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Evaluation of subacute and chronic cough in adults

Authors Ronald C Silvestri, MD Steven E Weinberger, MD Section Editors Peter J Barnes, DM, DSc, FRCP, FRS Talmadge E King, Jr, MD Deputy Editor Helen Hollingsworth, MD

Last literature review version 18.3: wrzesie 2010 | This topic last updated: sierpie 16, 2010 INTRODUCTION The symptom of cough, which is responsible for approximately 30 million clinician visits annually in the United States, is one of the most common symptoms for which outpatient care is sought [1]. In an outpatient pulmonary practice, evaluation and management of persistent cough can account for up to 40 percent of the practice volume [2]. Cough can be classified based upon the duration of the cough; within each category are likely diagnostic possibilities. Acute cough exists for less than three weeks and is most commonly due to an acute respiratory tract infection. Other considerations include an acute exacerbation of underlying chronic pulmonary disease, pneumonia, and pulmonary embolism. Cough that has been present longer than three weeks is either subacute (three to eight weeks) or chronic (more than eight weeks) [1]. Patients who seek medical attention for chronic cough are more likely to be female [3-5]. Among patients with chronic cough, women tend to cough more often and to have heightened cough reflex sensitivity compared to men [4]. The common etiologies, complications, and evaluation, of subacute and chronic cough will be reviewed here. The treatment of subacute and chronic cough is described separately. (See "Treatment of subacute and chronic cough in adults".) COUGH REFLEX ARC Each cough occurs through the stimulation of a complex reflex arc. This is initiated by the irritation 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. Chemical receptors sensitive to acid, cold, heat, capsaicin-like compounds, and other chemical irritants trigger the cough reflex via activation of ion channels of the transient receptor potential vanilloid type 1 (TRPV1) and transient receptor potential ankyrin type 1 (TRPA1) classes [6-9]. (See "Neuronal control of the airways", section on 'Reflex regulation'.) Mechanical cough receptors can be stimulated by triggers such as touch or displacement. Laryngeal and tracheobronchial receptors respond to both mechanical and chemical stimuli. 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 explain the observation that women are more likely than men to develop chronic cough [1,10-12]. 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). ETIOLOGIES The most common etiologies of chronic cough are upper airway cough syndrome (due to postnasal drip), asthma, and gastroesophageal reflux [1-3,13-17]. However, a number of other important etiologies must also be considered in patients presenting with persistent cough. As an example, a postinfectious etiology is a particularly common cause of subacute cough, with the cough often lingering long after the other acute symptoms of the infection have dissipated. One study showed that in nearly half of patients, subacute cough was post infectious and resolved without specific therapy [18]. Cough may also be a complication of drug therapy, particularly with angiotensin converting enzyme (ACE)

inhibitors. Other less common causes of chronic cough include a number of disorders affecting the airways (nonasthmatic eosinophilic bronchitis, chronic bronchitis, bronchiectasis, neoplasm, foreign body) or the pulmonary parenchyma (interstitial lung disease, lung abscess) (table 1). A cause is identified in 75 to 90 percent of patients with chronic cough [2,13,15]. However, some patients may experience chronic cough of unclear etiology for years, despite extensive evaluation. The etiology of so-called "chronic idiopathic cough" is unknown; exaggerated cough reflex sensitivity induced by upper respiratory infection has been suggested [5]. Upper airway cough syndrome Several studies suggest that upper airway cough syndrome related to postnasal drip is a common cause of subacute and chronic cough [2,3,15,18]. Underlying reasons for postnasal drip include allergic, perennial nonallergic, and vasomotor rhinitis; acute nasopharyngitis; and sinusitis [19]. Once secretions are present in the upper airway, cough is probably induced by stimulation of cough receptors within the laryngeal mucosa. Symptoms of postnasal drip include frequent nasal discharge, a sensation of liquid dripping into the back of the throat, and frequent throat clearing [2]. However, postnasal drip may also be "silent," so that the absence of these symptoms does not necessarily exclude the diagnosis [15]. Clues on physical examination are a cobblestone appearance to the nasopharyngeal mucosa and the presence of secretions in the nasopharynx. 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. When an alternative specific cause for cough is not apparent, empiric therapy of postnasal drip should be attempted before embarking on an extensive diagnostic work-up for other etiologies [1]. Radiographic evidence of mucosal thickening is a relatively nonspecific finding, and radiographic studies generally are not indicated unless empiric treatment of chronic rhinitis has failed [20]. Asthma Asthma is the second leading cause of persistent cough in adults, and the most common cause in children [21]. 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" [22-24]. Cough variant asthma can progress to include wheezing and dyspnea [25]. (See "Diagnosis of asthma in adolescents and adults".) A diagnosis of asthma is suggested when the patient is atopic or has a family history of asthma. Asthmarelated cough may be seasonal, may follow an upper respiratory tract infection, or may worsen upon exposure to cold, dry air, dust, mold, or to 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 [26]. In other patients, baseline spirometry is normal, but airways hyperreactivity can be demonstrated by bronchoprovocation testing [13,22]. 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 [2]. 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 [27]). 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 [28], However, some studies have shown exhaled NO to be a good predictor of response of chronic cough to inhaled steroids [29], while other studies have not [30]. The explanation for this discrepancy may in

part be related what value is chosen to reflect an abnormally elevated exhaled NO. Gastroesophageal reflux Gastroesophageal reflux is often reported to be the second or third most common cause of persistent cough [1,2,13,15], although it is the most common cause in some reports, occurring in 30 to 40 percent of patients [16,31]. Many patients complain of symptoms of gastroesophageal reflux (heartburn or a sour taste in the mouth); however, these symptoms are absent in more than 40 percent of patients in whom cough is due to reflux [2,13,32,33]. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults".) Several factors are potentially responsible for the cough associated with gastroesophageal reflux [33-35]: Stimulation of receptors in the upper respiratory tract (eg, in the larynx). Aspiration of gastric contents, leading to stimulation of receptors in the lower respiratory tract. 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 [36]. 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. The presence of cough induced by gastroesophageal reflux may be suggested by an abnormal barium swallow, but this study is negative in the majority of patients and many patients with reflux do not have cough [2]. Prolonged (24 hour) esophageal pH monitoring, ideally performed with event markers to allow correlation of cough with esophageal pH, is generally considered the optimal diagnostic study, with a sensitivity exceeding 90 percent [1,2,13,33]. However, even with maximal antireflux therapy, some patients with positive results on esophageal pH monitoring continue to cough [37]. 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 [38-40]. Gastroesophageal reflux can also contribute to asthma symptoms. (See "Gastroesophageal reflux and asthma".) 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 [41]. 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".) LPR is seen as 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. Respiratory tract infection Cough following viral or other upper respiratory tract infection can persist for more than eight weeks after the acute infection [42]. Such cases increase in frequency during outbreaks of Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Bordetella pertussis [1,43,44]. (See "Acute bronchitis in adults".) Several possibly interrelated mechanisms may be responsible for cough in this setting: Secretions from a postnasal drip may stimulate receptors in the upper respiratory tract. Antihistamine-

decongestant therapy may be effective in reducing nasal discharge, nasal obstruction, throat clearing, and cough [45]. 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 [46]. 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 [47]. Airway inflammation following acute viral respiratory infections is associated with airway hyperresponsiveness and the potential for cough as well as airway constriction [47,48]. Pertussis is a common, but under recognized, cause of persistent cough in adolescents and adults [49]. In the United States, the recognition of pertussis in adolescents and adults has increased dramatically over the past decade [50,51]. In one series of 75 adults with cough lasting more than two weeks, 21 percent met serologic criteria for pertussis infection despite a negative culture for Bordetella pertussis [52]. However, accurate serologic studies are infrequently available and may be difficult to interpret, further complicating confirmation of this diagnosis [53,54]. (See "Clinical features and diagnosis of Bordetella pertussis infection in adolescents and adults".) Some patients appear to have unsuspected bacterial suppurative disease of the large airways, in the absence of bronchiectasis, 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 [55]. 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, remains to be determined. ACE inhibitors A nonproductive cough is a well-recognized complication of treatment with angiotensin converting enzyme (ACE) inhibitors, occurring in up to 15 percent of patients treated with these agents [12,56]. Although the pathogenesis of the cough is not known with certainty, it has commonly been hypothesized that accumulation of bradykinin, which is normally degraded in part by ACE, may stimulate afferent C-fibers in the airway [57]. The important observation that cough does not appear to occur with increased frequency in patients treated with angiotensin II receptor antagonists (which do not increase kinin levels) 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 to 3.4 percent) and well below that seen with ACE inhibitors (10.6 percent) [58]. 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) [59]. (See "Renin-angiotensin system inhibition in the treatment of hypertension".) ACE inhibitor-induced cough has the following general features [56]: 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 [1]. It typically resolves within one to four days of discontinuing therapy, but can take up to four weeks. It generally recurs with rechallenge, either with the same or a different ACE inhibitor. It is a more common complication in women than in men, and is also more common in those of Chinese ancestry [60].

It does not occur more frequently in asthmatics than in non-asthmatics. It is generally not accompanied by airflow obstruction [61]. 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 [62]. Cough did not necessarily accompany these other respiratory problems. Treatment consists of discontinuing the ACE inhibitor and, if necessary, switching the patient to losartan or another angiotensin II receptor antagonist [57]. (See "Major side effects of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers".) 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, except a small number who have chronic exposure to and airway inflammation due 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 [2]. 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 "Diagnosis and treatment of infection in acute exacerbations of chronic obstructive pulmonary disease" and "Overview of the risk factors, pathology, and clinical manifestations of lung cancer".) Bronchiectasis Bronchiectasis results from severe, repeated, or persistent airway inflammation that leads to progressive airway damage. Bronchi become dilated and cystic, leading to poor mucus clearance, secretion pooling, and chronic infection of the lower respiratory tract. This, in turn, serves to worsen airway inflammation and bronchial destruction. (See "Clinical manifestations and diagnosis of bronchiectasis in adults".) Cough is a major symptom of bronchiectasis, and in some studies, bronchiectasis is the cause of chronic cough in 4 percent of patients [2,63]. While some patients with bronchiectasis have only a dry cough, most produce chronic sputum that is mucopurulent, and which becomes frankly purulent during an exacerbation. The lung examination may be surprisingly 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 chest CT with high resolution imaging is the optimal method of securing the diagnosis. Once bronchiectasis is diagnosed, one should attempt to define its cause. Focal bronchiectasis is often the result of a prolonged or severe remote lower respiratory infection. Multifocal bronchiectasis, especially in a middle aged woman, is often due to chronic lower airway infection with Mycobacterium avium complex (MAC). More diffuse bronchiectasis, especially in a younger individual, raises the possibility of cystic fibrosis or an immunoglobulin deficiency state. Lung cancer Bronchogenic carcinoma is a feared diagnosis in which cough is present in a significant number of cases [64]. However, lung cancer is the etiology in less than 2 percent of the cases of chronic cough [1,2,64]. Most cases of lung cancer that manifest with cough are due to neoplasms originating in the large central airways, where cough receptors are common. Physical examination may reveal focal wheezing or diminished breath sounds, indicative of focal airway obstruction from tumor. Pulmonary lymphangitic carcinomatosis from extrapulmonary malignancies can also present as cough, but is generally accompanied by dyspnea. 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 (see "Overview of the risk factors, pathology, and clinical manifestations of lung cancer"). Nonasthmatic eosinophilic bronchitis Nonasthmatic eosinophilic bronchitis is an increasingly recognized cause of chronic nonproductive cough, particularly in patients who lack any of the risk factors described above [65-69]. Patients with this disorder demonstrate atopic tendencies, with elevated sputum eosinophils and active airway inflammation in the absence of airway hyperresponsiveness [65]. These same findings with evidence of hyperresponsiveness are consistent with the diagnosis of cough-variant asthma [66]. (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 [65]. 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 [67,70]. 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 differences in airway reactivity [71-73]. 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 [74]. Patients with recurrent episodes of symptomatic eosinophilic bronchitis appear to be at increased risk of asthma and chronic airway obstruction [75]. Rare causes In the elderly or infirm, swallowing dysfunction may lead to recurrent aspiration and chronic cough. Formal assessment by a speech pathologist may be needed for clinically silent aspiration. (See "Aspiration pneumonia in adults", section on 'Predisposing conditions'.) Lesions that compress the upper airway, including arteriovenous malformations and retrotracheal masses, may present with chronic cough [76-78]. 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 [79]. Tracheal diverticuli have also been noted in association with chronic cough [80]. (See "Radiology of the trachea".) 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 [81]. The diagnosis was made by laryngeal electromyography or videostroboscopy, usually after exclusion or treatment of other causes of chronic cough. 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 8 individuals (3.4 percent) [82]. 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. Irritation of the external auditory canal by impacted foreign bodies or cerumen is another unusual cause of chronic dry cough [83]. The etiology of the "ear-cough" (or oto-respiratory) reflex is related to stimulation of the auricular branch of the vagus nerve (Arnold's nerve) [84,85]. For this reason, otoscopic examination should be performed in patients with an undiagnosed chronic cough. 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 [86].

Another rare cause of chronic cough is Holmes-Adie syndrome due to autonomic dysfunction affecting the vagus nerve [87]. (See "Tonic pupil".) Patients present with anisocoria, abnormal deep tendon reflexes, and patchy areas of hyperhidrosis or anhidrosis. In adults, habit (also known as "psychogenic") cough may rarely be the cause of a chronic cough that remains troublesome despite a thorough evaluation, including ruling out tic disorders (figure 2) [88]. No particular clinical manifestations or associated conditions have been confirmed, although patients should be evaluated for common problems such as anxiety, depression, and domestic violence. The diagnostic features are the lack of a diagnosis following a complete evaluation and improvement with behavior modification or psychiatric therapy. COMPLICATIONS During vigorous coughing, intrathoracic pressures may reach 300 mmHg and expiratory velocities approach 500 miles per hour [89]. While these pressures and velocities are responsible for the beneficial effects of cough on mucus clearance, they are also responsible for many of the complications of cough, including exhaustion, self-consciousness, insomnia, headache, dizziness, musculoskeletal pain, hoarseness, excessive perspiration, urinary incontinence, and concern that "something is wrong" (table 2) [1,90]. Cough-induced rib fractures are another painful and potentially serious complication of chronic cough. Fractures often involve multiple ribs, particularly ribs five through seven. Women with decreased bone density are at the greatest risk of this complication; however, fractures can occur in patients with normal bone density as well [91]. DIAGNOSTIC APPROACH The history often provides important initial clues in the patient with subacute or chronic cough. All patients should be questioned about the use of ACE inhibitors and about the presence of an upper respiratory tract infection at the onset of the cough [92]. A history of coexisting symptoms might suggest an underlying diagnosis (eg, asthma, postnasal drip, gastroesophageal reflux, chronic bronchitis, bronchiectasis). Somewhat surprisingly, one study found that the character and timing of the cough and the presence or absence of sputum production do not appear to aid in the differential diagnosis [16]. In patients whose cough has lasted more than eight weeks, a chest radiograph should be considered as part of the initial evaluation, especially if upper airway cough syndrome, asthma, or gastroesophageal reflux are not considered clinically likely [1]. Upper airway cough syndrome, asthma, and gastroesophageal reflux, alone or in combination, are responsible for approximately 90 percent of cases of chronic cough [2,3,15,16]. However, one study found that these disorders were responsible for 99.4 percent of patients who had the following characteristics [16]: Nonsmoker No use of an ACE inhibitor Normal or near normal and stable plain chest radiograph Methacholine challenge and esophageal pH monitoring are useful diagnostic studies in the evaluation of selected patients with chronic cough [2,13]. Using an approach that stresses the importance of these studies, one report was able to document an etiology for chronic cough in 99 percent of patients, and specific therapy was reported to be successful in 98 percent [2]. Another study stressed the high frequency of postnasal drip contributing to cough and suggested initial empiric therapy with an antihistamine-decongestant combination [15]. In this report, the antihistamine-decongestant was the only therapy needed in 16 of 45 patients (36 percent), while an additional 23 patients had at least some benefit. If empiric treatment of postnasal drip is unsuccessful, a stepwise approach should be initiated that emphasizes sequential diagnostic testing and/or empiric therapy for asthma, non-asthmatic eosinophilic bronchitis, and gastroesophageal reflux disease [1]. In general, flexible fiberoptic bronchoscopy adds little to the diagnostic evaluation of patients with normal or nonspecific findings on plain chest radiographs or thoracic CT [93]. However, fiberoptic bronchoscopy may rarely identify an unsuspected foreign body. INFORMATION FOR PATIENTS Educational materials on this topic are available for patients. (See "Patient information: Chronic cough in adults".) We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics. SUMMARY AND RECOMMENDATIONS Based on findings primarily from cohort and case control studies

SUMMARY AND RECOMMENDATIONS Based on findings primarily from cohort and case control studies, and synthesized by experts in the field, we recommend the stepwise approach shown in the figure (figure 2) [1]. This approach emphasizes empirical therapy and relatively simple diagnostic evaluation if the initial basic evaluation does not provide clues to possible etiology. More detailed diagnostic evaluation can be reserved for those patients whose diagnosis remains unclear and in whom empiric therapy does not successfully treat the cough. Initial evaluation including history and physical examination should be performed, with particular attention paid to the possibility of a postinfectious etiology. If the patient has been on an ACE inhibitor, the medication should be discontinued. Therapy aimed at a particular etiology should be given based on clues from the initial evaluation. If no clues are provided by the initial evaluation or if there is no improvement on initial therapy, a chest radiograph should be done. If the radiograph is normal or shows an unrelated abnormality, the patient should be started on empiric therapy for postnasal drip with a first generation antihistamine-decongestant combination. If the patient obtains complete relief with this empiric regimen, then no further evaluation is needed. If postnasal drip is felt likely to be allergic in origin, the patient can be changed to more specific treatment for allergic rhinitis. (See "Treatment of subacute and chronic cough in adults".) If the patient has only partial relief from a first generation antihistamine-decongestant combination, then addition of topical therapy with a nasal glucocorticoid, a nasal anticholinergic agent, or a nasal antihistamine should be considered. If there is no improvement after two to three weeks of empiric therapy for postnasal drip, then pre- and post-bronchodilator spirometry should be performed. If this testing does not suggest reversible airflow obstruction, then a methacholine challenge study should be considered. The patient should be treated with bronchodilators and/or inhaled glucocorticoids if there is baseline airflow obstruction or if the methacholine challenge is positive. An alternative approach is empiric inhaled glucocorticoid therapy for asthma rather than extensive diagnostic testing, using the response to such therapy as both a diagnostic and therapeutic trial. If the above studies are negative, then the patient should be evaluated (through demonstration of sputum eosinophilia) or simply treated empirically (with inhaled glucocorticoids) for nonasthmatic eosinophilic bronchitis. If the cough remains problematic, the patient should be treated empirically for gastroesophageal reflux with a proton pump inhibitor and with appropriate lifestyle and dietary modifications. At present, conclusive data regarding the cost effectiveness and long-term outcome of this, or any, strategy of evaluation and treatment are lacking. More detailed discussion of specific therapy for the causes of chronic cough as well as nonspecific suppressive therapy of cough is presented separately. (See "Treatment of subacute and chronic cough in adults".) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Irwin, RS, Baumann, MH, Bolser, DC, et al. Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest 2006; 129:1S. 2. Irwin, RS, Curley, FJ, French, CL. Chronic cough. The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Am Rev Respir Dis 1990; 141:640. 3. Irwin, RS, Corrao, WM, Pratter, MR. Chronic persistent cough in the adult: the spectrum and frequency of causes and successful outcome of specific therapy. Am Rev Respir Dis 1981; 123:413. 4. Kelsall, A, Decalmer, S, McGuinness, K, et al. Sex differences and predictors of objective cough

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GRAPHICS
Simplified schematic diagram of the cough reflex

* Cough receptors include rapid acting receptors (RAR), slow acting receptors (SAR), C fibers, and other cough receptors. Some receptors are mechanosensitive and others are chemosensitive. Impulses from these receptors are all carried by the vagus nerve.

Less common causes of chronic cough

Bronchiectasis Angiotensin-converting enzyme inhibitors Nonasthmatic eosinophilic bronchitis Bronchogenic carcinoma Interstitial lung disease Occult pulmonary infection Occult heart failure Occult aspiration Tracheobronchial foreign body or mass (other than bronchogenic carcinoma) Occupational asthma Nasal polyps Disorders of the external auditory canals, pharynx, larynx, diaphragm, pleura pericardium, esophagus, stomach, or thyroid Psychogenic Adapted from Pratter, MR, Bartter, T, Akers, S, DuBois, J, Ann Intern Med 1993; 119:977, Poe, RH, Israel, RH, J, Respir Dis 1997; 18:629, Irwin, RS, Boulet, LP, Cloutier, MM, et al, Chest 1998; 114(suppl):133S.

Evaluation of subacute or chronic cough in adults

ACE: angiotensin-converting enzyme; GERD: gastroesophageal reflux disease. * Also consider post-infectious etiology for subacute cough (3 to 8 weeks duration).

Complications of cough
Cardiovascular
Arterial hypotension Loss of consciousness Rupture of subconjunctival, nasal and anal veins Dislodgement/malfunctioning of intravascular catheters Bradyarrhythmias, tachyarrhythmias

Neurologic
Cough syncope Headache Cerebral air embolism CSF rhinorrhea Acute cervical radiculopathy Malfunctioning ventriculoatrial shunts Seizures Stroke due to vertebral artery dissection

Gastrointestinal
Gastroesophageal reflux events Hydrothorax in peritoneal dialysis Malfunction of gastrostomy button Splenic rupture Inguinal hernia

Genitourinary
Urinary incontinence Inversion of bladder through urethra

Musculoskeletal
From asymptomatic elevations of serum creatine phosphokinase to rupture of rectus abdominis muscles Rib fractures

Respiratory
Pulmonary interstitial emphysema, with potential risk of pneumatosis intestinalis, pneumomediastinum, pneumoperitoneum, pneumoretroperitoneum, pneumothorax, subcutaneous emphysema Laryngeal trauma Tracheobronchial trauma (eg, bronchitis, bronchial rupture) Exacerbation of asthma Intercostal lung herniation

Miscellaneous
Petechiae and purpura

Disruption of surgical wounds Constitutional symptoms Lifestyle changes Self-consciousness, hoarseness, dizziness Fear of serious disease Decrease in quality of life Reproduced with permission from Irwin, RS, Boulet, LP, Cloutier, MM, et al. Managing a cough as a defense mechanism and as a symptom. A consensus panel report of the American College of Chest Physicians. Chest 1998; 114(suppl 2):133S.

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