Causes and epidemiology of subacute and chronic cough in adults

INTRODUCTION — The symptom of cough is one of the most common symptoms for which adult outpatient care is sought [1,2].

The physiology of the cough reflex arc and common etiologies of subacute and chronic cough will be reviewed here. The evaluation and treatment of subacute and chronic cough are described separately. (See "Evaluation and treatment of subacute and chronic cough in adults".)

DEFINITIONS — Cough in adults can be classified based upon the duration of the cough at the time of presentation to the health care provider [3]. This classification helps to narrow the list of potential causes, although there can be considerable overlap.

●Acute cough – Present for up to three weeks

●Subacute cough – Present for three to eight weeks

●Chronic cough – Present for longer than eight weeks

EPIDEMIOLOGY — Determining the precise prevalence of chronic cough is difficult given that it is not a unique disease but rather a symptom caused by a number of medical conditions.

Chronic cough affects approximately 10 to 12 percent of the population [4-7]. Patients who seek medical attention for chronic cough are more likely to be female than male (2:1) [8-11]. The peak age at onset is the sixth decade. Among patients with chronic cough, females tend to cough more often and to have heightened cough reflex sensitivity compared with males [8].

COUGH REFLEX ARC — Each cough occurs through the stimulation of a complex reflex arc. This is initiated by the activation of cough receptors that exist not only in the epithelium of the upper and lower respiratory tracts but also in the pericardium, esophagus, diaphragm, and stomach.

●Mechanical cough receptors can be stimulated by triggers such as touch, displacement, or acidity. The afferent signals are then carried by vagal A-delta-fibers, whose cell bodies are located in the nodose ganglion [12].

●Chemical receptors sensitive to cold, heat, capsaicin-like compounds, and other chemical irritants trigger the cough reflex via activation of ion channels, such as transient receptor potential vanilloid type 1 (TRPV1) and transient receptor potential ankyrin type 1 (TRPA1) classes [13-18]. The afferent signals are then carried by vagal C fibers, whose cell bodies are located in the jugular (superior vagal) ganglion [12]. (See "Neuronal control of the airways", section on 'Vagus nerves' and "Neuronal control of the airways", section on 'Chronic cough'.)

Impulses from stimulated cough receptors traverse an afferent pathway via the vagus nerve to a "cough center" in the medulla, which itself may be under some control by higher cortical centers. Sex-related differences in cough reflex sensitivity may explain the observation that women are more likely than men to develop chronic cough [19,20]. The cough center generates an efferent signal that travels down the vagus, phrenic, and spinal motor nerves to expiratory musculature to produce the cough (figure 1).

While the cough reflex arc seems a ready explanation of the onset of acute cough following inhalation of noxious vapors, patients with chronic cough may have cough reflex hypersensitivity. With cough reflex hypersensitivity, low-level exposures to irritants such as eosinophilic inflammation, reflux of esophageal contents into the airway, air pollution, and tobacco smoke can trigger coughing. (See "Neuronal control of the airways", section on 'Chronic cough'.)

CAUSES OF ACUTE COUGH — Most commonly, acute cough (present for <3 weeks) in adults is caused by an acute upper or lower respiratory tract infection (eg, common cold, acute bronchitis, coronavirus disease 2019 [COVID-19]) or an exacerbation of a chronic condition (eg, asthma, bronchiectasis, chronic obstructive pulmonary disease [COPD], chronic rhinosinusitis, heart failure), although other processes (eg, reactive airways disease syndrome [RADS], tuberculosis, lung cancer) remain in the differential diagnosis [3,21,22]. These disease processes are discussed separately. (See "Acute bronchitis in adults" and "Acute exacerbations of asthma in adults: Home and office management" and "COPD exacerbations: Clinical manifestations and evaluation".)

CAUSES OF SUBACUTE COUGH — The most common causes of subacute cough (present for three to eight weeks) are postinfectious cough (eg, respiratory viruses, pertussis, COVID-19) and exacerbations of underlying diseases (eg, asthma, chronic obstructive pulmonary disease [COPD], and chronic rhinitis) [3].

Postinfectious cough — Postinfectious cough refers to a cough that begins during a respiratory viral infection and lingers for several weeks after the other acute symptoms of infection have dissipated. The rates of postinfectious cough vary among studies, as shown in the following reports:

●In one study of 184 patients with subacute cough, nearly half of patients had a postinfectious cough that resolved without specific therapy [23].

●In a separate study of 41 patients with subacute cough, postinfectious cough was the cause in 12 percent [21].

Pertussis — Pertussis, also known as "whooping cough," is a highly contagious, acute respiratory illness caused by the coccobacillus, Bordetella pertussis. The paroxysmal stage, characterized by paroxysms of coughing that may be associated with an inspiratory whoop and/or post-tussive emesis, usually begins during the second week of illness and can last two to three months [24]. Symptoms may be worse at night. The choice of diagnostic tests (culture, polymerase chain reaction [PCR], serology) depends upon the duration of cough (table 1), as discussed separately. (See "Pertussis infection in adolescents and adults: Clinical manifestations and diagnosis".)

For patients with suspected pertussis and a cough less than three weeks in duration, empiric antibiotic therapy should be initiated at the same time as diagnostic testing. (See "Pertussis infection in adolescents and adults: Treatment and prevention".)

CAUSES OF CHRONIC COUGH — The most common etiologies of chronic cough (present for >8 weeks) are asthma, nonasthmatic eosinophilic bronchitis, chronic obstructive pulmonary disease (COPD), gastroesophageal reflux disease, and upper airway cough syndrome (due to postnasal drip) [3,25-31]. However, a number of other important etiologies must also be considered in patients presenting with persistent cough, including disorders affecting the airways (bronchiectasis, neoplasm, foreign body) or the pulmonary parenchyma (interstitial lung disease, lung abscess) (algorithm 1).

A cause is identified in 75 to 90 percent of patients with chronic cough [25,27,28], although some patients may experience chronic cough of unclear etiology for years, despite extensive evaluation. In some patients, "chronic idiopathic cough" appears due to exaggerated cough reflex sensitivity [9,32]. (See 'Cough reflex arc' above.)

Asthma — Asthma is a leading cause of persistent cough in adults and the most common cause in children [3,20]. Cough due to asthma is commonly accompanied by episodic wheezing and dyspnea; however, it can also be the sole manifestation of a form of asthma called "cough-variant asthma" [33-35]. Cough-variant asthma can progress to include wheezing and dyspnea [36]. (See "Asthma in adolescents and adults: Evaluation and diagnosis".)

A diagnosis of asthma is suggested when the patient is atopic or has a family history of asthma. Asthma-related cough may be seasonal, may follow an upper respiratory tract infection, or may worsen upon exposure to specific triggers such as cold or dry air, dust, mold, or certain fumes or fragrances. A cough accompanied by wheezing or dyspnea, or one that occurs following initiation of beta-blocker therapy, also suggests asthma.

In some cases, the cough is accompanied by reversible airflow obstruction [37]. In other patients, baseline spirometry is normal, but airway hyperreactivity can be demonstrated by bronchoprovocation testing [27,33]. However, in a patient with persistent cough, the presence of reversible airflow obstruction or a positive bronchoprovocation test does not necessarily prove that the cough is secondary to asthma. One study, for example, evaluated the utility of spirometry pre- and post-bronchodilator in predicting that asthma was responsible for cough [25]. Spirometry was falsely positive in 33 percent of patients, and methacholine challenge was falsely positive in 22 percent. Thus, the best way to confirm asthma as a cause of cough is to demonstrate improvement in the cough with appropriate therapy for asthma (eg, two to four weeks of inhaled glucocorticoids [38]).

Patients with active asthma typically have eosinophilic bronchitis. The diagnosis of nonasthmatic eosinophilic bronchitis should be considered in atopic patients with an idiopathic chronic cough and sputum eosinophilia in the absence of airway hyperreactivity. (See 'Nonasthmatic eosinophilic bronchitis' below.)

Exhaled nitric oxide (NO) has been studied as a predictor of response to inhaled glucocorticoids in both asthma and in nonasthmatic eosinophilic bronchitis. Exhaled NO and sputum eosinophilia are correlated in these conditions [39]. However, some studies have shown exhaled NO to be a good predictor of response of chronic cough to inhaled steroids [40], while other studies have not [41]. The explanation for this discrepancy may in part be related to what value is chosen to reflect an abnormally elevated exhaled NO.

Reflux disorders

Gastroesophageal reflux — The reported prevalence of cough due to gastroesophageal reflux disorder (GERD) varies widely [20]. Some studies report that GERD is the second or third most common cause of persistent cough [25,27,28,42], while other studies report a much lower prevalence of reflux-induced cough [29,43].

Many patients with chronic cough complain of symptoms commonly associated with GERD (eg, dysphonia, nasal symptoms, heartburn, or a sour taste in the mouth); however, these symptoms are absent in more than 40 percent of patients in whom cough is thought to be attributable to reflux [25,27,44,45]. While esophageal dysmotility is common among patients with chronic cough, a systematic review found no benefit to proton pump inhibitor therapy in patients without acid reflux and modest benefit in those with acid reflux [46]. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults".)

Several potential mechanisms have been hypothesized by which GERD might contribute to chronic cough [20,45,47-49]:

●Stimulation of receptors on vagal afferent nerves in the upper respiratory tract (eg, in the larynx).

●Aspiration of gastric contents, leading to stimulation of receptors in the lower respiratory tract and inflammation in the airways.

●An esophageal-tracheobronchial cough reflex induced by reflux of acid into the distal esophagus. In one study of patients with chronic cough and reflux, infusion of acid into the distal esophagus significantly increased cough frequency [50]. This effect was absent in control subjects without chronic cough. The acid-induced cough was significantly decreased by pretreatment with either inhaled ipratropium or a topical anesthetic (lignocaine) instilled into the esophagus.

Most often, the diagnosis of cough due to GERD is based on clinical features and a response to empiric therapy. Barium swallow examination is of limited diagnostic utility due to poor sensitivity and specificity in GERD.

Ambulatory esophageal pH monitoring, with impedance and event markers to allow correlation of cough with esophageal pH, is reserved for patients with persistent symptoms of GERD despite a three-month trial of antireflux therapy [49]. However, even with lifestyle modifications and maximal antireflux therapy, some patients with positive results on esophageal pH monitoring continue to cough [51]. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults", section on 'Evaluation in selected patients'.)

Esophageal dysmotility, with or without evidence of GERD, appears to be common in patients with chronic cough. However, the role of esophageal manometry in the evaluation remains to be defined [52-54].

Laryngopharyngeal reflux — Laryngopharyngeal reflux (LPR) is the retrograde movement of gastric contents (acid and enzymes such as pepsin) into the laryngopharynx leading to symptoms referable to the larynx/hypopharynx [55]. Most patients are relatively unaware of LPR with only 35 percent reporting heartburn. Typical LPR symptoms include dysphonia/hoarseness, chronic cough, mild dysphagia, and nonproductive throat clearing. (See "Laryngopharyngeal reflux in adults: Evaluation, diagnosis, and management".)

LPR is considered primarily an upper esophageal sphincter (UES) problem that mainly occurs in the upright position during periods of physical exertion (eg, bending over, Valsalva, exercise). In contrast, GERD is felt to be a problem of the lower esophageal sphincter and mainly occurs in a recumbent position. There appears to be a lower incidence of esophageal dysmotility in LPR versus GERD.

Direct laryngoscopic evaluation can assist in the diagnosis of cough from reflux. Arytenoid erythema and edema and pharyngeal inflammation often suggest laryngeal and pharyngeal reflux and when seen, suggest that a course of treatment for reflux is indicated with monitoring of the cough on such therapy.

Multichannel intraluminal impedance (MII) has been used to assess laryngopharyngeal and high esophageal reflux in patients with chronic cough. Among 49 patients with unexplained chronic cough who underwent MII, 73 percent had nonacid proximal esophageal events. Furthermore, in the nearly half of these who went on to antireflux surgery, 100 percent had either total or significant resolution of cough [56]. The authors concluded that a "pH-centric" approach may well be inadequate to evaluate cough related to reflux, which may explain the debate still present in some circles on the relationship between GERD and cough [57].

GERD in those with obstructive sleep apnea — The incidence of chronic cough in patients with obstructive sleep apnea (OSA) can exceed 30 percent [58], which may be related to GERD [59]. Continuous positive airway pressure (CPAP) treatment significantly improves cough in such OSA patients, and this benefit may be via an effect on GERD [60].

Upper airway cough syndrome — Upper airway cough syndrome (UACS) is thought to be due to "postnasal drip" or nasal secretions flowing into the nasopharynx caused by allergic, perennial nonallergic, or vasomotor rhinitis or rhinosinusitis [3,20]. The exact role of UACS as a cause of chronic cough is unclear [20], although several studies suggest that UACS related to postnasal drip is a common cause of subacute and chronic cough [23,25,26,28]. Once secretions are present in the upper airway, cough is probably induced by stimulation of cough receptors within the laryngeal mucosa. (See "An overview of rhinitis".)

Other symptoms attributed to postnasal drip include frequent nasal discharge, a sensation of liquid flowing into the back of the throat, and frequent throat clearing [25]. However, postnasal drip may also be "silent," so that the absence of these symptoms does not necessarily exclude the diagnosis [28]. Clues on physical examination are a cobblestone appearance to the pharyngeal mucosa and the presence of secretions in the pharynx.

Because the symptoms and signs of postnasal drip are nonspecific, there are no definitive criteria for its diagnosis, and it is ultimately the response to therapy that secures the diagnosis. Radiographic evidence of mucosal thickening of the sinuses is a relatively nonspecific finding, and radiographic studies of the sinuses are generally not indicated unless empiric treatment of chronic rhinitis has failed [20,61].

Nonasthmatic eosinophilic bronchitis — Nonasthmatic eosinophilic bronchitis (NAEB) is an increasingly recognized cause of chronic nonproductive cough, particularly in patients who lack risk factors for other common causes of chronic cough [62-66]. Patients with NAEB demonstrate atopic tendencies, with elevated sputum eosinophils and active airway inflammation, but airway hyperresponsiveness is absent [62]. These same atopic features with evidence of hyperresponsiveness are consistent with the diagnosis of cough due to asthma [63]. (See 'Asthma' above.)

In one series of 20 patients with chronic isolated (nonspecific) cough, no apparent cause, and no airway hyperresponsiveness, bronchial biopsy revealed eosinophilic bronchitis in 16 [62].

Although bronchial mucosal biopsies are required to definitively diagnose eosinophilic bronchitis, a trial of therapy is usually performed without biopsy since most patients respond well to inhaled glucocorticoids [67,68]. On histopathology, airway eosinophils and basement membrane thickening are present in both asthma and eosinophilic bronchitis, but mast-cell infiltration is noted only in asthmatics, which may explain the difference in airway reactivity [69-71].

The natural history of nonasthmatic eosinophilic bronchitis is variable. One-year follow-up of a cohort of 367 patients with normal lung function and eosinophilic inflammation noted that 55 percent remained symptomatic with normal lung function, 32 percent were free of symptoms, and 13 percent developed asthma [72]. Patients with recurrent episodes of symptomatic eosinophilic bronchitis appear to be at increased risk of asthma and chronic airway obstruction [73].

ACE inhibitors and other medications — Cough is a common complication of several classes of medications, particularly angiotensin converting enzyme (ACE) inhibitors. Cessation of these medications is a diagnostic and therapeutic trial. Cough will generally resolve within several days.

●ACE inhibitors – A nonproductive cough is a well-recognized complication of treatment with angiotensin converting enzyme (ACE) inhibitors [3,20,74]. It is more common in females than males and also more common in Chinese people [75].

Although the pathogenesis of the cough is not known with certainty, it is thought that ACE inhibitors increase the sensitivity of the cough reflex [76], possibly an effect of accumulation of bradykinin, which is normally degraded by ACE and can stimulate afferent C-fibers in the airway [77]. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers", section on 'Cough'.)

ACE inhibitor-induced cough has the following general features [74]:

•It usually begins within one week of instituting therapy, but the onset can be delayed up to six months.

•It often presents with a tickling, scratchy, or itchy sensation in the throat.

•It does not occur more frequently in asthmatics than in nonasthmatics.

•It is generally not accompanied by airflow obstruction [78]. In one study, for every 10 patients with cough induced by ACE inhibitors, there was approximately one patient with development or aggravation of asthma, bronchospasm, or dyspnea [79]. Cough did not necessarily accompany these other respiratory problems.

•It typically resolves within one to four days of discontinuing therapy but can take up to four weeks [76].

•It generally recurs with rechallenge, either with the same or a different ACE inhibitor.

●Calcium channel blockers and bisphosphonates – Medications that increase gastroesophageal reflux, such as calcium channel blockers and bisphosphonates, can theoretically worsen pre-existing reflux and potentially increase cough.

●Glaucoma medications – Heightened cough sensitivity has been reported in an isolated case with latanoprost, a topical prostaglandin F2-alpha analog [80]. Latanoprost was thought to pass through the lacrimal ducts to the nasopharynx, where it caused sensitivity of cough receptors. Timolol is a nonselective beta-blocker that can cause bronchoconstriction and cough in patients with asthma [81].

●Medications NOT likely to cause cough – Although the following have previously raised concerns about causing cough, available data suggest that they do not increase the incidence of cough.

•Angiotensin II receptor blockers – Cough does not appear to occur with increased frequency in patients treated with angiotensin II receptor antagonists (which do not increase kinin levels), a finding that is consistent with the kinin hypothesis. A review of clinical trials found that the incidence of cough with losartan was similar to that with placebo (3.1 versus 2.6 percent) and well below that seen with ACE inhibitors (8.8 percent) [82]. Another large study evaluated patients with a prior history of ACE inhibitor-induced cough; the incidence of recurrent cough was much higher with readministration of an ACE inhibitor (72 percent) than with either losartan or hydrochlorothiazide (29 to 34 percent) [83]. (See "Renin-angiotensin system inhibition in the treatment of hypertension".)

•Sitagliptin – Although one small case series described subacute cough in patients newly prescribed sitagliptin for type II diabetes [84], additional data from randomized trials do not support this association. A meta-analysis of treatment trials with sitagliptin found a slight increase in nasopharyngitis but no mention of cough [85]. A randomized trial with over 14,000 participants and three years of follow-up did not identify nasopharyngitis or cough in the adverse event reporting [86].

Prolonged postinfectious cough — Cough following viral or other upper respiratory tract infection can persist for more than eight weeks after the acute infection [87]. Such cases increase in frequency during outbreaks of Mycoplasma pneumoniae, Chlamydia pneumoniae, B. pertussis, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; cause of COVID-19) [42,88-90]. (See "Acute bronchitis in adults".)

●Bordetella pertussis – Pertussis is a common but under-recognized cause of chronic cough in adolescents and adults [91-96]. As noted above, cough often begins in the second week of illness and can persist for several weeks to months. In one series, the median duration of cough was 112 days (range 38 to 191) [97]. The evaluation and diagnosis of pertussis are described separately. (See 'Pertussis' above and "Pertussis infection in adolescents and adults: Clinical manifestations and diagnosis".)

●Unsuspected bacterial suppurative disease – Some cases of unsuspected bacterial suppurative disease of the large airways, in the absence of bronchiectasis, have been reported as a cause of chronic cough. Bronchoscopic evaluation and microbiologic sampling of the airways led to this diagnosis in a series of 15 patients undergoing evaluation at a single center for cough that remained unexplained after extensive evaluation [98]. While four of these patients had underlying systemic disease, the remainder had no evidence of immune compromise. Aggressive antibiotic therapy, based upon the results of bronchoscopic culture, led to improvement or elimination of the cough in all patients. The prevalence of this disorder and the appropriate duration of antibiotic therapy remain to be determined.

●COVID-19 – In our experience during the pandemic, COVID-19 has become a common cause of cough, both acute and chronic [90]. Management of cough in recovery is discussed separately. (See "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")".)

Several possibly interrelated mechanisms are thought to contribute to postinfectious cough:

●Secretions from a postnasal drip may stimulate receptors in the upper respiratory tract.

●Enhanced sensitivity of airway nerves, assessed experimentally by the concentration of inhaled capsaicin required to elicit cough, may be present after upper respiratory tract infections, particularly in those patients who develop a nonproductive cough [99]. A possible explanation for this response is exposure of afferent nerves, located immediately below epithelial tight junctions, as a consequence of viral-induced epithelial necrosis [100].

●Airway inflammation following acute viral respiratory infections is associated with airway hyperresponsiveness and the potential for cough as well as airway constriction [100,101].

Other pulmonary diseases

Chronic bronchitis — Chronic bronchitis is defined as the presence of cough and sputum production on most days over at least a three-month period for more than two consecutive years in a patient without other explanations for cough. Almost all patients are smokers or former smokers with a long exposure history, except for a small number who have chronic exposure to other fumes or dusts. Because of the high prevalence of smoking, chronic bronchitis remains one of the most frequent causes of chronic cough. However, most smokers with chronic bronchitis do not seek medical attention for their cough, and in most series of chronic cough, chronic bronchitis accounts for 5 percent or less of cases [25]. (See "Chronic obstructive pulmonary disease: Diagnosis and staging", section on 'Chronic bronchitis'.)

The sputum produced is usually clear or white. A purulent appearance to sputum often suggests a concomitant upper or lower respiratory infection, such as acute bronchitis, bronchiectasis, or sinusitis. In any smoker who presents for evaluation of cough, one must ensure that the symptoms do not represent a change in a chronic cough that is suggestive of a neoplasm. (See 'Lung cancer' below and "COPD exacerbations: Clinical manifestations and evaluation".)

Bronchiectasis — Bronchiectasis accounts for less than 2 percent of patients with chronic cough overall, but up to 4 percent of those with excessive sputum production [1,102].

Among patients with bronchiectasis, cough is a major symptom. While some patients with bronchiectasis have only a dry cough, most produce chronic sputum that is mucopurulent, which becomes frankly purulent during an exacerbation. The lung examination may sometimes be normal but more often reveals focal or bilateral rhonchi, crackles, or wheezes.

The chest radiograph may suggest the disease by demonstrating crowded lung markings, thickened bronchial walls, or small fluid-filled cystic structures. However, these findings are insensitive and nonspecific, and high-resolution computed tomography (CT) of the chest is the optimal method of securing the diagnosis in patients with suspicious clinical findings.

Once bronchiectasis is diagnosed, further study should be directed at finding the underlying cause, as specific treatment may improve outcomes. (See "Clinical manifestations and diagnosis of bronchiectasis in adults" and "Bronchiectasis in adults: Treatment of acute and recurrent exacerbations".)

Interstitial lung disease — Cough is a common symptom in patients with any type of interstitial lung disease, but it is frequently accompanied by dyspnea. Clinical examination typically features fine crackles, often in the dependent zones, and chest imaging may yield a wide variety of abnormal findings. (See "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis", section on 'Clinical manifestations'.)

Lung cancer — Cough is present in 50 to 75 percent of lung cancer patients at the time of diagnosis [103-105]. However, lung cancer is the etiology in less than 2 percent of cases of chronic cough [3,105]. (See "Clinical manifestations of lung cancer".)

Most often, when chronic cough is due to lung cancer, the cancer originates in the large central airways, where cough receptors are common. Patients with central airway tumors may have focal wheezing or diminished breath sounds on physical examination, indicative of partial or complete airway obstruction.

Pulmonary lymphangitic carcinomatosis from extrapulmonary malignancies can also present as cough but is generally accompanied by dyspnea. Physical examination may reveal bilateral crackles.

Bronchogenic cancer should be considered as a possible etiology of cough in any current or former smoker and should be particularly suspected in those with:

●A new cough or a recent change in chronic "smoker's cough"

●A cough that persists more than one month following smoking cessation

●Hemoptysis that does not occur in the setting of an airway infection

Smoldering infection — Certain pulmonary infections, including tuberculosis, nontuberculous mycobacterial infections, endemic fungal infections (eg, histoplasmosis), parasitic infections (eg, strongyloidiasis), nocardiosis, or lung abscess, may present with ongoing chronic cough and additional infectious symptoms. In areas of high prevalence for Mycobacterium tuberculosis or endemic fungi/parasites, increased suspicion for smoldering infection is appropriate, particularly in those with fever, productive cough, fatigue, weight loss, hemoptysis, or immunocompromise. Many smoldering pulmonary infections also demonstrate opacities and/or lymphadenopathy on chest imaging that should prompt a thorough infectious work-up. (See "Diagnosis of pulmonary tuberculosis in adults" and "Pathogenesis and clinical features of pulmonary histoplasmosis" and "Strongyloidiasis" and "Lung abscess in adults" and "Nocardia infections: Epidemiology, clinical manifestations, and diagnosis" and "Epidemiology of pulmonary infections in immunocompromised patients".)

Aspiration — Airway irritation and cough can occur in the setting of aspiration of food, liquids, or other foreign bodies into the lower airways. Common settings are discussed below.

Swallowing dysfunction with recurrent aspiration — In the older adult or infirm, swallowing dysfunction may lead to recurrent aspiration and chronic cough. Coarse crackles or chronic consolidations or atelectasis in the lower lobes, resulting from recurrent aspiration events, and recurrent pneumonia are common. Cough while eating or drinking, particularly with thin liquids, is a common symptom. Formal assessment by a speech pathologist may be needed to identify clinically silent aspiration. (See "Aspiration pneumonia in adults", section on 'Predisposing conditions'.)

Foreign body aspiration — The presence of foreign bodies in the lower airways can present dramatically, particularly in children. However, aspiration of smaller nondissolving objects into the bronchus intermedius or more distal subsegmental airways can lead to chronic cough that can be surprisingly difficult to diagnose. Focal wheezing, hemoptysis, and foul-smelling sputum are the most common clinical signs, with lower lobe atelectasis or consolidation the most frequent imaging abnormality. (See "Airway foreign bodies in adults".)

Chronic heart failure — Pulmonary edema may result in a dry cough from airway edema and irritation or a characteristic wet cough with frothy sputum arising from alveolar fluid accumulation. Other typical signs and symptoms of heart failure (eg, peripheral edema, abnormal heart sounds, elevated jugular venous pressure, ascites, pleural effusions, and vascular redistribution in the lung fields) may be present. (See "Clinical manifestations and diagnosis of advanced heart failure", section on 'Symptoms and signs'.)

Irritation of the vagus nerve — Multiple other conditions may occasionally contribute to irritation of vagus efferents and stimulation of the cough reflex arc (figure 1). These include disorders of the external auditory canals, pharynx, larynx, diaphragm, pleura, pericardium, esophagus, stomach, or thyroid. The mechanism of vagal irritation is not always well understood.

Some specific examples include:

●Central airway compression or abnormalities – Lesions that compress the central airways, including arteriovenous malformations and retrotracheal masses, may present with chronic cough [106-108]. Cough also can be a symptom of tracheobronchomalacia, which results from loss of rigid support of the large airways and inspiratory collapse, and is usually seen in conjunction with obstructive lung disease in patients with a history of cigarette smoking [109]. Tracheal diverticula have also been noted in association with chronic cough [110]. (See "Radiology of the trachea".)

●Laryngeal sensory neuropathy – Laryngeal sensory neuropathy has been identified as the cause of chronic cough in 18 of 26 patients with acute onset of cough that was often associated with laryngospasm or throat clearing [111]. The diagnosis was made by laryngeal electromyography or videostroboscopy, usually after exclusion or treatment of other causes of chronic cough.

●Chronic tonsillar enlargement – Chronic tonsillar enlargement has been proposed as a cause of chronic cough, but clinical evidence of this association is limited. One series of 236 patients referred for evaluation in a specialized clinic noted tonsillar enlargement in the absence of other known causes of chronic cough in eight individuals (3.4 percent) [112]. Following tonsillectomy, these patients had decreased cough sensitivity and significantly improved symptom control. These intriguing preliminary observations require further investigation before this approach can be recommended. (See "Tonsillectomy in adults: Indications".)

●Arnold "ear-cough" reflex – Irritation of the external auditory canal by impacted foreign bodies or cerumen is another unusual cause of chronic dry cough [113]. The etiology of the "ear-cough" (or oto-respiratory) reflex is related to stimulation of the auricular branch of the vagus nerve (Arnold nerve) [114,115]. For this reason, otoscopic examination should be performed in patients with an undiagnosed chronic cough.

●Premature ventricular contractions – Premature ventricular contractions (PVCs) may rarely cause a chronic cough. In a series of 120 patients referred to an electrophysiology center for evaluation of PVCs, six had a chronic cough that either disappeared upon spontaneous resolution of the PVCs or markedly improved with treatment of the arrhythmia [116].

●Holmes-Adie syndrome – Autonomic dysfunction of the vagus nerve, known as Holmes-Adie syndrome, is a rare cause of chronic cough [117] (see "Tonic pupil"). Patients present with anisocoria, abnormal deep tendon reflexes, and patchy areas of hyperhidrosis or anhidrosis.

Diagnoses of exclusion

Somatic cough disorder — In adults, somatic cough disorder or tic cough (also known as "psychogenic" or habit cough) may rarely be the cause of a chronic cough that remains troublesome despite a thorough evaluation (algorithm 1) [118,119]. No clinical manifestations or associated conditions have been confirmed, although patients should be evaluated for common problems such as anxiety, depression, and domestic violence [120]. The diagnostic features are the lack of a diagnosis following a complete evaluation and improvement with behavior modification or psychiatric therapy.

Chronic refractory cough — A portion of patients with chronic cough experience persistence of the cough despite a thorough investigation, including systematic, guideline-based trials of empiric therapy for the common causes of cough. For these patients, the cough is described as chronic refractory cough, idiopathic chronic cough, unexplained chronic cough, neurogenic cough, or cough hypersensitivity syndrome [20,121,122]. It is seen in approximately 20 to 46 percent of patients presenting to specialist cough clinics [122].

The onset of chronic refractory cough may be precipitated by a respiratory viral infection [122]. Associated symptoms may include a globus sensation, dyspnea, and dysphonia. The diagnosis is made after exclusion of other possible causes. Treatment strategies for this condition are discussed separately. (See "Evaluation and treatment of subacute and chronic cough in adults", section on 'Unexplained chronic cough'.)

In one European cohort of 68 patients with refractory chronic cough, approximately one quarter of patients carried repeat expansions in the replication factor C subunit 1 gene (8.8 percent monoallelic, 16.2 percent biallelic), a significantly higher carrier frequency than the expected 0.7 percent seen in the European population [123]. Biallelic RFC1 repeat expansions (RE-RFC1) are associated with Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome (CANVAS), a neurologic syndrome that frequently manifests with chronic cough long before onset of other neurologic sequelae. In this cohort, patients with mono- or biallelic RE-RFC1 were younger than patients without RE-RFC1 and more likely to have cough triggered by dusts or food. For patients with RE-RFC1, chronic cough is likely related to vagal neuropathy, but the pathologic mechanism is not yet confirmed.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Subacute and chronic cough in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Cough in adults (The Basics)" and "Patient education: Asthma in adults (The Basics)" and "Patient education: Acid reflux and GERD in adults (The Basics)")

●Beyond the Basics topics (see "Patient education: Chronic cough in adults (Beyond the Basics)" and "Patient education: Gastroesophageal reflux disease in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Cough reflex arc – Cough occurs through a complex reflex arc (figure 1). Mechanical cough receptors can be stimulated by triggers such as touch or displacement. Specialized chemical receptors sensitive to acid, cold, heat, capsaicin-like compounds, and other chemical irritants send signals via the vagus nerve to a "cough center" in the medulla, which in turn generates an efferent signal that travels down the vagus, phrenic, and spinal motor nerves to expiratory musculature to produce the cough. (See 'Cough reflex arc' above.)

●Classification – Cough in adults can be classified based upon the duration of the cough at the time of presentation to the health care provider.

•Acute cough – Present for up to three weeks

•Subacute cough – Present for three to eight weeks

•Chronic cough – Present for longer than eight weeks

●Causes of subacute cough (three to eight weeks) – The most common causes of subacute cough are postinfectious cough, pertussis, and exacerbations of underlying diseases (eg, asthma, chronic obstructive pulmonary disease [COPD], and chronic rhinitis). (See 'Causes of subacute cough' above.)

●Causes of chronic cough (>8 weeks)

•Asthma – Asthma is a leading cause of persistent cough in adults. Cough due to asthma is commonly accompanied by episodic wheezing and dyspnea; however, it can also be the sole manifestation of a form of asthma called "cough-variant asthma." (See 'Asthma' above.)

•Gastroesophageal reflux disorder (GERD) – Reports of GERD as a cause of cough are varying. (See 'Reflux disorders' above.)

•Upper airway cough syndrome (UACS) – UACS is thought to be due to "postnasal drip" or nasal secretions flowing into the nasopharynx caused by allergic, perennial nonallergic, or vasomotor rhinitis or rhinosinusitis. (See 'Upper airway cough syndrome' above.)

•Nonasthmatic eosinophilic bronchitis (NAEB) – NAEB is an increasingly recognized cause of chronic nonproductive cough, particularly in patients who lack risk factors for other common causes of chronic cough. Patients with NAEB demonstrate atopic tendencies, with elevated sputum eosinophils and active airway inflammation, but airway hyperresponsiveness is absent. (See 'Nonasthmatic eosinophilic bronchitis' above.)

•Other specific causes – Patients taking certain medications (particularly angiotensin converting enzyme inhibitors), patients with recent viral or upper respiratory tract infection, patients with a significant smoking history, patients with a history of aspiration, and patients with other signs and symptoms of cardiopulmonary disease are at risk for other less common causes of cough. Disorders of other extrathoracic organs may irritate vagal efferents and uncommonly cause cough. (See 'ACE inhibitors and other medications' above and 'Prolonged postinfectious cough' above and 'Other pulmonary diseases' above and 'Aspiration' above and 'Chronic heart failure' above and 'Irritation of the vagus nerve' above.)

•Chronic refractory cough – Chronic refractory cough is the term used for a persistent cough despite a thorough investigation, including systematic trials of empiric therapy for the common causes of cough. The onset may follow a viral upper respiratory tract infection and may be associated with globus sensation, dyspnea, and/or dysphonia. Other terms that have been used include idiopathic chronic cough, unexplained chronic cough, and cough hypersensitivity syndrome. (See 'Chronic refractory cough' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Ronald C Silvestri, MD, who contributed to earlier versions of this topic review.