therapy, opiates, and neuromodulators, have had limited success in improving cough frequency, severity, and QOL in patients affected. As a result, increased research has focused on the development of novel therapeutic targets based on an increased understanding of the neurobiology associated with the cough reflex. These new agents have demonstrated positive benefits for reducing cough frequency, severity, and QOL while being generally well tolerated in clinical trials. Therefore, it is likely that some of these agents may become available for treating patients and may help improve their QOL.

Author affiliation: Phung C. On, PharmD, BCPS, is assistant professor of pharmacy practice, Massachusetts College of Pharmacy and Health Sciences; and a clinical pharmacy specialist—transitions of care, Boston Health Care for the Homeless Program, both in Boston, MA.

Funding source: This activity is supported by an educational grant from Merck Sharp & Dohme Corp.

Author disclosure: Dr On has no relevant financial relationships with commercial interests to disclose.

Authorship information: Substantial contributions to concept and design; supervision; and drafting of the manuscript.

Address correspondence to: phung.on1@mcphs.edu

Medical writing and editorial support: Brittany Hoffmann-Eubanks, PharmD, MBA

REFERENCES

1. Smith JA, Woodcock A. Chronic cough. N Engl J Med. 2016;375(16):1544-1551. doi: 10.1056/NEJMcp1414215

2. Gibson P, Wang G, McGarvey L, Vertigan AE, Altman KW, Birring SS; CHEST Expert Cough Panel. Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest. 2016;149(1):27-44. doi: 10.1378/chest.15-1496

3. 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

4. Irwin RS, French CL, Chang AB, Altman KW; CHEST Expert Cough Panel. Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report. Chest. 2018;153(1):196-209. doi: 10.1016/j.chest.2017.10.016

5. Vertigan AE, Theodoros DG, Gibson PG, Winkworth AL. Efficacy of speech pathology management for chronic cough: a randomised placebo controlled trial of treatment efficacy. Thorax. 2006;61(12):1065-1069. doi: 10.1136/thx.2006.064337

6. Chamberlain S, Birring SS, Garrod R. Nonpharmacological interventions for refractory chronic cough patients: systematic review. Lung. 2014;192(1):75-85. doi: 10.1007/s00408 013-9508-y

7. Vertigan AE, Haines J, Slovarp L. An update on speech pathology management of chronic refractory cough. J Allergy Clin Immunol Pract. 2019;7(6):1756-1761. doi: 10.1016/j.jaip.2019.03.030

8. Pratter MR, Bartter T, Akers S, DuBois J. An algorithmic approach to chronic cough. Ann Intern Med. 1993;119(10):977-983. doi: 10.7326/0003-4819-119-10-199311150-00003

9. Kaplan AG. Chronic cough in adults: make the diagnosis and make a difference. Pulm Ther. 2019;5(1):11-21. doi: 10.1007/s41030-019-0089-7

10. Michaudet C, Malaty J. Chronic cough: evaluation and management. Am Fam Physician. 2017;96(9):575-580.

11. Dicpinigaitis PV. Angiotensin-converting enzyme inhibitor-induced cough: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(suppl 1):169s-173s. doi: 10.1378/chest.129.1_suppl.169S

12. Reddel HK, Bateman ED, Becker A, et al. A summary of the new GINA strategy: a roadmap to asthma control. Eur Respir J. 2015;46(3):622-639. doi: 10.1183/13993003.008532015

13. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2020. Accessed September 8, 2020. ginasthma.org

14. Global Initiative for Chronic Obstructive Lung Disease. 2020 GOLD Reports. Published 2020. Accessed June 22, 2020. goldcopd.org/gold-reports/

15. Kahrilas PJ, Altman KW, Chang AB, et al; CHEST Expert Cough Panel. Chronic cough due to gastroesophageal reflux in adults: CHEST guideline and expert panel report. Chest. 2016;150(6):1341-1360. doi: 10.1016/j.chest.2016.08.1458

16. Brightling CE. Cough due to asthma and nonasthmatic eosinophilic bronchitis. Lung. 2010;188(suppl 1):S13-S17. doi: 10.1007/s00408-009-9163-5

17. Dicpinigaitis PV, Morice AH, Birring SS, et al. Antitussive drugs--past, present, and future. Pharmacol Rev. 2014;66(2):468-512. doi: 10.1124/pr.111.005116

18. Dicpinigaitis PV. Clinical perspective - cough: an unmet need. Curr Opin Pharmacol. 2015;22:24-28. doi: 10.1016/j.coph.2015.03.001

19. Song WJ, Chung KF. Pharmacotherapeutic options for chronic refractory cough. Expert Opin Pharmacother. 2020;21(11):1345-1358. doi: 10.1080/14656566.2020.1751816

20. Smith J, Owen E, Earis J, Woodcock A. Effect of codeine on objective measurement of cough in chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2006;117(4):831-835. doi: 10.1016/j.jaci.2005.09.055

21. Morice AH, Menon MS, Mulrennan SA, et al. Opiate therapy in chronic cough. Am J Respir Crit Care Med. 2007;175(4):312-315. doi: 10.1164/rccm.200607-892OC

22. Neurontin. Prescribing information. Pfizer, Inc; 2020. Accessed September 9, 2020. labeling.pfizer.com/ShowLabeling.aspx?format=PDF&id=630

23. 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

24. Chung KF, McGarvey L, Mazzone SB. Chronic cough as a neuropathic disorder. Lancet Respir Med. 2013;1(5):414-422. doi: 10.1016/s2213-2600(13)70043-2

25. Halum SL, Sycamore DL, McRae BR. A new treatment option for laryngeal sensory neuropathy. Laryngoscope. 2009;119(9):1844-1847. doi: 10.1002/lary.20553

26. 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

27. Thour A, Marwaha R. Amitriptyline. In: StatPearls. StatPearls Publishing. Updated July 10, 2020. Accessed September 9, 2020. ncbi.nlm.nih.gov/books/NBK537225/

28. Bowen AJ, Nowacki AS, Contrera K, et al. Short- and long-term effects of neuromodulators for unexplained chronic cough. Otolaryngol Head Neck Surg. 2018;159(3):508-515. doi: 10.1177/0194599818768517

29. Jeyakumar A, Brickman TM, Haben M. Effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough resulting from postviral vagal neuropathy. Laryngoscope. 2006;116(12):2108-2112. doi: 10.1097/01.mlg.0000244377.60334.e3

30. Mazzone SB, Chung KF, McGarvey L. The heterogeneity of chronic cough: a case for endotypes of cough hypersensitivity. Lancet Respir Med. 2018;6(8):636-646. doi: 10.1016/s2213-2600(18)30150-4

31. Canning BJ, Chang AB, Bolser DC, Smith JA, Mazzone SB, McGarvey L. Anatomy and neurophysiology of cough: CHEST guideline and expert panel report. Chest. 2014;146(6):1633-1648. doi: 10.1378/chest.14-1481

32. 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

33. Lee LY, Ni D, Hayes D Jr, Lin RL. TRPV1 as a cough sensor and its temperature-sensitive properties. Pulm Pharmacol Ther. 2011;24(3):280-285. doi: 10.1016/j.pupt.2010.12.003

34. Belvisi MG, Birrell MA, Wortley MA, et al. XEN-D0501, a novel transient receptor potential vanilloid 1 antagonist, does not reduce cough in patients with refractory cough. Am J Respir Crit Care Med. 2017;196(10):1255-1263. doi: 10.1164/rccm.201704-0769OC

35. Khalid S, Murdoch R, Newlands A, et al. Transient receptor potential vanilloid 1 (TRPV1) antagonism in patients with refractory chronic cough: a double-blind randomized controlled trial. J Allergy Clin Immunol. 2014;134(1):56-62. doi: 10.1016/j.jaci.2014.01.038

36. Birrell MA, Belvisi MG, Grace M, et al. TRPA1 agonists evoke coughing in guinea pig and human volunteers. Am J Respir Crit Care Med. 2009;180(11):1042-1047. doi: 10.1164/rccm.200905-0665OC

37. Hilton E, Marsden P, Thurston A, Kennedy S, Decalmer S, Smith JA. Clinical features of the urge-to-cough in patients with chronic cough. Respir Med. 2015;109(6):701-707. doi: 10.1016/j.rmed.2015.03.011

38. Vertigan AE, Gibson PG. Chronic refractory cough as a sensory neuropathy: evidence from a reinterpretation of cough triggers. J Voice. 2011;25(5):596-601. doi: 10.1016/j.jvoice.2010.07.009

39. Won HK, Kang SY, Kang Y, et al. Cough-related laryngeal sensations and triggers in adults with chronic cough: symptom profile and impact. Allergy Asthma Immunol Res. 2019;11(5):622-631. doi: 10.4168/aair.2019.11.5.622

40. Morice AH. TRPA1 receptors in chronic cough. Pulm Pharmacol Ther. 2017;47:42-44.
doi: 10.1016/j.pupt.2017.05.004

41. Muccino D, Green S. Update on the clinical development of gefapixant, a P2X3 receptor antagonist for the treatment of refractory chronic cough. Pulm Pharmacol Ther. 2019;56:75-78. doi: 10.1016/j.pupt.2019.03.006

42. Abdulqawi R, Dockry R, Holt K, et al. P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2015;385(9974):1198-1205. doi: 10.1016/s0140-6736(14)61255-1

43. Smith JA, Kitt MM, Butera P, et al. Gefapixant in two randomised dose-escalation studies in chronic cough. Eur Respir J. 2020;55(3):1901615. doi: 10.1183/13993003.01615-2019

44. Smith JA, Kitt MM, Morice AH, et al; Protocol 012 Investigators. Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group, phase 2b trial. Lancet Respir Med. 2020;8(8):775-785. doi: 10.1016/s2213-2600(19)30471-0

45. Phase 3 Study of Gefapixant (MK-7264) in Adult Participants With Chronic Cough (MK-7264-027). ClinicalTrials.gov identifier: NCT03449134. Updated August 25, 2020. Accessed September 9, 2020. clinicaltrials.gov/ct2/show/NCT03449134

46. A Study of Gefapixant (MK-7264) in Adult Participants With Chronic Cough (MK-7264-030). ClinicalTrials.gov identifier: NCT03449147. Updated August 26, 2020. Accessed September 9, 2020. clinicaltrials.gov/ct2/show/NCT03449147

47. Merck's gefapixant (45 mg twice daily) significantly decreased cough frequency compared to placebo at week 12 and 24 in patients with refractory or unexplained chronic cough. Business Wire; September 8, 2020. Accessed September 17, 2020. merck.com/news/mercks-gefapixant-45-mg-twice-daily-significantly-decreased-cough-frequency-compared-to-placebo-at-week-12-and-24-in-patients-with-refractory-or-unexplained-chronic-cough/

48. Repeat Doses of BAY 1817080 in Healthy Males & Proof of Concept in Chronic Cough Patients. ClinicalTrials.gov identifier: NCT03310645. Updated July 18, 2019. Accessed September 9, 2020. clinicaltrials.gov/ct2/show/NCT03310645

49. A Dose Escalation Study of BLU-5937 in Unexplained or Refractory Chronic Cough (RELIEF). ClinicalTrials.gov identifier: NCT03979638. Updated September 2, 2020. Accessed September 9, 2020. clinicaltrials.gov/ct2/show/NCT03979638

50. Evaluation of S-600918 in Adults With Refractory Chronic Cough. ClinicalTrials.gov identifier: NCT04110054. Updated August 7, 2020. Accessed September 9, 2020. clinicaltrials.gov/ct2/show/NCT04110054

51. Morice AH, Smith J, McGarvey L, et al. Safety and efficacy of BAY 1817080, a P2X3 receptor antagonist, in patients with refractory chronic cough (RCC). Am J Respir Crit Care Med. 2020;201(A7648). Accessed September 9, 2020. atsjournals.org/doi/abs/10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A7648

52. BELLUS Health announces completion of dosing in phase 2 RELIEF trial with BLU-5937 for the treatment of refractory chronic cough. News release. Business Wire; April 6, 2020. Accessed June 22, 2020. businesswire.com/news/home/20200406005773/en

53. Ujiie Y, Sekizawa K, Aikawa T, Sasaki H. Evidence for substance P as an endogenous substance causing cough in guinea pigs. Am Rev Respir Dis. 1993;148(6 Pt 1):1628-1632. doi: 10.1164/ajrccm/148.6_Pt_1.1628

54. Morice AH, Lowry R, Brown MJ, Higenbottam T. Angiotensin-converting enzyme and the cough reflex. Lancet. 1987;2(8568):1116-1118. doi: 10.1016/s0140-6736(87)91547-9

55. Katsumata U, Sekizawa K, Inoue H, Sasaki H, Takishima T. Inhibitory actions of procaterol, a beta-2 stimulant, on substance P-induced cough in normal subjects during upper respiratory tract infection. Tohoku J Exp Med. 1989;158(1):105-106. doi: 10.1620/tjem.158.105

56. Hope-Gill BD, Hilldrup S, Davies C, Newton RP, Harrison NK. A study of the cough reflex in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2003;168(8):995-1002. doi: 10.1164/rccm.200304-597OC

57. Lim KG, Rank MA, Kita H, Patel A, Moore E. Neuropeptide levels in nasal secretions from patients with and without chronic cough. Ann Allergy Asthma Immunol. 2011;107(4):360-363. doi: 10.1016/j.anai.2011.07.010

58. Bae YJ, Moon KA, Kim TB, et al. The role of nitrosative stress in the pathogenesis of unexplained chronic cough with cough hypersensitivity. Am J Rhinol Allergy. 2012;26(1):e10-e14. doi: 10.2500/ajra.2012.26.3730

59. Patterson RN, Johnston BT, Ardill JE, Heaney LG, McGarvey LP. Increased tachykinin levels
in induced sputum from asthmatic and cough patients with acid reflux. Thorax. 2007;62(6):491-495. doi: 10.1136/thx.2006.063982

60. Otsuka K, Niimi A, Matsumoto H, et al. Plasma substance P levels in patients with persistent cough. Respiration. 2011;82(5):431-438. doi: 10.1159/000330419

61. Harle A, Blackhail F, Molassiotis A, et al. Neurokinin-1 receptor antagonism for the treatment of cough in lung cancer. Eur Respir J. 2016;48:PA3547.

62. Di Fabio R, Alvaro G, Braggio S, et al. Identification, biological characterization and pharmacophoric analysis of a new potent and selective NK1 receptor antagonist clinical candidate. Bioorg Med Chem. 2013;21(21):6264-6273. doi: 10.1016/j.bmc.2013.09.001

63. Smith J, Allman D, Badri H, et al. The neurokinin-1 receptor antagonist orvepitant is a novel antitussive therapy for chronic refractory cough: results from a phase 2 pilot study (VOLCANO-1). Chest. 2020;157(1):111-118. doi: 10.1016/j.chest.2019.08.001

64. A Dose-ranging Study of Orvepitant in Patients With Chronic Refractory Cough. ClinicalTrials.gov identifier: NCT02993822. Updated March 13, 2020. Accessed September 9, 2020. clinicaltrials.gov/ct2/show/NCT02993822

65. Smith J, Ballantyne E, Kerr M, et al. The neurokinin-1 receptor antagonist orvepitant improves chronic cough symptoms: results from a phase 2b trial. Published 2019. Accessed June 22, 2020. nerretherapeutics.com/wp-content/uploads/2019/09/ers-2019-poster.pdf

66. NeRRe Therapeutics announces positive findings from phase 2b study with orvepitant in chronic cough. News release. NeRRe Therapeutics; June 7, 2019. Accessed June 22, 2020. nerretherapeutics.com/nerre-therapeutics-announces-positive-findings-from-phase-2b-study-with-orvepitant-in-chronic-cough

Understanding the Foundations of Chronic Cough | AJMC - AJMC.com Managed Markets Network

Posted: 15 Oct 2020 08:05 AM PDT

Am J Manag Care. 2020;26:S232-S238. https://doi.org/10.37765/ajmc.2020.88514

Introduction

Cough continues to be one of the most common reasons that adults consult medical doctors in the United States, including both primary care physicians and specialists within pulmonology, allergy/immunology, otolaryngology, and gastroenterology.^1,2 Within pulmonology clinics, up to 40% of patient visits are to evaluate chronic cough.³ Coughing is an essential reflex that is considered innate; however, in some patients, coughing can become a chronic, debilitating condition leading to negative outcomes. At its most extreme presentation, chronic cough can impact quality of life (QOL) and lead to depression, anxiety, urinary incontinence, and dysphonia.⁴ The impact of chronic cough on a patient's QOL is frequently underappreciated by healthcare professionals.

The impact of chronic cough is not isolated to the United States, with the global prevalence recently estimated to be close to 10% in a meta-analysis conducted by Song et al.⁵ Despite how frequently patients present with chronic cough, the exact underlying etiology can be challenging to diagnose, leading to multiple referrals and repeat office visits, along with extensive and often expensive testing. Results of a recent study published by Koskela et al found that 5.5% of patients with chronic cough underwent at least 3 consultations in the preceding 12 months.⁶ These patients accounted for approximately 50% of all physician consultations for cough, leading to a disproportionate usage of care.⁶ When evaluating a patient with chronic cough, physicians often repeat many unnecessary tests, are unaware of formal definitions of types of cough, and routinely stray from established professional society guidelines, which can complicate both current and future management.⁶

It is critical to understand the basics of chronic cough to accurately and appropriately make the underlying diagnosis as well as to identify effective treatments, especially as medications with new mechanisms of action are being increasingly developed. This review will focus on the definitions and epidemiology of chronic cough and the underlying pathophysiology that contributes to several etiologies and its impact on managed care in adult patients.

Cough: Definitions

There is often confusion on how to define chronic cough, especially as many clinical trials have used varying definitions over the years. In a recent meta-analysis, Song et al reported 19 different definitions of chronic cough among 90 studies.⁵ However, both the American College of Chest Physicians (ACCP, or CHEST) and the European Respiratory Society define chronic cough as cough of greater than 8 weeks' duration.^7,8 Therefore, when evaluating a patient with chronic cough, it is critical to stay consistent and follow guideline-established definitions. As new treatments for chronic cough are being developed, it is also important to be cognizant of these definitions as they will be routinely used in protocols and eventual prescribing information.

Based on the 2006 ACCP guidelines published by Irwin et al, cough can be defined based on duration of symptoms: (1) acute, less than 3 weeks; (2) subacute, 3 to 8 weeks; and (3) chronic, longer than 8 weeks.⁷ Therefore, the initial first step in evaluating someone for cough is to determine the duration, as this will help to narrow the differential diagnosis. In 2018, Irwin et al conducted a systematic review on the usefulness of the 2006 CHEST definitions in clinical studies and published their findings along with an updated guideline and expert panel report in Chest, further reviewing the critical nature of this determination and definition.⁹ Acute cough was most likely to be caused by infectious etiologies, especially with underlying viral causes; exacerbations of chronic medical conditions, such as asthma and chronic obstructive pulmonary disease (COPD); pneumonia; and environmental exposures.^7,9 The most common causes of subacute cough included postinfectious cough, exacerbations of underlying conditions (eg, asthma, COPD), and upper airway cough syndrome (UACS). The predominant causes of chronic cough were found to be UACS, asthma, gastroesophageal reflux disease (GERD), and nonasthmatic eosinophilic bronchitis (NAEB), as well as a combination of these causes. Although considered a cause of chronic cough, allergies are typically considered a component within UACS and asthma. It is important to note that many of the studies included in this review are heterogeneous and associated with a degree of bias. The authors concluded that CHEST's 2006 definitions appeared useful when reviewing the literature.^7,9 A more detailed review of etiologies of chronic cough will be covered in later sections.

Another subtype of chronic cough defined in the literature includes refractory chronic cough (RCC). RCC is defined as a persistent cough despite thorough investigation and treatment according to published practice guidelines.^8,10,11 RCC has also been used interchangeably with chronic refractory cough (CRC) and unexplained chronic cough (UCC). The key component of RCC is the requirement of failure of guideline-based modalities, which may not always be followed in real-world settings. Therefore, it is paramount to obtain a thorough medication history from the patient as well as prior records from referring physicians. It has been estimated that RCC can be seen in 20% to 46% of patients presenting to a specialist cough clinic.¹¹

Epidemiology of Chronic Cough

As noted, the global prevalence of chronic cough among 90 studies was reported as 9.6% (95% CI, 7.6%-11.7%) by Song et al.⁵ This meta-analysis was limited by varying definitions of chronic cough and had significant heterogeneity between studies but indicates the global burden that chronic cough has on the healthcare system. Chronic cough was found to be significantly more common in Europe and America compared with Africa and Asia.⁵ There are previously published data to support that there is no significant ethnic difference in cough reflex sensitivity among Caucasian, Indian, or Chinese patients using laboratory-measured, capsaicin-induced cough reflex sensitivity.¹² The regional variations in chronic cough observed in Song et al are most likely due to additional factors outside of ethnicity and may include environmental factors (eg, urbanization) as well as variations in diet and obesity.⁵

In addition to these regional variations, there is also a clear impact of gender on chronic cough. In an evaluation of 10,032 patients with chronic cough from 11 cough clinics worldwide, Morice et al found that approximately two-thirds were women.¹³ This female predominance was observed in each country studied, except for China, but was not as prominent in smaller cough clinics. The explanation for this gender difference has been postulated to be secondary to differences in the respiratory tract anatomy and increased sensitivity to the cough reflex in women. Within the same study, Morice et al evaluated the neural processing associated with cough in 10 healthy men and women to further investigate this difference.¹³ In addition to having a lower maximum tolerable dose of inhaled capsaicin compared with men, the healthy women also had significantly greater activation of the somatosensory cortex as measured on magnetic resonance imaging of the brain despite this lower stimulus. The somatosensory cortex has been established to receive airway sensory inputs, and its respective activation is closely correlated with a patient's perceived urge to cough.

This increased somatosensory response in healthy women may be similar to what is seen with lower cutaneous and visceral pain thresholds observed in chronic pain syndrome.¹³ Future studies can further aim to characterize this neural processing link specifically in patients with chronic cough. The heightened sensitivity of cough in women, specifically women of childbearing age, may have an evolutionary component by preventing aspiration in women who could potentially become pregnant.¹³ The specific hormonal pattern is most likely not the contributing factor in these clinical scenarios, based on the prominence of cough in postmenopausal women.¹³ In addition, the inherent, multifactorial pathophysiology underlying these gender differences can also be provoked by certain medications, with prior studies showing that women are approximately twice as likely to develop cough while taking angiotensin-converting enzyme (ACE) inhibitors.¹⁴

Patients with chronic cough typically present later in life. Morice et al reported similar findings to prior studies, with the most common age for presentation being age 50 to 69 years.¹³ More than two-thirds of the patients were 50 years and older, with 20% aged 70 years and older, which somewhat mirrors the prevalence of other chronic conditions that can lead to chronic cough, such as GERD, but not asthma.¹³ Although the population evaluated was quite diverse, the similarities seen between the clinics indicated an underlying link that continues to be heavily researched: cough hypersensitivity syndrome (CHS).13 CHS could potentially link these patients through a proposed heightened response of afferent nociceptors within the upper airways of patients with chronic cough.¹⁵ This, as well as additional pathophysiologic mechanisms to explain chronic cough, will be reviewed in the following paragraphs.

Pathophysiology of Cough

As with any chronic condition, the pathophysiology associated with chronic cough is multifactorial and complex. It is also important to emphasize the underlying pathophysiologic differences between men and women that contribute to chronic cough. This review will focus on some basic pathophysiology while also covering some of the newer pathways that have become of increased interest in therapeutics; a complete review of all included pathways is beyond the scope of this review.

At its most basic premise, cough serves as a defense mechanism by helping to prevent aspiration and enhancing airway clearance.⁸ At its most extreme, loss of this reflex can lead to aspiration, infections, and nutritional deterioration, as is observed in patients with neurological deficits.⁸

Cough receptors can respond to either chemical or mechanical stimuli and are located both within and outside (eg, ear canals, eardrums, distalesophagus) the respiratory tract.¹⁶ Chemical receptors include transient receptor potential vanilloid type 1 (TRPV1) and transient receptor potential ankyrin type 1 (TRPA1).^16-18 Inhalation of capsaicin has been shown to induce cough via activation of TRPV1 receptors.¹⁸ TRPV1 receptors are not only activated by vanilloids such as capsaicin but also via other stimuli, including acidity and inflammatory mediators (eg, prostaglandins, bradykinin, and leukotrienes).¹⁸ Similarly, activating TRPA1 receptors can produce cough, with stimuli including cold temperatures, environmental irritants, and inflammatory mediators.¹⁷ P2X3 receptors are found on airway vagal afferent nerves, which, when stimulated, can lead to increased sensitivity to multiple stimuli and chronic cough.^19,20

Once the receptors are stimulated, the signal is carried to the brain for central processing and eventually leads to the actual motor act of a cough. Cough is a 3-phase expulsive motor act characterized by an inspiratory effort (inspiratory phase), followed by a forced expiratory effort against a closed glottis (compressive phase), and finally the expulsive phase, where the glottis opens and there is rapid expiratory airflow.²¹ This motor response is preceded by a complex interaction of sensory and chemical triggers that help form the cough reflex arc. This reflex arc is initially stimulated by the irritation of cough receptors found in the lining of the upper and lower respiratory tracts. The afferent pathways have cough receptors innervated by the vagus, glossopharyngeal, and trigeminal nerves.²² The highest concentration of cough receptors is found in the larynx, carina, and bifurcation of larger bronchi. These receptors respond to a multitude of stimuli, both intrinsic (eg, histamine, bradykinin, prostaglandins) and extrinsic (eg, smoke, environmental allergens). The afferent nerves then transmit signals to the cough center of the brain that is located in the nucleus tractus solitarius of the medulla. Impulses are then subsequently sent via the vagus nerve to the spinal motor and phrenic nerves that control the diaphragm, intercostal muscles, pelvic floor muscles, and abdominal wall that are responsible for generation of the cough.²²

A recently proposed concept developed to provide a mechanistic basis for RCC is that of CHS, which involves vagal nerve hypersensitivity enhancing the sensitivity of the cough reflex, thus rendering individuals with cough induced by certain ubiquitous triggers (cold air, strong smells, prolonged talking, laughing) that do not induce cough in the vast majority of the population.^8,15,23 In 2011, Morice et al used the Hull Airway Reflux Questionnaire (HARQ) to evaluate both normal volunteers and patients with chronic cough. The authors concluded that patients with chronic cough could have an overall increased afferent hypersensitivity that predisposes them to chronic cough.¹⁵ The authors also proposed that gaseous nonacid reflux not detectable by testing at that time was a major driver of CHS, among other low levels of thermal, mechanical, or chemical exposures.^15,23 This underlying hypersensitivity could also be explained by an underlying neuropathic condition that includes nerve damage as well as increased neuronal excitability via upregulated TRP nociceptors.²³ Upregulation of both central and peripheral components of neuronal mechanisms contribute to CHS as well.²³ The hypersensitivity seen in CHS is also different from the methacholine bronchial responsiveness in entities such as asthma, which reflects its afferent hypersensitivity to many different stimuli.²³ The entire range of receptors involved in CHS has not yet been fully elucidated, but TRPV1 and TRPA1 have been implicated. In addition, there may be a component of increased T2 inflammation in the airways also contributing to CHS.^8,23 Patients with CHS may experience a dry, chronic cough with additional symptoms including persistent tickling or irritating sensation in the chest or throat, hoarse voice, dysphonia, and the perception of laryngeal obstruction that is provoked by low levels of environmental irritants.²³

Etiology

To identify the underlying etiology of a patient's chronic cough, a thorough history and physical examination must be performed. Cough duration, triggers, and preceding illnesses should be elicited. A detailed medical history should be obtained including both pulmonary and extrapulmonary conditions, such as GERD, hypertension, allergies, and immunological conditions. Surgical history is pertinent, especially within the cardiac, pulmonary, gastrointestinal, and otolaryngological organ systems. An extensive social history including recent travel, country of origin, potential sick contacts, occupational and environmental exposures, and smoking historyshould be completed.^8,9 Interestingly, a majority of patients with chronic cough are either lifetime nonsmokers or former smokers.²⁴ After evaluating 1000 patients with chronic cough at a specialized cough center, it was found that 2.7% being evaluated were active smokers and 27% were former smokers.²⁴ A detailed medication reconciliation should be performed, with an emphasis on inquiring about medications specifically used for GERD, allergies, and hypertension (such as ACE inhibitors). In addition to this reconciliation, patients should be asked what medications have been tried for cough and if any have provided relief.

The review of systems should include both pulmonary and extrapulmonary symptoms. Based on the 2018 CHEST guidelines, there is an emphasis on specifically evaluating for hemoptysis, which is considered a red-flag symptom that should prompt a more expedited workup for infectious causes, such as tuberculosis as well as malignancy.⁹ Physicians should also make a concerted effort to decide on which validated cough severity tool will be used throughout their evaluation in order to stay consistent. Options include a simple cough score from 0 to 10, visual analog scale, cough QOL measures (eg, Leicester Cough Questionnaire [LCQ], Cough Quality of Life Questionnaire [CQLQ]), and additional, validated questionnaires (eg, HARQ).⁸

The CHEST 2018 guidelines recommend a routine follow-up 4 to 6 weeks after the initial evaluation.⁹ If patients have undergone prior evaluations by specialists, it is critical to obtain these medical records, including laboratory values, diagnostic reports, and treatments prescribed. After the history is completed, a thorough physical exam should be performed, with special attention to the respiratory,otolaryngological, cardiac, and gastrointestinal systems. An extensive review of all diagnostic tests to perform will not be the focus of this review; instead, the focus will be on the 3 most common causes of chronic cough, including UACS, asthma, and GERD.⁸ A patient's prior evaluations must be reviewed in order to determine if these etiologies have been accurately assessed, diagnosed, and treated. Many patients may not have been completely evaluated for these conditions yet diagnosed based on their response (or lack thereof) to certain medications, which is a critical part of the history to ascertain. There are a series of other etiologies of chronic cough; however, these are beyond the scope of this review. Malignancy, infections, foreign body inhalation, and medications should always be kept on the differential diagnosis.⁸

UACS

UACS includes signs and symptoms referred to by similar names including postnasal drip syndrome, rhinitis, and rhinosinusitis.⁸ Patients can develop these symptoms secondary to allergies and infectious causes (eg, sinusitis, acute nasopharyngitis), which subsequently increase secretions in the upper airway and lead to stimulation of cough receptors within the laryngeal mucosa to stimulate a cough.⁸ Patients will frequently report increased nasal discharge, a sensation of liquid dripping into the back of the throat, and frequent throat clearing. As there are no formal diagnostic criteria, patients with suspected UACS may be prescribed and respond to first-generation oral antihistamines and/or nasal anticholinergics and steroids.

Asthma

Asthma, along with NAEB, is a clinical diagnosis with no clear-cut, absolute diagnostic test available to either rule asthma in or out as the cause of the patient's chronic cough.⁸ Asthma is mediated by eosinophilic inflammation, which can be challenging to objectively measure in real-world settings where testing, such as sputum eosinophilia and exhaled nitric oxide (NO), are not routinely available, time consuming, costly, not patient-friendly, and require expert evaluation.8 A complete blood count (CBC) with differential can be evaluated for eosinophilia; however, this is not a specific test and can vary based on season and time of day.⁸ Although nonspecific, an eosinophil count greater than 0.27 to 0.3 cells/μL may be representative of eosinophilic airway inflammation.^8,25

Within asthma, 3 subtypes of cough have been identified. Classic asthma is associated with bronchial hyperresponsiveness and airflow variability for which spirometry is indicated.⁸ Cough-variant asthma represents an entity where cough is the primary symptom and wheezing and dyspnea are not. In this clinical scenario, treatment with a combination of β-agonist bronchodilators, inhaled corticosteroids, and/or leukotriene receptor antagonists (LTRAs) can improve coughing.⁸ There are mixed opinions on whether performing bronchial provocation testing is indicated in these clinical scenarios. Eosinophilic bronchitis without bronchoconstriction or hyperresponsiveness, also termed NAEB, is the third and final type of asthmatic cough.⁸ A detailed review of medications used in chronic cough due to asthma will be the focus of future reviews; however, in general, the anti-inflammatory medications used in treating asthma include inhaled or oral steroids.

Reflux

Although established as a leading cause of chronic cough in the literature, there is some debate over the true contribution of reflux to chronic cough.⁸ When evaluating a patient for reflux, it is important to inquire about both classic and atypical reflux symptoms, including chest pain and dysphagia.⁸ A patient's diet is also important to evaluate as well as how it correlates with their reflux and cough. Esophageal motility disorders may play a more integral part of reflux-mediated chronic cough than previously realized, especially in the setting of esophagopharyngeal reflux.⁸ In evaluation of reflux as a cause of chronic cough, many patients will undergo extensive and costly testing, including upper endoscopy, high resolution manometry, barium swallows, and pH monitoring. Similar to asthma, many of these tests require advanced facilities with gastroenterologists who have extensive experience evaluating the results.

Reflux likely contributes to chronic cough via several mechanisms, including aspiration of gastric contents leading to a proinflammatory reaction with mucus hypersecretion in the respiratory tract.²⁶ In addition, cough receptors in the upper respiratory tract can be stimulated by both acid and nonacid reflux.²⁷ Laryngopharyngeal reflux (LPR) can be considered a variant of GERD and occurs when gastric contents irritate the laryngopharynx.²⁸ Patients with LPR may not report classic GERD symptoms but rather experience dysphagia, frequent throat clearing without mucus, and dysphonia.

Results of a systematic review of 9 randomized controlled trials conducted by Kahrilas et al found modest benefit in using proton pump inhibitors (PPIs) in patients with acid reflux but no significant benefit over placebo in those patients without reflux.²⁷ Despite these findings, both acid and nonacid reflux have been implicated in chronic cough.²⁹ An underappreciated cause of chronic cough is nonacid reflux. Indeed, a trial of a combination of antacid and prokinetic/promotility therapy may be required to evaluate the role of nonacid reflux in a patient's chronic cough.⁸

A subgroup of patients with reflux-associated chronic cough are those with obesity. There is evidence in the literature that chronic cough is more common in patients who are obese, yet this link has not yet been fully elucidated.³⁰ Recently, a group led by Descazeaux et al noted a higher prevalence of GERD in obese versus nonobese patients with chronic cough (47.3% vs 34.6%, P = .0188) as well as obstructive sleep apnea (OSA) (9.8% vs 3.1%, P = .0080).31 There were no statistical differences in prevalence of asthma and UACS between the groups. Patients with suspected GERD-induced cough underwent at least 1 of the following tests: endoscopy, manometry, and/or pH monitoring. There was no statistical difference between the obese and nonobese patients with respect to normal and abnormal gastrointestinal testing. PPI therapy was also found to be more successful in obese patients compared with nonobese patients (32.5% vs 17.0%, P <.05); however, there was a trend toward an increased proportion of patients responding to PPI as body mass index increased, yet no statistical difference was found. In addition, obese patients treated with PPIs were less likely to report refractory cough at 12 months (22.3% vs 34.1%, P <.05). The authors postulated that the underlying dysregulation in the neural and central processing associated with CHS may contribute to the 22.3% and will undoubtedly be of research interest in the future. This study reinforces the importance of assessing a patient with chronic cough for OSA and obesity as possible contributors. In addition to obesity itself lending to chronic cough, its downstream consequences can also contribute, including worsening hiatal hernia and increasing intragastric pressure and hypotensive lower esophageal sphincter.³¹ The authors also hypothesized that OSA worsens the main triggers of chronic cough, such as UACS, asthma, and GERD, and/or increases overall airway inflammation.

To further expand on the link between OSA and chronic cough, Sundar et al evaluated the impact of continuous positive airway pressure (CPAP) on patients with OSA who also had unexplained chronic cough.³² Patients with OSA and chronic cough treated with CPAP for 6 weeks had statistically significant improvements in their LCQ compared with sham CPAP. There were no differences found in the exhaled breath condensate markers of airway inflammation. Similar to results from Descazeaux et al, the authors proposed that OSA can lead to increased airway inflammation, laryngeal hypersensitivity, and rapid changes in oxygenation, all of which can lead to chronic cough. Although OSA is not within the top 3 etiologies of chronic cough, it is an important medical condition that may be concurrently present in certain patients with more classic etiologies. Therefore, CPAP may represent an adjunctive therapy in this population subset.

The role of PPI treatment in chronic cough will be covered more thoroughly in later sections; however, it is important to address all potential adverse effects (AEs) with the patient and thoroughly document this discussion in the patient's chart. A full review of these AEs is beyond the scope of this article, but they are increasingly important to discuss with patients. In addition, when reviewing a patient's medications, it is also crucial to evaluate whether or not the PPI is indicated and/or working for the patient's chronic cough or other indications; if not, consideration should be given to slowly tapering the PPI off to avoid unnecessary polypharmacy.

Healthcare and Socioeconomic Burden

As previously discussed, chronic cough represents one of the most common reasons for visits to both primary care providers and specialists, creating substantial socioeconomic impact as well as contributing to global healthcare burden. In the United States alone, there were 21 million outpatient consultations for cough in 2015 per the Centers for Disease Control and Prevention.³³ The impact of chronic cough on the healthcare system is multifactorial. Patients are often referred to several specialists and occasionally obtain multiple opinions from physicians within the same specialty. This can lead to unnecessary repeat testing, increased costs to both payers and patients, less time for patients with other symptoms, and exposure to polypharmacy as well as possible AEs of these medications.⁶ Because there can be potentially life-threatening etiologies to explain the chronic cough, it is also not a symptom that should be easily dismissed.

To try to further understand this healthcare burden, a research group led by Koskela et al performed a cross-sectional email survey in Finland to try to determine the factors associated with repetitive doctor consultations for chronic cough.⁶ This was defined as at least 3 doctor consultations in the previous 12 months. Of 3695 patients who responded, 5.5% reported repetitive consultations, accounting for 50.4% of doctor consultations for cough. Repetitive consultations were most likely secondary to the presence of asthma and chronic rhinosinusitis. In addition, depression, smoking, presence of comorbidities, and low cough-related QOL scores were also associated with repetitive consultations. High medical costs associated with chronic cough have been traditionally attributed to acute care utilization, such as emergency department visits and inpatient stays; however, results of this study highlight the increasing burden of chronic cough on costs associated with outpatient care usage.

The impact of chronic cough on a patient's QOL is often overlooked or underappreciated by healthcare practitioners.^23,34 Patients with chronic cough can develop anxiety and depression, which may lead to significant alterations in their social and family lives.³⁴ This is based on their symptoms being considered highly disruptive to the affected patient as well as their surrounding environment.⁸ Aside from the cough itself, this may lead to increased physician visits for insomnia, speech difficulties, anxiety, urinary incontinence, and depression.³⁵ In one study, 53% of patients undergoing evaluation for chronic cough were found to score positive for depression.³⁶ Improvement in cough score correlated with improvement in depression scores as well.

More physician visits may lead to additional testing, referrals, missed work or school, and more out-of-pocket expenses. Despite these additional visits, certain symptoms may be overlooked, including urinary incontinence experienced by women with chronic cough.⁸ This symptom may be embarrassing to many women, and it can lead to a delay in diagnosis as well as development of potential complications if care is delayed.^8,35 This is a key symptom to review during a patient's evaluation. There are multiple cough-specific QOL tools, including the LCQ or CQLQ, that are frequently used in clinical studies, but may be challenging to use on a daily basis in real-world settings.^37,38 Therefore, it may be more practical to use a simpler score, such as assessing the severity and impact on QOL using a "cough score" from 0 to 10 or a 100-unit visual analog scale.⁸

^Conclusions

Chronic cough will undoubtedly continue to have a profound impact on patients, physicians, and the healthcare system. A thorough evaluation with attention to evidence-based guidelines is critical to improving patient outcomes. Although there are similarities among patients with chronic cough as reviewed in epidemiology, pathophysiology, and etiology, each patient should be treated as an individual. The 3 most common etiologies, UACS, asthma, and GERD, must be systematically evaluated in all patients. Physicians must be cognizant of the predominance of women presenting with chronic cough and the subtleties associated with potential extrapulmonary symptoms. The foundations of chronic cough covered in this review can assist in both current evaluations of patients with chronic cough as well as prepare for future treatments.

Author affiliation: Peter Dicpinigaitis, MD, is a professor of medicine, Division of Critical Care Medicine at Albert Einstein College of Medicine in Bronx, NY.

Funding source: This activity is supported by an educational grant from Merck Sharp & Dohme Corp.

Author disclosure: Dr Dicpinigaitis has the following relevant financial relationships with commercial interests to disclose:

Consultancies or paid advisory boards—Bayer HealthCare Pharmaceuticals, Bellus Health Inc, Merck Sharp & Dohme Corp, Shionogi

Authorship information: Substantial contributions to the concept and design; drafting of the manuscript; provision of study materials or patients; and critical revisions of the manuscript for important intellectual content.

Address correspondence to: pdicpin@gmail.com

Medical writing and editorial support: C. Andrew Kistler, MD, PharmD

REFERENCES

1. Cherry DK, Hing E, Woodwell DA, Rechtsteiner EA. National Ambulatory Medical Care Survey: 2006 summary. Natl Health Stat Report. 2008;(3):1-39.

2. Finley CR, Chan DS, Garrison S, et al. What are the most common conditions in primary care? systematic review. Can Fam Physician. 2018;64(11):832-840.

3. 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

4. Chamberlain SA, Garrod R, Douiri A, et al. The impact of chronic cough: a cross-sectional European survey. Lung. 2015;193(3):401-408. doi: 10.1007/s00408-015-9701-2

5. Song WJ, Chang YS, Faruqi S, et al. The global epidemiology of chronic cough in adults: a systematic review and meta-analysis. Eur Resp J. 2015;45(5):1479-1481.doi: 10.1183/09031936.00218714

6. Koskela HO, Latti AM, Pekkanen J. Risk factors for repetitive doctor's consultations due to cough: a cross-sectional study in a Finnish employed population. BMJ Open. 2019;9(6):e030945. doi: 10.1136/bmjopen-2019-030945

7. Irwin RS, Baumann MH, Bolser DC, et al. Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(1 suppl):1S-23S. doi: 10.1378/chest.129.1_suppl.1S

8. 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

9. Irwin RS, French CL, Chang AB, Altman KW; CHEST Expert Cough Panel. Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report. Chest. 2018;153(1):196-209. doi: 10.1016/j.chest.2017.10.016

10. Gibson P, Wang G, McGarvey L, Vertigan AE, Altman K, Birring SS; CHEST Expert Cough Panel. Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest. 2016;149(1):27-44. doi: 10.1378/chest.15-1496

11. Gibson PG, Vertigan AE. Management of chronic refractory cough. BMJ. 2015;351:h5590. doi: 10.1136/bmj.h5590

12. Dicpinigaitis PV, Allusson VR, Baldanti A, Nalamati JR. Ethnic and gender differences in cough reflex sensitivity. Respiration. 2001;68(5):480-482. doi: 10.1159/000050554

13. Morice AH, Jakes AD, Faruqi S, et al; Chronic Cough Registry. A worldwide survey of chronic cough: a manifestation of enhanced somatosensory response. Eur Respir J. 2014;44(5):1149-1155. doi: 10.1183/09031936.00217813

14. Yeo WW, Foster G, Ramsay LE. Prevalence of persistent cough during long-term enalapril treatment: controlled study versus nifedipine. Q J Med. 1991;80(293):763-770.

15. Morice AH, Faruqi S, Wright CE, Thompson R, Bland JM. Cough hypersensitivity syndrome: a distinct clinical entity. Lung. 2011;189(1):73-79. doi: 10.1007/s00408-010-9272-1

16. Canning BJ, Chang AB, Bolser DC, Smith JA, Mazzone SB, McGarvey L, CHEST Expert Cough Panel. Anatomy and neurophysiology of cough: CHEST guideline and expert panel report. Chest. 2014;146(6):1633-1648. doi: 10.1378/chest.14-1481

17. Belvisi MG, Dubuis E, Birrell MA. Transient receptor potential A1 channels: insights into cough and airway inflammatory disease. Chest. 2011;140(4):1040-1047. doi: 10.1378/chest.10-3327

18. Khalid S, Murdoch R, Newlands A, et al. Transient receptor potential vanilloid 1 (TRPV1) antagonism in patients with refractory chronic cough: a double-blind randomized controlled trial. J Allergy Clin Immunol. 2014;134(1):56-62. doi: 10.1016/j.jaci.2014.01.038

19. Abdulqawi R, Dockry R, Holt K, et al. P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2015;385(9974):1198-1205. doi: 10.1016/S0140-6736(14)61255-1

20. Dicpinigaitis PV, McGarvey LP, Canning BJ. P2X3-receptor antagonists as potential antitussives: summary of current clinical trials in chronic cough. Lung. 2020;198(4):609-616. doi: 10.1007/s00408-020-00377-8

21. Morice AH, Fontana GA, Belvisi MG, Birring SS, Chung KF, Dicpinigaitis PV, et al. ERS guidelines on the assessment of cough. Eur Resp J. 2007;29(6):1256-1276. doi: 10.1183/09031936.00101006

22. Kaplan AG. Chronic cough in adults: make the diagnosis and make a difference. Pulm Ther. 2019;5(1):11-21. doi: 10.1007/s41030-019-0089-7

23. Morice AH, Millqvist E, Belvisi MG, et al. Expert opinion on the cough hypersensitivity syndrome in respiratory medicine. Eur Respir J. 2014;44(5):1132-1148. doi: 10.1183/09031936.00218613

24. Dicpinigaitis PV. Thoughts on one thousand chronic cough patients. Lung. 2012;190(6):593-596. doi: 10.1007/s00408-012-9420-x

25. Wagener AH, de Nijs SB, Lutter R, et al. External validation of blood eosinophils, FE(NO) and serum periostin as surrogates for sputum eosinophils in asthma. Thorax. 2015;70(2):115-120. doi: 10.1136/thoraxjnl-2014-205634

26. Pacheco A, Faro V, Cobeta I, Royuela A, Molyneux I, Morice AH. Gastro-oesophageal reflux, eosinophilic airway inflammation and chronic cough. Respirology. 2011;16(6):994-999. doi: 10.1111/j.1440-1843.2011.02010.x

27. Kahrilas PJ, Altman KW, Chang AB, et al; CHEST Expert Cough Panel. Chronic cough due to gastroesophageal reflux in adults: CHEST guideline and expert panel report. Chest. 2016;150(6):1341-1360. doi: 10.1016/j.chest.2016.08.1458

28. Koufman JA, Aviv JE, Casiano RR, Shaw GY. Laryngopharyngeal reflux: position statement of the committee on speech, voice, and swallowing disorders of the American Academy of Otolaryngology-Head and Neck Surgery. Otolaryngol Head Neck Surg. 2002;127(1):32-35. doi: 10.1067/mhn.2002.125760

29. Patterson N, Mainie I, Rafferty G, et al. Nonacid reflux episodes reaching the pharynx are important factors associated with cough. J Clin Gastroenterol. 2009;43(5):414-419. doi: 10.1097/MCG.0b013e31818859a3

30. Morice AH, McGarvey L, Pavord I; British Thoracic Society Cough Guideline Group. Recommendations for the management of cough in adults. Thorax. 2006;61(suppl 1):i1-i24. doi: 10.1136/thx.2006.065144

31. Descazeaux M, Brouquieres D, Didier A, et al. Obesity predicts treatment response to proton pump inhibitor therapy in patients with chronic cough. Lung. 2020;198(3):441-448. doi: 10.1007/s00408-020-00359-w

32. Sundar KM, Willis AM, Smith S, Hu N, Kitt JP, Birring SS. A randomized, controlled, pilot study of CPAP for patients with chronic cough and obstructive sleep apnea. Lung. 2020;198(3):449-457. doi: 10.1007/s00408-020-00354-1

33. National Ambulatory Medical Care Survey: 2015 state and national summary tables. US Dept of Health and Human Services, Centers for Disease Control and Prevention. Accessed June 10, 2020. cdc.gov/nchs/data/ahcd/namcs_summary/2015_namcs_web_tables.pdf

34. Marchant JM, Newcombe PA, Juniper EF, Sheffield JK, Stathis SL, Chang AB. What is the burden of chronic cough for families? Chest. 2008;134(2):303-309. doi: 10.1378/chest.07-2236

35. French CL, Crawford SL, Bova C, Irwin RS. Change in psychological, physiological, and situational factors in adults after treatment of chronic cough. Chest. 2017;152(3):547-562. doi: 10.1016/j.chest.2017.06.024

36. Dicpinigaitis PV, Tso R, Banauch G. Prevalence of depressive symptoms among patients with chronic cough. Chest. 2006;130(6):1839-1843. doi: 10.1378/chest.130.6.1839

37. French CT, Irwin RS, Fletcher KE, Adam TM. Evaluation of cough-specific quality-of-life questionnaire. Chest. 2002;121(4):1123-1131. doi: 10.1378/chest.121.4.1123

38. Birring SS, Prudon B, Carr AJ, Singh SJ, Morgan MD, Pavord ID. Development of a symptom specific health status measure for patients with chronic cough: Leicester Cough Questionnaire (LCQ). Thorax. 2003;58(4):339-343. doi: 10.1136/thorax.58.4.339

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