Chronic Cough: Seeking the Cause and the Solution

The cough reflex serves a protective function by preventing foreign material from entering the respiratory tract and by facilitating the expulsion of mucus from the airways. Cough is triggered by stimulation of sensory receptors within the respiratory tract, whose afferent impulses activate a brain stem cough center.¹ Persistent cough with no apparent benefit is a maladaptive response that results in significant discomfort.

Cough is the most common complaint for which outpatients seek medical attention in the United States.² Acute cough, commonly caused by a viral upper respiratory tract infection, is usually self-limited. Other causes, such as congestive heart failure, pneumonia, pulmonary embolism, and endobronchial foreign body or malignancy, may need to be considered in the appropriate clinical setting. Cough of 3 to 8 weeks' duration is termed "subacute." Chronic cough is defined as cough that persists for more than 8 weeks.³

In this article, we will review the evaluation and treatment of chronic cough in adults. We will focus on its most common causes: postnasal drip syndrome, recently renamed upper airway cough syndrome (UACS); asthma; non-asthmatic eosinophilic bronchitis; and gastroesophageal reflux disease (GERD).⁴

EVALUATION

Multiple prospective studies have demonstrated that a systematic evaluation of chronic cough leads to successful diagnosis in most cases.^3,5-7 In the vast majority of patients who are nonsmokers, are not receiving angiotensin-converting enzyme (ACE) inhibitors, and have normal or stable chest radiographic findings, chronic cough can be explained by 4 causes, either alone or in combination: UACS, asthma, non-asthmatic eosinophilic bronchitis, and GERD.^3-7 If a specific cause is determined, treatment is usually very effective.

In at least 25% of patients, multiple causes of chronic cough exist simultaneously, and a partial response to specific therapy may indicate that only one of the causes has been addressed. The American College of Chest Physicians (ACCP) has recently published updated guidelines for the management of cough, which include a diagnostic algorithm.⁴ We provide a simplified Algorithm for evaluating chronic cough, as well as a summary of highlights from the new ACCP guidelines (Table 1).

It is essential to perform a meticulous history taking and physical examination. Because UACS, asthma/ non-asthmatic eosinophilic bronchitis, and GERD may all present with cough as the sole symptom, a high index of suspicion is required. In the absence of associated symptoms, an empiric drug trial is often indicated in the evaluation of chronic cough. A chest radiograph should be considered in any adult who presents with chronic cough.

Upper airway cough syndrome (formerly postnasal drip syndrome). Multiple prospective studies have shown that UACS is the most common cause of chronic cough in adults.^3,5,6 A clue to the presence of UACS is the sensation of mucus accumulation in the throat, leading to frequent throat clearing and cough. UACS may result from seasonal or perennial allergic rhinitis, perennial nonallergic rhinitis, vasomotor rhinitis, postinfectious (postviral) rhinitis, or chronic bacterial rhinosinusitis. Options for treatment are dictated by the specific cause (Table 2).⁸

In the minority of patients whose UACS is caused by bacterial rhinosinusitis, prolonged antibiotic therapy (3 weeks or more) for Streptococcus pneumoniae, Haemophilus influenzae, and anaerobes is warranted. For all other forms of UACS, the combination of a first-generation antihistamine and a decongestant is the most effective therapy.⁴

The newer nonsedating antihistamines, however, have proved ineffective in treating acute cough caused by the common cold.⁹ These second-generation antihistamines lack antitussive action against induced cough in both healthy volunteers and patients with upper respiratory tract infection.¹⁰ This is likely a result of their lower penetration into the CNS and consequent lower anticholinergic potency.¹⁰

Because UACS is probably the most common cause of chronic cough, it seems reasonable to initially prescribe empiric therapy for patients in whom other causes are not evident. When Pratter and colleagues⁵ evaluated this strategy, they found first-generation antihistamine/ decongestant therapy to be beneficial in 87% of such patients and the only therapy necessary in 36% of 45 patients. The remaining patients were further evaluated according to a stepwise algorithm.

Asthma and non-asthmatic eosinophilic bronchitis. Asthma causes 24% to 29% of chronic cough in adults.^3-6 Asthma in which cough is the predominant or sole symptom is termed "cough-variant asthma." In patients with this form of asthma, findings from the physical examination and from spirometric testing may be normal. Unexplained chronic cough is probably the most common indication for methacholine inhalation challenge (MIC) testing, which can identify nonspecific bronchial hyperresponsiveness and confirm the diagnosis of asthma.

Given its high negative predictive value, a negative MIC result essentially excludes asthma from the differential diagnosis of chronic cough.¹¹ A positive result is consistent with, but not diagnostic of, cough-variant asthma. Diagnosis is confirmed only on resolution of the cough with specific asthma treatment. Irwin and colleagues¹² reported that cough resolved with specific asthma therapy in only 9 of 15 patients with chronic cough and positive MIC results. The remaining patients were found to have other causes, mainly UACS and GERD.

In general, the therapeutic approach to cough-variant asthma is similar to that of the typical form of asthma. Many patients have symptomatic improvement after 1 week of therapy with inhaled bronchodilators. For persistent cough, inhaled corticosteroids should be added. Complete resolution of symptoms may require up to 8 weeks of therapy.¹²

A prospective, randomized, double-blind, placebo-controlled trial showed that the leukotriene receptor antagonist zafirlukast diminishes cough and decreases the sensitivity of the cough reflex in patients with cough-variant asthma, including a subgroup whose cough had been refractory to inhaled corticosteroids.¹³ In a subset of patients with severe cough-variant asthma refractory to inhaled therapy, a trial of 40 mg/d of prednisone was successful.¹⁴

A stepwise approach to the treatment of cough-variant asthma has been recommended.¹⁵ Whether leukotriene receptor antagonists should be used instead of, rather than in addition to, inhaled corticosteroids for the treatment of cough-variant asthma remains unclear at this time. At issue is the lack of information regarding the efficacy of leukotriene receptor antagonists against the chronic inflammation and airway remodeling that occur in persons with asthma.

Thickening of the subepithelial layer, an indication of chronic airway inflammation, has been demonstrated in cough-variant asthma, albeit to a lesser extent than in typical asthma.¹⁶ Long-term anti-inflammatory therapy, therefore, seems appropriate in patients who have cough-variant asthma, but whether monotherapy with a leukotriene receptor antagonist is sufficient to prevent the sequelae of chronic airway inflammation in this setting awaits further elucidation.

Another subgroup of patients with chronic cough and sputum eosinophilia, a condition termed "non-asthmatic eosinophilic bronchitis," also responds well to inhaled corticosteroids. The diagnosis is made with documentation of more than 3% of eosinophils in induced sputum and negative MIC results. Eosinophilic bronchitis differs from asthma by the absence of reversible airway obstruction and bronchial hyperresponsiveness to methacholine, and by the lack of airway smooth muscle infiltration by mast cells. In observational studies conducted in Europe, eosinophilic bronchitis was shown to be the cause of chronic cough in 13% of patients referred to a specialist¹⁷ and in 11% of those evaluated by a primary care physician.¹⁸

Gastroesophageal reflux disease. Patients who have GERD-induced cough often do not report typical reflux symptoms. Because cough may be the sole presenting symptom of GERD, a high index of suspicion is necessary.

Chronic cough likely results from the presence of gastric acid in the distal esophagus, which stimulates a vagally mediated tracheobronchial reflex.¹⁹ The chronic cough, in turn, may promote dysfunction of the lower esophageal sphincter, thereby increasing reflux and perpetuating a vicious cycle. In addition, refluxate may reach the proximal esophagus and upper airway, further stimulating afferent cough receptors. Recently, the term "laryngopharyngeal reflux"(LPR) has gained favor to reflect this process.

The diagnostic gold standard for GERD is 24-hour ambulatory esophageal pH monitoring. However, because this test is invasive and not universally available, a diagnostic therapeutic drug trial may be indicated. Further complicating the diagnostic process is the fact that patients with chronic cough caused by LPR often have negative results with pH monitoring.

Conservative measures, such as maintenance of a high-protein, low-fat diet; avoidance of tobacco, coffee, alcohol, chocolate, peppermint, and other substances that may promote reflux; and elevation of the head of the bed, can be combined with pharmacological means of acid suppression. In addition, patients should not eat or drink at least 2 hours before going to bed or reclining.

Although some studies have shown that H₂-receptor antagonists have a high success rate in GERD-induced cough,²⁰ this therapy alone may be ineffective or may require a prolonged period before symptomatic improvement (2 to 3 months) or resolution of cough (5 to 6 months) is achieved.^4,21 Therefore, initial empiric therapy with a proton pump inhibitor (PPI), twice daily, a half hour before breakfast and dinner, may be preferable. Such an approach has been shown to be more effective and to achieve an initial clinical response more promptly, sometimes within 2 weeks.²² For more aggressive acid suppression therapy, ranitidine (300 mg at bedtime) may be added to the twice-daily PPI regimen.

Because the initial response to GERD therapy may be delayed in some patients, other potential causes of chronic cough (UACS, asthma) should be empirically treated and excluded before empiric GERD therapy is initiated. If prolonged therapy with a PPI is unsuccessful, a formal diagnostic evaluation for GERD is indicated. If the diagnosis is confirmed, antireflux surgery, such as open or laparoscopic closed fundoplication, may be considered. Initial data from an observational study demonstrated that surgery was effective in 86% of 21 patients with GERD and provided sustained improvement in GERD-induced cough up to 12 months postoperatively.²³

In a subgroup of patients, cough persists despite total or near-total elimination of esophageal acid with medical therapy yet improves after surgery. This suggests that in some patients, the cough may be caused by reflux of nonacid or weakly acidic material.

²⁴

It has been demonstrated that esophageal dysmotility in the absence of acid reflux may play a role in chronic GERD-induced cough.

²⁵

Hence, before considering surgery, the addition of a prokinetic agent (such as metoclopramide, a half hour before meals and at bedtime) may be appropriate in the setting of GERD-induced cough refractory to antacid therapy.

Postinfectious cough. In a subgroup of patients with recent upper respiratory tract infection, cough may persist for weeks or months after the resolution of other symptoms. Such postinfectious cough is caused most often by viral infections; Mycoplasma pneumoniae,Chlamydia pneumoniae, and Bordetella pertussis have also been implicated. The mechanism, although poorly understood, probably involves airway inflammation with a resultant increase in the sensitivity of cough-inducing afferent nerves in the airway epithelium.²⁶

Traditional antitussive therapy, including codeine, is of limited benefit.²⁷ Inhaled corticosteroids may be useful, but they have not been adequately evaluated in clinical trials. Oral corticosteroids have been used with success in this setting and may be appropriate for severe cough.²⁸

ACE inhibitor-induced cough. About 10% to 30% of patients who receive ACE inhibitors have a dry, persistent cough, sometimes associated with a tickling or scratching sensation in the throat.²⁹ Cough may occur within hours of receiving the first dose of medication, or its onset may be delayed for weeks to months after initiation of therapy. Cough resulting from ACE inhibitor use occurs more commonly in women, nonsmokers, and persons of Chinese origin.⁸ Patients receiving this therapy for congestive heart failure cough more frequently than those receiving it for hypertension.⁸

The mechanism of ACE inhibitor-induced cough remains unclear. Probable mediators include bradykinin and substance P, tussive agents that are degraded by ACE and, therefore, accumulate in the lungs when the enzyme is inhibited; and prostaglandins, whose production may be stimulated by bradykinin.³⁰

ACE inhibitors should be discontinued in any patient who presents with chronic cough, regardless of the time between initiation of ACE inhibitor therapy and the onset of cough. The diagnosis is confirmed by resolution of cough, usually within 1 to 4 weeks of termination of therapy. However, resolution of cough may be delayed in a subgroup of patients.⁴

In randomized, double-blind, placebo-controlled trials, drugs found to attenuate cough resulting from the use of an ACE inhibitor include cromolyn, theophylline, sulindac, indomethacin, the calcium channel antagonists amlodipine and nifedipine, and the thromboxane receptor antagonist picotamide.⁸ However, the only uniformly effective therapy for ACE inhibitor-induced cough is cessation of the offending agent.

TREATMENT

In general, pharmacological treatment for cough may be categorized as antitussive therapy, whose aim is to eliminate a bothersome cough, and protussive therapy, which is used to increase the efficiency of cough when mobilization of secretions is desired. Antitussive therapy is further subdivided into specific therapy targeting an established or presumed cause of cough, and suppressant therapy (formerly referred to as nonspecific antitussive therapy) aimed at inhibiting the cough reflex regardless of the cause of cough. Options for specific antitussive therapy are provided in Table 3.³¹

Suppressant therapy. This therapy is often ineffective but may be indicated for the following:

• Cough resulting from untreatable causes, such as lung cancer or idiopathic pulmonary fibrosis.

• Severe cough from which transient relief is needed while awaiting effects of specific therapy.

• Unexplained (previously termed "idiopathic") cough.

Cough-suppressant therapy (nonspecific antitussive therapy) is broadly classified as central or peripheral, based on the site of action. Central antitussives act within the CNS to inhibit the cough reflex. The opioid narcotics codeine, hydrocodone, and hydromorphone are approved for use as antitussives.

Codeine has been shown to be effective in various forms of pathological and experimentally induced cough but has been found to be ineffective in cough caused by acute upper respiratory tract infection.²⁷ The recommended dosage for adults is 10 to 30 mg every 4 to 6 hours, not to exceed 120 mg/d. A recent study has demonstrated low-dose morphine to be effective in chronic, refractory cough.³²

Dextromethorphan, a nonnarcotic opioid, is one of the most widely used antitussive agents. This drug is used either alone or in combination with various over-the-counter cough and cold remedies. The recommended dosage for adults is 10 to 30 mg every 4 to 8 hours, not to exceed 120 mg/d. Randomized, double-blind, placebo-controlled studies have demonstrated its efficacy in various forms of pathological cough, including cough associated with upper respiratory tract infections.³³ A dose of at least 30 mg appears necessary for effective cough suppression.

Diphenhydramine, a first-generation histamine-receptor antagonist, has been shown to be useful in chronic cough caused by bronchitis and in induced cough in healthy volunteers.³⁴ The typical dosage for adults is 25 mg every 4 hours, not to exceed 150 mg/d. Potential side effects include sedation and anticholinergic effects, such as confusion (in elderly persons) and dry mouth.

Peripherally acting antitussive agents include benzonatate, a long-chain polyglycol derivative that is chemically related to procaine. Benzonatate is administered orally and acts via inhibition of peripheral stretch receptors. The capsule must be swallowed whole and without chewing to prevent oral anesthetic effects. The recommended dosage for adults is 100 mg (1 capsule) 3 times daily, not to exceed 600 mg/d. Antitussive efficacy was demonstrated in trials soon after the drug's release almost a half century ago,³⁵ but more recent controlled trials are lacking.

Inhaled anesthetics can be effective antitussives. A few case reports have described the successful use of inhaled lidocaine and bupivacaine in refractory cough. The requirement for nebulization, however, renders these agents of limited practical value.

Protussive therapy. Protussive agents are classified as expectorants, mucolytics, and mucokinetic agents. They may be useful in promoting mobilization of secretions in disorders such as cystic fibrosis and bronchiectasis. Studies evaluating the efficacy of these agents are difficult to perform because an improvement in the volume or consistency of respiratory secretions need not correlate with improvement in cough effectiveness or symptoms.

Expectorants, such as guaifenesin, act by hydrating and thus decreasing the viscosity of respiratory secretions ("hydration hypothesis"), thereby facilitating their expulsion.³⁶ One study demonstrated that guaifenesin inhibits cough reflex sensitivity in persons with upper respiratory tract infection whose cough receptors are transiently hypersensitive.³⁷ Thus, guaifenesin may also have an antitussive action in addition to its expectorant effect.

CLINICAL HIGHLIGHTS

• In at least 25% of patients, multiple causes of chronic cough exist simultaneously; a partial response to specific therapy may indicate that only one of the causes has been addressed.
• Given its high negative predictive value, a negative methacholine inhalation challenge result essentially excludes asthma from the differential diagnosis of chronic cough. A positive result is consistent with, but not diagnostic of, cough-variant asthma.
• Traditional antitussive therapy, including codeine, is of limited benefit in patients with postinfectious cough. Inhaled corticosteroids may be useful, but they have not been adequately evaluated in clinical trials. Oral corticosteroids may be appropriate for severe cough.
• Discontinue angiotensin-converting enzyme (ACE) inhibitors in any patient who presents with chronic cough, regardless of the time between initiation of ACE inhibitor therapy and the onset of cough. The diagnosis is confirmed by resolution of cough, usually within 1 to 4 weeks of termination of therapy.

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EVIDENCE-BASED GUIDELINES

•Irwin RS, Baumann MH, Bolser DC, et al. Diagnosis and management of cough: ACCP evidence-based clinical practice guidelines.

Chest

. 2006;129 (suppl):1S-292S.