Introduction

Cough is a complex reflex involving coordination between various muscles and neural pathways. Coughing is a protective mechanism for the respiratory system, helping to keep the airways clear of substances that could potentially cause harm or hinder normal breathing. While coughing is generally a healthy response, persistent or chronic coughing can be a symptom of an underlying health issue and may require further investigation and management.

Cough can be divided into 3 types based on the duration of symptoms: acute, subacute, and chronic cough. Chronic cough is a persistent cough that lasts 8 weeks or longer in adults, while subacute cough usually lasts 3 to 8 weeks, and acute cough typically lasts for less than 3 weeks.[1] Chronic cough is a widespread yet underappreciated condition that imposes substantial illness on affected individuals.[2] This activity will focus on chronic cough, a common respiratory symptom for apparent and covert diseases that can significantly impact the quality of life and contribute to a diagnostic dilemma for physicians.[3][4][5] This article will also discuss the etiology, epidemiology, clinical manifestation, evaluation, and management associated with chronic cough.

Etiology

The most common etiologies of chronic cough involve a range of respiratory and nonrespiratory conditions. 

Asthma 

In asthma, cough can be the sole symptom, especially in patients with cough-variant asthma.[6] This form of asthma may not present with classic symptoms like wheezing or shortness of breath. Instead, cough may be the predominant or sole manifestation of asthma. This is often referred to as cough-variant asthma. In cough-variant asthma, the airways are hyperresponsive to various triggers, leading to bouts of coughing. The cough can be persistent and may occur during the day or night. Diagnosing cough-variant asthma may involve pulmonary function tests, such as spirometry, to assess how well the lungs function.[7] Other diagnostic measures, such as bronchial provocation tests, may be used to induce and evaluate cough responses.[8]

Nonasthmatic Eosinophilic Bronchitis 

NAEB is characterized by eosinophilic inflammation in the airways, similar to asthma. However, it lacks the variable airflow obstruction characteristic of asthma.[9] There is no verifiable airflow limitation on spirometry in NAEB, and methacholine challenge testing (MCT) is usually negative.[10] Chest x-ray results are typically normal. The lack of airflow limitation on spirometry distinguishes NAEB from asthma. In NAEB, sputum examination can reveal eosinophilia in the airways. Unlike asthma, there is usually no mast-cell infiltration in eosinophilic bronchitis.[11] Patients with recurrent episodes of symptomatic NAEB are at an increased risk of developing asthma, and chronic airway obstruction suggests that NAEB may represent an early stage or precursor to asthma in some individuals. This supports the notion that there might be a spectrum of airway diseases, and various factors could influence the progression from eosinophilic bronchitis to asthma.[12]

Chronic Bronchitis 

Chronic bronchitis, a type of chronic obstructive pulmonary disease (COPD), is characterized by persistent cough due to increased mucus production in the airways. Chronic bronchitis is often associated with smoking and remains a significant cause of chronic cough. However, despite the high prevalence of smoking, most smokers with chronic bronchitis do not seek medical attention for their cough. Chronic bronchitis typically accounts for 5% or less of cases of chronic cough.[13] Chronic bronchitis often develops gradually over time. Smokers may adapt to the persistent cough as it becomes a part of their daily life, and they may not consider it a significant enough issue to seek medical attention. Therefore, it is necessary to consider the possibility of neoplasms or lung cancer in individuals with a history of smoking who present with a change in a chronic cough. A cough may become persistent, severe, or accompanied by other concerning symptoms.

Gastroesophageal Reflux Disease 

Reflux-induced cough can occur through direct and indirect mechanisms. These mechanisms are related to the effects of stomach acid and lead to chronic cough.[14] GERD can directly affect the airway when gastric acid flows back into the esophagus and irritates the proximal esophagus and the laryngopharyngeal areas. This irritation triggers a cough reflex as a protective response to clear the airways. The gastric content can also indirectly cause chronic cough by stimulating the distal part of the esophagus, resulting in irritation to the vagus nerve and triggering reflexes like coughing. In some cases, reflux-induced cough may occur without typical symptoms of acid reflux, such as heartburn. This is known as silent reflux. Most cases of reflux-induced cough are silent reflux, making it challenging to diagnose based on symptoms alone.[15][16]

Upper Airway Cough Syndrome 

Formerly known as postnasal drip syndrome, UACS is a significant contributor to chronic cough, comparable to other major causes, such as asthma and gastroesophageal reflux. The mechanisms underlying cough in individuals with nasal and sinus diseases involve several factors, including postnasal drip, direct irritation of nasal mucosa, inflammation in the upper and lower airways, and sensitization of the cough reflex. The cough observed in UACS patients is suggested to arise from the hypersensitivity of sensory nerves in the upper and lower airways or a combination of these factors.[17]

Medications 

Cough is an adverse effect of some medications, particularly angiotensin-converting enzyme (ACE) inhibitors.[18] ACE inhibitors are prescribed to treat hypertension and heart failure. Thirty percent of patients develop dry cough symptoms usually a few hours after taking the medication but can be delayed for weeks or months after starting the drug.[19] The exact mechanism behind ACE inhibitor-induced cough is not entirely clear, but it is believed to be related to the increased sensitivity of the cough reflex. One proposed mechanism involves the accumulation of bradykinin, a substance usually broken down by ACE. When bradykinin levels rise due to ACE inhibition, this can stimulate afferent C-fibers in the airway, which leads to cough.[20] Medications that increase gastroesophageal reflux (GER), such as calcium channel blockers and bisphosphonates, can theoretically exacerbate preexisting reflux and cough. Study results revealed that the cough rate with calcium channel antagonists was similar to losartan but significantly less than that with ACE inhibitors.[21] Finally, prostanoid eye drops, including latanoprost, are commonly used to treat glaucoma by reducing intraocular pressure. There have been reports of adverse effects related to these eye drops, specifically, irritation of the pharynx.[22]

Bronchiectasis 

Bronchiectasis is characterized by abnormal, irreversible dilation of the bronchi (the airways leading to the lungs). Bronchiectasis accounts for <2% of patients with chronic cough but can be seen in up to 4% of those with excessive sputum production.[23] The cardinal symptom of bronchiectasis is a chronic productive cough; patients with this condition typically experience a persistent cough that produces sputum or phlegm. The dilation and damage to the airways make it difficult for the lungs to effectively clear mucus, leading to chronic cough and, often, mucus production. While some individuals with this condition may experience only a dry cough, most tend to produce chronic sputum that is mucopurulent (containing mucus and pus). During exacerbations, the sputum may become frankly purulent. There are reports of overlap between bronchiectasis and other airway diseases associated with increased lung inflammation and frequent exacerbations, which precipitate chronic cough.[24]

Postinfection 

Respiratory tract pathogens are a common cause of cough. Although cough typically resolves within days, cough reflex hypersensitivity might last for several weeks or even longer, perhaps related to inflammation of the vagal nerves. Twenty-five percent of patients with chronic cough report a postinfectious etiology due to upper respiratory infection.[25] During outbreaks of respiratory infections caused by pathogens like Mycoplasma pneumoniae, Chlamydia pneumoniae, Bordetella pertussis (whooping cough), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19), there tends to be an increase in cases of cough.[26][27][28] Exposure to various allergic or non-allergic irritants can lead to local tissue inflammation. This inflammation can affect the vagal nerves or their central pathways, contributing to the development of cough hypersensitivity.[29] Inflammation or irritation of the vagal nerves during the infection can contribute to prolonged cough hypersensitivity. The vagus nerve plays a central role in regulating the cough reflex, and any disturbance in its function can lead to persistent coughing.[30] Individual responses to infections must be followed, and the subsequent cough reflex can vary. Some individuals may experience heightened sensitivity and a lingering cough, while others recover without complications.[31]

Neoplasm 

Tumors in the respiratory system can irritate airways and lead to a persistent cough. Cough is a common symptom among patients with lung cancer (57%) and is often a presenting symptom that can significantly impact the patient's quality of life.[32] Half of patients reported the need for treatment due to the severity of their cough, with 23% experiencing associated pain.[33] The prevalence of cough in lung cancer can be attributed to various factors. Tumors in the lung can irritate or obstruct airways, triggering the cough reflex. Cancer-related inflammation, infections, or the body's response to the presence of cancer cells can contribute to coughing.

Interstitial Lung Disease (ILD) 

Cough is a common symptom associated with ILD and idiopathic pulmonary fibrosis (IPF). The etiology of coughing in IPF remains poorly understood.[34] Eighty percent of patients with IPF may experience a chronic cough. Therefore, it is crucial to identify chronic cough and assess its severity and impact on an individual's quality of life.[35] When patients have a persistent cough, it's crucial to investigate alternative causes before assuming it's due to interstitial lung disease (ILD). Common causes like upper airway cough syndrome (UACS), asthma, and gastroesophageal reflux disease (GERD) should be considered. Due to overlapping symptoms, a diagnosis of ILD should only be made after ruling out other potential causes. Several validated tools, such as 24-hour cough monitoring and health-related quality of life questionnaires, assess cough in IPF. These tools help objectively measure the frequency and severity of cough and understand its impact on the patient's quality of life.[36] The mechanism of cough in ILD is complex and may involve multiple factors. Cough in IPF can be attributed to mechanical distortion associated with lung parenchymal fibrosis. The scarring and lung fibrosis may lead to irritation and cough reflexes. This heightened sensitivity can contribute to the persistent cough seen in these patients. Additionally, gastroesophageal reflux is another potential contributor to cough in IPF. The backflow of stomach contents into the esophagus can irritate the airways and trigger a cough. This is particularly relevant because GERD is a common comorbidity in patients with IPF.[37] Finally, airway inflammation is also considered a potential mechanism for cough in IPF. Inflammation in the airways can lead to increased irritability and coughing.[38] 

Idiopathic 

A chronic cough with an unknown cause that does not respond to empirical treatment and is refractory can be considered idiopathic. The association of idiopathic chronic cough with organ-specific autoimmune disease raises the possibility that it may be caused by lymphocyte homing from the primary site of autoimmune inflammation or due to an autoimmune process in the lung.[39]

Epidemiology

Chronic cough has a global prevalence of 3% to 18% in the general adult population and is affected by several factors, such as smoking and age.[40][41] Eighteen percent of adults in the United States who smoke have chronic coughs.[42] The prevalence is variable, however, based on the location of the population studied.[43] Chronic cough was significantly more frequent in Europe and America than in Asia and Africa. However, the geographic variation is not genetic or ethnically related.[44][45] The regional variation in chronic cough prevalence may be attributed to environmental factors, particularly urbanization in Western countries, which can lead to increased inhalational exposure to irritants.[2]

The findings from the KNHANES 2010–2012 study indicate that the prevalence of chronic cough increases significantly with age. The odds ratio (OR) of 2.20 and 95% confidence interval of 1.53 to 3.16 suggests a substantial increase in the likelihood of chronic cough among individuals 65 or older compared to those aged 18 to 39.[46] This finding aligns with the general trend observed in various studies, where chronic cough becomes more prevalent in older age groups.[47] The cumulative effects of environmental exposures over time may also play a role. One study by Dicpinigaitis et al assessed ethnic and sex differences in cough reflex sensitivity and found no significant ethnic differences in cough reflex sensitivity among 3 distinct ethnic groups: White, Indian, and Chinese. This suggests that the variation in the prevalence of chronic cough among different races may not be directly attributed to differences in cough reflex sensitivity.[45] 

In addition to age and smoking, the factors that contribute to the increased prevalence of chronic cough include obesity, atopy, asthma, COPD, GERD, ACE inhibitors, and sleep-disordered breathing. Other factors, such as air pollution and air quality, do not significantly affect the prevalence of chronic cough, and study results have been inconclusive, except for metal exposure.[47]

Pathophysiology

There are 3 phases of a cough: 1) Inhalation, which generates enough volume for an effective cough; 2) Compression, with pressure against a closed larynx by the contraction of the chest wall, diaphragm, and abdominal muscles; 3) Expiration, which begins when the glottis opens, resulting in high airflow. A cough can be a voluntary or involuntary act. A voluntary cough is manifested by cough inhibition or initiation. The central projections of vagal afferents, specifically those involved in the cough reflex, terminate in the brainstem (see Image. Cough and the Nervous System).[17]

The cough reflex is not a fixed, unchanging response but rather a dynamic process that can be influenced by various inputs and stimuli, a phenomenon called "cough plasticity." Vagal afferent fibers, part of the vagus nerve (cranial nerve X), play a crucial role in sensing and transmitting information from the airways to the brainstem, particularly the nucleus tractus solitarius (NTS). These afferent fibers can be classified into subtypes based on how they respond to various stimuli.[48]

The initiation and control of cough involve a complex interplay of neural pathways, including the activation of vagal afferents and central processing in the NTS. The central projections of vagal afferents, specifically those involved in the cough reflex, terminate in the brainstem. The NTS is a critical nucleus in the medulla oblongata, where these afferents synapse with second-order neurons. The NTS processes sensory information from various organs, including the respiratory and gastrointestinal tracts.[49] Afferent signals move down the phrenic and spinal motor nerves to the expiratory muscles, producing the cough. A chronic cough may also be brought about by abnormalities of the cough reflex and sensitization of its afferent and central components with exaggerated cough reflex sensitivity to stimuli that generally do not cause a cough (cough hypersensitivity syndrome).[50]

History and Physical

The initial evaluation of a patient with a chronic cough should include a focused history and physical examination. The full assessment should include documentation of its characteristics, such as the duration, its productive or nonproductive nature, and any accompanying symptoms, such as rhinorrhea, nasal congestion, sneezing, fever, hemoptysis, dyspnea, weight loss, dysphonia, dysphagia, and whooping cough.[51]

Furthermore, it is vital to inquire about any prior occurrences of cough and to gather information regarding the patient's or their family's history of allergic rhinitis. Additionally, a history of tobacco smoking, vaping (eg, electronic cigarettes), occupational exposure, and travel-related exposure should be obtained, as these not only serve as irritants but also increase the likelihood of developing chronic bronchitis and lung cancer.[52]

The patient's medical history includes questioning regarding the use of medication that may contribute to a chronic cough, such as ACE inhibitors. Among adults, the most common causes of chronic cough include asthma, UACS, and GERD. Therefore, it is essential to screen for symptoms that suggest these disorders.

Silent UACS is a condition in which patients experience a cough as the sole symptom, often due to nasopharyngeal conditions such as allergic rhinitis and rhinosinusitis.[1] This may result in a subtle sensation of irritation in the back of the throat and upper airways secondary to postnasal drip. Examination of the throat may reveal signs of pharyngitis and a "cobblestone" appearance. Sometimes, these conditions may be asymptomatic, with cough being the only presenting symptom. Due to the chronicity of the disease, patients may become desensitized to other symptoms over time, making the cough seem more bothersome in comparison. The diagnosis of silent UACS can only be reliably made after patients demonstrate significant improvement with prescribed treatment directed at the identified features in their history, physical examination, or laboratory test results.[53]

Clinicians must promptly identify any life-threatening signs and consider the presence of fevers, night sweats, or weight loss that suggests chronic infections (eg, tuberculosis, lung abscess), cancer (pulmonary, bronchial, or laryngeal), or rheumatic diseases. The presence of purulent sputum warrants further evaluation. Hemoptysis may indicate infections, cancer, rheumatic diseases, heart failure, or foreign body inhalation.

Associated dyspnea can indicate airway obstruction (laryngeal, tracheal, bronchial, bronchiolar) or lung parenchymal disease. Other features can aid in narrowing down the cause of chronic cough. These include specific triggers, associated hoarseness, focal abnormalities on examination, and waxing and waning versus progressively worsening severity.

Evaluation

Assessing a persistent cough necessitates an organized methodology and a personalized strategy.[6] 

The initial assessment of a chronic cough typically involves a chest radiograph and pulmonary function tests (PFTs). A chest x-ray is generally recommended for most adults with a cough that has persisted for over 8 weeks (see Image. Assessment of Cough in Adults). There may be exceptions for individuals in whom the suspected diagnosis is asthma or UACS, who may receive empiric therapy instead.[54] Chest CT scans should not be routinely performed for patients with normal chest examinations and radiographs. Still, they may be necessary for further evaluation of abnormalities detected on the radiograph or for diagnosing conditions that may not be visible on plain radiography, such as bronchiectasis.[55] The threshold for obtaining a chest CT for patients with a chronic cough may be lower for those at increased risk for lung cancer, such as individuals with a history of heavy smoking.

PFTs, including spirometry before and after administering a bronchodilator, may also be used to evaluate the possibility of asthma or COPD. When PFT results are normal, some professionals advocate further investigation of bronchial hyperresponsiveness using either methacholine or histamine inhalational challenge. However, the utility of these modalities in diagnosis is still debated.

The present guidelines offer recommendations for utilizing noninvasive techniques for measuring airway inflammation when evaluating and managing cough associated with asthma or NAEB, based on a thorough review of the pertinent literature.[56] Evidence for ongoing airway eosinophilic inflammation can be sought by performing differential cell counts on samples from sputum induction or bronchoalveolar lavage (BAL). In such cases, elevated eosinophils (>3%) in the airways without bronchial hyperresponsiveness would suggest eosinophilic bronchitis, reported in up to 13% of patients attending cough clinics.[57] The usefulness of fractional exhaled nitric oxide (FeNO) or blood eosinophils in diagnosing or predicting treatment response in patients with chronic cough has yet to be fully assessed in a clinical setting. Despite this, there is currently insufficient high-quality evidence available. Controlled trials with a placebo group are necessary to determine efficacy, and consensus regarding the threshold levels for patients with chronic cough is needed.[58] 

Idiopathic chronic cough lasts longer than 3 weeks without an apparent cause despite negative treatment trials. Elevated lymphocyte levels in the BAL fluid sometimes accompany this condition.[39]

Treatment / Management

Patients taking an ACE inhibitor may benefit from a trial of switching to another drug class. Sequential empirical therapy is advised before embarking on an extensive workup. If UACS is suspected, a trial of nasal saline rinses, a first-generation antihistamine, and nasal steroids is recommended.

For adult patients with chronic cough due to chronic bronchitis, there is insufficient evidence to recommend routine pharmacologic treatments (eg, antibiotics, bronchodilators, mucolytics) to relieve cough.[13]

Empiric therapy for GERD involves dietary modifications, lifestyle changes, antacids, and proton pump inhibitors for 3 months, which should be prescribed before considering 24-hour esophageal pH monitoring. If sputum or BAL testing reveals >3% eosinophils, inhaled steroids can be used to treat NAEB.

Some patients, particularly those referred to specialized clinics, may exhibit multiple underlying causes for their persistent cough. In such instances, it is essential to address all contributing factors simultaneously to resolve the cough completely.

The management of chronic cough caused by asthma is similar to the initial treatment of asthma using a stepwise approach.[8] Like in asthma, inhaled corticosteroids (ICS) are the mainstay of therapy for cough due to asthma.[56] In adult patients with chronic cough due to asthma as a sole symptom (cough-variant asthma), we suggest inhaled ICS as a first-line treatment. Increasing the ICS dose is recommended if the response is incomplete in those with cough-variant asthma. This is also the recommendation if cough is the remaining isolated symptom following treatment with ICS. A therapeutic trial of a leukotriene inhibitor can also be considered. Beta-agonists can also be considered in combination with ICS.[56] 

In idiopathic chronic cough, several treatments may be considered, including opiates and nonopioid pharmacological treatments. A randomized controlled trial (RCT) was conducted to assess the efficacy of low-dose, slow-release morphine (5 to 10 mg twice daily) in adult individuals with persistent, treatment-resistant idiopathic chronic cough, a sample of patients was evaluated and was found to be more effective in reducing cough severity than placebo.[59] The utility of nonopioid medications such as gabapentin or pregabalin was also assessed as a treatment for idiopathic cough. In a study conducted to evaluate the efficacy of gabapentin therapy (maximum daily dose of 1800 mg) in adults with persistent, refractory cough, it was found that there were significant improvements in quality of life compared to placebo.[60] Another study looked at the combination of pregabalin therapy (300 mg daily) with speech pathology therapy and found this approach effective in improving cough-specific quality of life in adult patients with chronic refractory cough.[61]

Below are detailed recommended therapies for different types of chronic cough in adults based on the most recent guidelines.[6]

Nonpharmacological treatments in adult patients with chronic cough (eg, physiotherapy, speech and language therapy) are recommended.[54] Two RCTs have been undertaken to evaluate the efficacy of cough control therapy in adult patients with chronic refractory cough. The first study by Vertigan et al revealed that a 2-month intervention led to a statistically significant reduction in subjective cough scores compared to placebo treatment.[68] The second study by Chamberlain Mitchell et al demonstrated improvements in cough-specific quality of life and objective cough frequency in the intervention group compared to placebo.[69] The benefits in the intervention group were sustained for up to 3 months. Neither study reported any adverse effects.

Differential Diagnosis

The differential diagnosis of chronic cough includes the following conditions:

• Bronchiolitis
• Bronchogenic carcinoma
• Chronic aspiration
• Congestive heart failure
• Foreign body aspiration
• Neuromuscular disorders
• Psychogenic cough

Prognosis

Cough is a distinct and independent factor that can serve as an indicator of disease progression. The prognostic implications of cough in patients with idiopathic pulmonary fibrosis (IPF) are significant. A study of 242 IPF patients revealed that the presence of cough was an independent predictor of disease progression, regardless of the severity of the disease. Furthermore, cough was more prevalent in patients with advanced pulmonary fibrosis. Nevertheless, it is crucial to differentiate whether the cough results from the underlying inflammation or fibrosis or is due to a comorbidity when assessing cough in patients with interstitial lung disease (ILD).[70]

A recent study revealed that many individuals diagnosed with chronic cough continued to experience persistent coughing for at least 5 years.[71] This finding was somewhat more optimistic than a prior study on the same subject, which reported that 60% of patients experienced worsening or unchanged cough symptoms at a 7-year follow-up.[72] The disparity in the results can be attributed to differences in the patient populations studied. The earlier investigation was limited to patients with unexplained chronic cough, whereas the recent study enrolled individuals with various cough-related disorders and idiopathic cough. Thus, the latter study may provide a more accurate representation of the general chronic cough patient population. Notably, the prevalence of autoimmune diseases was high in the more recent group, a characteristic commonly observed in patients with idiopathic chronic cough.[73] Among the study participants, most asthma and chronic rhinitis patients were effectively managed with local corticosteroid preparations or antihistamines. However, most reflux disease patients did not receive treatment with proton pump inhibitors, an ineffective regimen for reflux-associated cough.[16] Consequently, the study population likely reflects the real-life medication regimens of patients. The study further identified obesity as a significant predictor of continued cough-related quality of life impairment. Indeed, subjects who met the current criteria for obesity were found to be at a higher risk for ongoing cough-related distress.

Complications

Chronic cough, when left unaddressed, can lead to a range of complications that significantly impact an individual's quality of life. Prolonged coughing episodes may result in physical exhaustion, disturbed sleep patterns, and increased stress, ultimately affecting one's overall well-being. Persistent coughing can also contribute to the development of musculoskeletal issues, such as chest pain and soreness in the abdominal muscles. Socially, chronic cough may lead to embarrassment and social isolation due to its disruptive nature in public settings. Repeated irritation of the airways can exacerbate underlying respiratory conditions, potentially leading to complications such as bronchitis or pneumonia. Long-term coughing can also contribute to stress urinary incontinence, particularly in women. Therefore, addressing chronic cough promptly through medical intervention and lifestyle modifications is crucial to prevent these complications and improve the overall health and daily functioning of individuals affected by this persistent condition.

Deterrence and Patient Education

Deterrence and prevention strategies for chronic cough aim to mitigate the underlying causes and reduce the risk of persistent respiratory symptoms. Emphasizing lifestyle modifications, such as smoking cessation and avoidance of environmental pollutants, forms a crucial aspect of deterrence. Educational campaigns can play a pivotal role in raising awareness about the adverse health effects of smoking and the importance of maintaining a clean indoor environment. Regular check-ups with healthcare professionals facilitate early detection and intervention, preventing acute respiratory conditions from progressing into chronic cough. Immunization against preventable respiratory infections is another key preventive measure. Additionally, implementing workplace policies that reduce exposure to occupational hazards and airborne irritants can significantly deter chronic cough. By fostering a comprehensive approach that combines individual responsibility, public education, and healthcare interventions, society can work towards reducing the burden of chronic cough on both individual health and healthcare systems.

Enhancing Healthcare Team Outcomes

Chronic cough necessitates an interprofessional team due to its multitude of potential causes. Primary care clinicians and nurse practitioners must consistently consider the possibility of malignancy when evaluating patients presenting with a persistent cough. In cases where the cough persists, referring the patient for appropriate diagnostic evaluations is highly advisable. The prognosis for chronic cough is contingent upon the underlying cause.[74][75][76][77]