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Understanding the Foundations of Chronic Cough
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Abstract
Despite chronic cough being one of the most frequent reasons for both primary care and specialty physician visits, its diagnosis and treatment remain challenging. The most common causes are upper airway cough syndrome, asthma, and gastroesophageal reflux disease; however, new research has implicated a cough hypersensitivity syndrome that may link many underlying etiologies. To accurately diagnose and treat patients with chronic cough, a thorough understanding of the various definitions, epidemiology, and pathophysiology is crucial. This article reviews these factors as well as the healthcare and socioeconomic burden of chronic cough.
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
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