Overview of Chronic Cough

ABSTRACT

The estimated global prevalence of chronic cough (CC) is close to 10%; however, this is likely higher, as many epidemiologic surveys do not adequately capture symptoms or diagnoses of CC. There is a large healthcare burden associated with CC as well as decreased quality of life (QOL). CC has previously been considered a symptom of other comorbidities. Now that it is regarded as a disease state on its own, education is needed to ensure a CC diagnosis is not missed and is adequately treated. CC is associated with many complications and triggers. Unfortunately, there are few effective therapies for CC, and many have severe adverse effects that limit use. Many people experience decreased QOL because of the impact of CC on daily activities. Because there is not a standard definition of chronic cough in the literature, a comprehensive approach to taking a cough history is essential. It is important to consider all triggers, including occupational and geographic triggers. Identified gaps in care include appropriate history taking, efficacious treatments, and more clinicians specializing in cough. Pharmacists require education on the background of CC and current and future therapies to improve disease competency, clinical decision making, and interventions to enhance the QOL by treating CC. Improved decision making will allow pharmacists to educate people with CC and provide resources to enhance their cough-related QOL.

Am J Manag Care. 2022;28(suppl 9):S152-S158. https://doi.org/10.37765/ajmc.2022.89243

Definition and Diagnosis of Cough

A cough is a physiologic reflex meant to protect the airways; however, it is also one of the most common symptoms that lead people to seek medical attention because “something is wrong.”^1-4 Cough is meant to clear the larynx, trachea, and large bronchi of mucus, harmful substances, foreign particles, and infectious organisms.⁵ It may be the first symptom or warning sign of an underlying disease, such as chronic obstructive pulmonary disease, and these underlying conditions should be assessed.⁶ Individuals report an average of 8 symptoms associated with their cough and may need a referral to a specialty cough clinic to rule out rarer causes of a cough (eg, interstitial lung disease).⁷ A cross-sectional, retrospective cohort study reported that 31% of people with a chronic cough (CC) had no recorded comorbidities.⁸ These data underpin the importance of the consideration of CC as its own condition.

There are 3 phases to a cough reflex mechanism: the inspiratory phase, forced expiratory effort against a closed glottis, and opening of the glottis. The rapid expiration that occurs with the glottis opening causes the characteristic cough sound, and these specific characteristics of the cough sound may aid with a diagnosis.⁵ An uncontrollable cough may lead to unwanted attention, embarrassment, and the need to explain to others that the cough is not infectious.⁹ The most common description of the cough is dry or productive with minimal sputum.⁶ CC after recovery from COVID-19 is common as part of the post-COVID syndrome.¹⁰

The duration of a cough is used to determine a pathologic condition and can be used to narrow potential diagnoses.¹ Acute, or self-limiting, cough lasts less than 3 weeks, and this type of cough is typically caused by an upper respiratory tract infection but may also be caused by environmental irritants or an asthma exacerbation.⁵ A subacute cough lasts between 3 and 8 weeks.^1,5 CC is considered as such if it lasts more than 8 weeks, and it likely warrants medical attention.^1,7 Refractory chronic cough (RCC), a subtype of CC, is defined as a cough that persists despite optimal, conventional treatment.^1,7,11 Frequency of cough should also be considered, although this is more difficult to readily measure in a clinic setting. A detailed history is necessary to understand the entire experience and identify any potential triggers. Unexplained CC is one with no diagnosable cause; however, this diagnosis still requires adequate assessment, investigation, and therapy.¹²

Epidemiology

A considerable limitation to an accurate understanding of the prevalence of CC is the lack of a standardized definition in the literature. A meta-analysis reported 19 different definitions among 90 studies.¹³ The exact burden is unknown because a cough is typically considered as a symptom of another respiratory condition.⁷ In a survey completed in the United States, a weighted prevalence of 5% of people (approximately 12.2 million adults) reported experiencing CC in the previous 12 months.¹⁴ Prevalence also increased with age, peaking in the fifth to sixth decade of life. Compared with those who had never smoked, those respondents with a history of smoking had a higher prevalence of CC (7.3% vs 3.4%; P <.001).¹⁴ There is a relationship between cumulative smoking exposure and CC.⁷ Studies have shown that otherwise healthy smokers have a decreased cough reflex sensitivity to inhaled capsaicin. There may be a transient increase in cough for 30 days after smoking cessation. People with a cough who intend to quit smoking should be informed of this potential temporary increase in cough.⁷ Commonly, medical advice is not sought by people who smoke cigarettes with a CC unless there is a change in the pattern or intensity of the cough.⁵

The global prevalence of CC in adults was reported to be almost 10% (95% CI, 7.6%-11.7%) in a meta-analysis. When restricted to the most stringent definition of cough, for greater than or equal to 3 months, the global prevalence was 7.9%. Regionally, prevalence was higher in Oceania (18.1%; 95% CI, 9.8%-27.2%), Europe (12.7%; 95% CI, 10.4-15.2%), and the United States (11.0%; 95% CI, 7.8%-14.4%), though it was lower in Asia (4.4%; 95% CI, 1.8-7.4%) and Africa (2.3%; 95% CI, 0.0%-6.7%).¹³ Regional differences may be explained by issues such as air pollution and tuberculosis.¹

One survey reported the prevalence of CC to be higher in women than men (5.2% vs 4.7%; P = .01).¹⁴ As approximately two-thirds of people presenting with CC are women, gender differences are likely present and may be due to anatomy differences as well as increased cough reflex sensitivity in adult women.^7,15 This can be demonstrated with inhaled capsaicin as women with and without CC had a greater response to inhaled capsaicin than men. Women are also more likely to seek medical care due to physical complaints associated with CC, such as urinary stress incontinence.¹⁵

Etiology

Etiologies of a cough typically vary depending on the duration of symptoms, triggers, and prior illness. A complete history and physical examination are needed to identify the cause. Medications causing iatrogenic CC should be considered in each individual, as this cause is often overlooked, and can include angiotensin-converting enzyme (ACE) inhibitors, bisphosphonates, and calcium channel antagonists.⁷ Medical attention is often sought because of vomiting, exhaustion, sleep disruption, and social embarrassment.⁷ Esophageal reflux and dysmotility are common factors that may exacerbate CC. Airway secretions also play a part in the severity of CC.¹⁵ Any condition that may impair the nervous or muscular systems can contribute to decreased cough efficiency.¹⁵ Other causes may be foreign bodies or lung cancer.¹⁶ Psychogenic causes may respond to treatment for anxiety, depression, or resolving social issues.⁵

In a meta-analysis, asthma (adjusted odds ratio [OR], 3.01; 95% CI, 2.33-3.70), persistent smoking (adjusted OR, 1.81; 95% CI, 1.36-2.26), and low education levels/socioeconomic status (adjusted OR, 1.46; 95% CI, 1.20-1.72) were associated with increased risk of CC, after adjusting for confounders such as smoking.¹⁷ In a separate meta-analysis, the regional prevalence of current smoking was correlated with regional cough prevalence.¹³

Triggers

A comprehensive scoping review reported a total of 214 total triggers for CC or RCC reported in the literature.¹⁸ Smoke from tobacco (consisting of smoke, smoking, and tobacco) accounted for over 50% of responses. Other common triggers included reflux, postnasal drip, odors, and airborne. Less common triggers included capsaicin, wood, cement, and metal. The breadth of triggers shows the importance of a thorough patient interview regarding cough symptoms and potential triggers.¹⁸ It is recommended that clinicians use a clinical checklist to avoid the possible miss of a trigger.

Triggers can be categorized based on occupational exposure, which can vary depending on one’s environment.¹⁸ Environmental irritants may include perfumes, bleaches, or cold air. Occupational exposure from irritants such as chemicals or dust particles may also occur.⁵ For example, mail carriers report air pollution, road dust, and construction activity. Those in the automobile industry report different types of oil triggers. Even students may have specific triggers based upon their major.¹⁸ Common triggers associated with farming included manure, pesticides, and fertilizer; urban triggers included pollution and air quality. Uncommon causes are arteriovenous malformations, retrotracheal masses, and premature ventricular contractions.¹⁶

Triggers should also be considered from an urban versus rural perspective.¹⁸ Questions regarding the geographic location of CC triggers should be part of the cough assessment. Another important note regarding triggers is that specialists and subspecialists may receive clinical assessments that already include triggers.¹⁸ It is critical that these assessments be conducted with each new visit to ensure nothing is missed.

Pathophysiology

Cough Reflex

A cough is caused by a vagal reflex, with receptive neuronal fields in the larynx, airways, alveolar septa, and lung parenchyma.⁷ The ear may also be involved via irritation of the external auditory meatus.⁵ The nerves regulating the cough response respond to various chemical and mechanical stimuli. Figure 1⁵ highlights causes and pathways leading to airway inflammation and distinguishes between acute cough and CC. Receptors along these pathways, such as purinergic 2X3 (P2X3) receptors, transient receptor potential vanilloid type 1 (TRPV1), and transient receptor potential ankyrin type 1 (TRPA1), are some of the targets for drug therapy. The P2X3 receptors, for example, are ATP-regulated and induce cough when activated.¹⁹ The goal of treatment is to suppress a pathologic cough without suppressing the protective cough reflex.⁷

The visceral cough reflex is controlled in the higher brain.²⁰ Cough receptors are mechanically gated ion channels. Inflammatory or mechanical changes in the airways may trigger a cough reflex, as will chemical or mechanical irritants.⁵ Sensory nerve receptors, which have properties of rapidly adapting receptors, slowly adapting receptors, or C-fiber receptors, respond to these stimuli and interact centrally to promote coughing.⁵ Each of these receptors is stimulated by different types of triggers. For example, rapidly adapting receptors are triggered by cigarette smoke, acidic and alkaline solutions, hypotonic and hypertonic saline, mechanical stimulation, pulmonary congestion, atelectasis, bronchoconstriction, and a reduction in lung compliance.⁵ C-fiber receptors are more sensitive to chemicals, including bradykinin, capsaicin, and hydrogen ions.⁵

The cough receptors in the airways are connected to the vagus nerves in the brain stem via afferent fibers.⁵ Combined respiratory neurons are referred to as the cough center or the central cough generator. The cough reflex may also be sensitized in brain stem neurons, though it is possible to voluntarily produce or inhibit a cough via higher cortical centers.⁵

Chronic Cough

CC is related to an increased number of coughs due to inhaled stimuli compared with non-coughers. This response may result from increased sensitivity of cough receptors or central changes in the brain stem (Figure 2⁵). Changes in neurotransmitters or neuromodulators, the excitability of the postsynaptic neuron, and the nerve structure may lead to sensitization.⁵

A cough may be caused by excessive stimulation of a normal cough response; however, most people presenting with CC have cough reflex hypersensitivity and complaints of sensitivity to environmental irritants that leads to a tickling sensation in the throat and the urge to cough.^5,7 Cough reflex hypersensitivity causes a response to a low level of stimuli from thermal, chemical, or mechanical means.⁷ This suggests a heightened sensitivity of the neuronal pathways controlling the cough reflex.

Chronic Cough Phenotypes

There are 4 main CC phenotypes: cough-variant asthma, reflux cough, upper airway cough syndrome, and iatrogenic cough (Table^5,7). Inflammation may be caused in the airways, as occurs in a quarter of people.⁷ This inflammation may occur through innate immune system stimulation instead of atopy. This phenotype is cough-variant asthma, atopic cough, or eosinophilic bronchitis.⁷ Typically, CC presents nocturnally in those with asthma, and it may or may not be associated with airflow obstruction, wheezing, or dyspnea.⁵ However, CC is largely suppressed when the person is asleep.⁵ Bronchial hyperresponsiveness is usually present for a diagnosis of asthma, though cough in people with asthma may indicate an acute worsening of lung function.⁵

Another phenotype that is often overdiagnosed is reflux cough caused by acid and nonacid reflux.^5,7 The diagnosis is typically dependent on symptoms.⁷ Gastric contents are able to move to the larynx and trachea because of an impaired lower esophageal sphincter, leading to symptoms including heartburn, chest pain, a sour taste in the mouth, and regurgitation. A cough may also cause increased esophageal reflux. Chronic exposure of the larynx to acid may result in reflux laryngitis.⁵ It is important to note that people presenting with reflux cough may have few esophageal reflux symptoms but report throat clearing, cough, and hoarseness.

Postnasal drip syndrome, also called rhinosinusitis or upper airway cough syndrome, is a phenotype that occurs when upper airway cough syndrome leads to cough hypersensitivity. However, the mechanism is not well understood.^5,7 This syndrome is caused by the sensation of nasal secretions, or drip, in addition to the extra need for throat clearing. It is often also associated with nasal discharge or stuffiness. Pathogenesis is related to direct stimulation by mucoid secretions, which contain inflammatory mediators.⁵

Iatrogenic cough is caused by several medications, including angiotensin-converting enzyme (ACE) inhibitors, bisphosphonates, or calcium channel antagonists.⁷ ACE inhibitor-induced cough may be caused by an accumulation of bradykinin and prostaglandins, which sensitize cough receptors.⁵

Chronic Cough Complications

CC affects nearly every organ system, and complications such as hemoptysis should be immediately addressed and evaluated.² Coughing can be detrimental and beneficial to the cardiovascular system. It may also cause excessive sweating, anorexia, exhaustion, vomiting, and temperature elevations. In addition, excessive coughing may cause rib fracture.⁵ Complications from a cough that have led to death include syncope, spontaneous arterial gas embolism, hematoma, intercostal hernia, and gas cerebral embolism.² Repetitive coughing or the cause of coughing may contribute to tissue remodeling, which then causes a further enhanced cough reflex in a positive feedback loop.⁵

Cough Receptor Targets

There are several potential medication targets for CC (Figure 3²¹).While there are several currently available medications for some of these targets both over the counter and as prescription agents, they are not without adverse effects or lack of efficacy. Emerging therapies are targeting newer pathways—receptors and channels in the sensory neurons—that may provide greater efficacy and fewer adverse effects. The focus in this report will be on the P2X3 antagonists as well as the neurokinin (NK)-1 receptor antagonist and voltage-gated sodium channel blockers, but clinicians and pharmacists are advised to investigate others in development as well, such as agents working on transient receptor potential channels and N-methyl-D-aspartate receptors.

The P2X family of receptors are ATP-gated ion channels. When the receptors on the airway vagal afferent nerves are activated by ATP, cough is induced.^19,22 The role of P2X3 and P2X2/3 in the treatment of CC is through the involvement of the ligand extracellular ATP in airway disease and inflammation.^19,22 Gefapixant is currently under investigation within the United States as a P2X3 receptor antagonist for CC as well as several other emerging agents.²³

Various neuromodulators have been targeted for the treatment of CC based on preclinical data and the use of neuromodulators for the treatment of other disease, including gamma-aminobutyric acid-related agents, several antidepressants, and morphine.²¹ NK-1 receptors are modulated by tachykinins in the brain and antagonism of these receptors blocks capsaicin-induced and citric acid-induced cough.²¹

Voltage-gated sodium channels are involved in action potential induction pathways that include sensory nerves responsible for cough.²¹ Blocking this sensory pathway leads to the inability to activate the cough cascade.

Transient receptor potential channels are a family of ion channels that may be expressed in the airways and centrally (specific to cough), as well as other body tissues and organs. These receptors include TRPV1, TRPA1, TRPV4, and TRPM8. All of these receptors are calcium-permeable channels activated by various stimuli, including temperature, pH, environmental irritants, and endogenous mediators.²¹ Oral capsaicin to induce sensitization of cough reflex through TRPV1 is being studied; however, there is potential mediation by unknown local action in the gastrointestinal tract.²¹

Targeting nicotinic receptors is thought to potentially affect pulmonary sensory neurons. However, the use of nicotine has been shown to reduce the urge to cough after a capsaicin challenge.²¹

N-methyl-D-aspartate receptors in the brain stem transmit cough signals from vagal afferent nerves.²¹ N-methyl-D-aspartate receptor antagonism inhibits an evoked cough response.²¹

Healthcare and Socioeconomic Burden

CC and RCC may result in an underrecognized disease burden. Social isolation, economic impact, and emotional impact are interrelated themes that affect the burden of CC.³ The most considerable impacts of CC on quality of life (QOL) can affect the individual and their social network due to embarrassment caused by urinary incontinence, interference with speech, and depression.⁷ Because women experience CC more than men, women with CC and incontinence may experience worse health-related QOL compared with those without incontinence. Incontinence may be severe but not discussed; therefore, it should be asked about during each consultation.⁷ Other issues associated with CC burden include cough syncope and dysphonia.⁷

As patient-reported outcome measurements are used to report the subjective end point of cough severity, it is essential to use consistent conceptual frameworks and domains to assess the true impact of CC.²⁴ A systematic survey provided specific domains to assess for cough severity, including urge-to-cough sensation, defined as laryngeal or chest sensations and subdomains to assess, including frequency and intensity, and cough symptoms. Of 82 potential items, 43 were considered unique and related to cough severity.²⁴ Cough subdomain assessment should include control, frequency, duration, intensity, and any associated features or sequelae.²⁴

Cough-specific QOL outcomes are recommended as end points in trials studying antitussives.⁷ However, cough-related complaints will vary with the individual, and QOL questionnaires may not capture all problems. One benefit to these tools is that they can be used to show clinically meaningful changes in cough related to treatments.⁷ For example, the Cough Severity Diary is a validated instrument that may be used to assess change in cough during clinical trials; it focuses on capturing perceptions of cough frequency as well as intensity and disruptions due to cough.²⁵

Repeated examinations and several treatments are often needed before a diagnosis is reached. Delays in diagnosis may lead to poor symptom control, worsening of QOL, and increased economic burden.⁴ A survey of public service employees (N = 3695) in Finland assessed repetitive doctor’s consultations due to cough.²⁶ In all, 205 participants had repetitive consultations defined as greater than or equal to 3 visits within the previous 12 months and accounted for 50.4% of consultations due to cough during that period. These consultations were mainly due to asthma and chronic rhinosinusitis. Overall, 22.5% of respondents had a consult due to cough at least once, 11.2% at least twice, 5.5% at least 3 times, 2.7% at least 4 times, and 1.4% at least 5 times.²⁶

In an analysis of results from 74,977 National Health and Wellness Survey respondents in the United States, 3654 experienced CC. Compared with matched respondents, those with CC had more anxiety and depression within the past 2 weeks, work productivity impairment, impaired sleep quality and daytime sleepiness, and more emergency department visits and hospitalizations in the previous 6 months (P <.001 for all comparisons).¹⁴ Those with CC also had lower mean scores on the Medical Outcomes Study 36-item Short Form Survey (P <.001), which measures health-related QOL.¹⁴

A study of 238 people (59.7% women) with CC and no other chest imaging abnormalities used the Hospital Anxiety and Depression Scale to measure anxiety and depression.²⁷ Cough severity was reported using the Cough Visual Analog Scale, and the Leicester Cough Questionnaire was used for assessing cough-related QOL. The authors reported that 9.2% of respondents had anxiety and 6.3% had depression.²⁷ Cough duration, cough severity, and a history of anaphylaxis were associated with reduced QOL in this group. In addition, cough severity was found to be a dependent risk factor for anxiety and depressive symptoms.²⁷ Those with a history of anaphylaxis experienced more severe anxiety symptoms, and more female respondents had a history of anaphylaxis and reduced cough-related QOL.²⁷

In a study of 447 self-completed questionnaires by participants with CC from 6 referral clinics in Korea,²⁸ almost all reported disturbances with relationships and that their CC affected their daily activities either frequently or sometimes. Approximately 75% of participants who were newly referred to the clinics had previously sought medical care on multiple occasions. Of these, 70.3% thought the effectiveness of their treatment was limited, and 17.3% thought it was absent.²⁸ Common unmet needs in this population included effective treatment and a clear diagnosis. Many participants also expressed a need to be able to access a cough specialist.²⁸

Early intervention with behavioral cough suppression therapy has been reported to be a cost-effective and efficient option for people with RCC, and it may be part of a decrease in the overall healthcare burden.²⁹ A small study suggested positive outcomes with repeated exposure to nebulized capsaicin paired with behavioral cough suppression therapy.³⁰

A qualitative study of patient perspectives of RCC highlighted themes that included the prominent role of the social aspects of how cough is experienced, perceived, and managed.⁹ The survey reported several issues, including individual vulnerability, cough as an identity, vicious circles of coughing, and the participants’ feeling it is “more than just a cough.”⁹ Patients reported feeling “at the end of the line,” and as though they had exhausted all avenues for treatment and relief.⁹

A retrospective cohort study reported the financial burdens of cough.³¹ Costs were associated with the need for multiple outpatient visits, prescriptions, and inpatient visits, as well as the need for multiple specialists. Those with asthma, chronic obstructive pulmonary disease, esophageal reflux, or ACE inhibitor-associated cough had higher healthcare resource use and overall costs. The authors concluded that people presenting with a cough, specifically CC, were challenging to treat.³¹ A prospective study of costs associated with CC reported that most costs are due to diagnostic investigations and clinic appointments.³² The study reported costs for 12 months prior to and after the first consultation with a specialist cough clinic. As measured by the Leicester Cough Questionnaire, health status and anxiety were predictors of cost. Speech therapy was reported to have higher costs than medications.³²

Need for New Agents to Control Chronic Cough

The reported efficacy of antitussive therapies is dependent on the clinical context, specifically the expected outcome or cough characteristics.⁷ Most of the currently available antitussives are centrally acting medications for pain or neuropathic conditions. Many treatments are used off label, have limited efficacy, or produce significant adverse effects.⁴ A focus on molecular pathways that control the cough reflex instead of neural mechanisms is needed for new treatment approaches, though any treatment will need to preserve the protective cough reflex.³³ In addition, better biomarkers are required in order to accurately predict response to treatment.⁷ Unmet clinical needs include more information about the disease, effective and curative treatments, and more medical professionals specializing in cough.³

Conclusions

CC causes a decreased QOL and a sizeable socioeconomic burden. Clinicians should recognize that people with CC may have comorbidities—including mental health comorbidities—that need to be considered when managing the treatment of cough. New and effective therapies are required in order to decrease the burden of this disease, but due to the heterogeneity of CC, a one-size-fits-all treatment is not possible. A better understanding of the phenotypes of chronic cough is necessary in tandem with a better understanding of potential treatment targets. Future research into CC phenotypes will allow for a personalized treatment approach to disease management. A standard definition of CC and RCC is necessary to facilitate future studies. More information is also needed on the long-term outcomes of those with CC.

Author affiliation: Phung C. On, PharmD, BCPS, is an Associate Professor of Pharmacy Practice, School of Pharmacy, Massachusetts College of Pharmacy and Health Sciences, 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 acquisition of data; analysis and interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.

Address correspondence to: Phung.On1@mcphs.edu

Medical writing and editorial support provided by: Milena Murray, PharmD, MSc, BCIDP, AAHIVP, FCCP

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