of causes of acute cough, clinical experience suggests that the most common causes are upper respiratory tract infections such as the common cold, acute bac-.
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Volume 343Number 23 á 1715 Primary Care PRIMARY CARE T HE D IAGNOSIS AND T REATMENT OF C OUGH R ICHARD S. I RWIN , M.D., AND J. M ARK M ADISON , M.D. From the Pulmonary, Allergy, and Critical Care Medicine Division, De- partment of Medicine, University of Massachusetts Medical School, Worcester. Address reprint requests to Dr. Irwin at the Division of Pulmo- nary, Allergy, and Critical Care Medicine, UMass Memorial Health Care, University Campus, 55 Lake Ave. N., Worcester, MA 01655. ©2000, Massachusetts Medical Society. OUGH is one of the most common symptoms for which patients seek medical attention from primary care physicians and pulmonologists, 1 probably because cough can so profoundly and ad- versely affect the quality of patientsÕ lives. 2 In this re- view, we present an approach to managing cough in adults. With a systematic approach based on the guide- lines we describe, it should be possible to diagnose and treat cough successfully in the great majority of cases. The cause of chronic cough can be determined in 88 to 100 percent of cases, and determination leads to specific therapies with success rates that range from 84 to 98 percent. 1 Because of this high degree of suc- cess, there is only a limited role for nonspecific therapy for cough, which has been reviewed comprehensively elsewhere. 1 DURATION OF COUGH Estimating the duration of cough is the first step in narrowing the list of possible diagnoses. There is controversy about how best to define chronic cough. 1 We propose that cough be divided into three catego- ries: acute, defined as lasting less than three weeks; subacute, lasting three to eight weeks; and chronic, lasting more than eight weeks. Since all types of cough are acute at the outset, it is the duration of the cough at the time of presentation that determines the spec- trum of likely causes. ACUTE COUGH For diagnosing the cause of acute cough, we recom- mend a clinical approach based on trials of empirical therapies. The physician should take a history and per- form a physical examination while keeping in mind the estimated frequency of conditions. Although there have been no studies of the spectrum and frequency of causes of acute cough, clinical experience suggests that the most common causes are upper respiratory tract infections such as the common cold, acute bac- terial sinusitis, pertussis in some communities, exac- erbations of chronic obstructive pulmonary disease, C allergic rhinitis, and rhinitis due to environmental ir- ritants. 1 Viral infections of the upper respiratory tract are the most common causes of acute cough. In the absence of any treatment, the prevalence of cough due to the common cold ranges from 83 percent within the first 48 hours of the cold to 26 percent on day 14. 3 Cough appears to arise from the stimulation of the cough re- flex in the upper respiratory tract by postnasal drip, clearing of the throat, or both. 3 The common cold is diagnosed when patients present with an acute respiratory illness characterized by symptoms and signs related primarily to the nasal passages (e.g., rhinorrhea, sneezing, nasal obstruction, and postnasal drip), with or without fever, lacrimation, and irritation of the throat, and when a chest exam- ination is normal. In such cases, diagnostic testing is not indicated, because it has a low yield. For instance, in immunocompetent patients with these symptoms and signs, more than 97 percent of chest radiographs will be normal. 4 For treating acute cough due to the common cold, we recommend medications that have been shown in randomized, double-blind, placebo-controlled studies (Table 1) to be efficacious in decreasing cough. These include dexbrompheniramine plus pseudoephedrine 3 and naproxen. 5 Although the effect on cough was not specifically assessed in a study that showed that in- tranasal ipratropium provided relief of rhinorrhea and sneezing due to the common cold, 6 the drug may be helpful for patients who cannot take or tolerate the older-generation antihistamines or naproxen. There is no convincing evidence that intranasal or systemic corticosteroids are beneficial 7,8 or that zinc lozenges are consistently beneficial, 9-11 and the relatively non- sedating histamine H 1 antagonists (e.g., loratadine), either alone or combined with a decongestant, are likely to be ineffective. 1,12 These H 1 antagonists have failed to alleviate cough in patients with the common cold, probably because they have little or no anticho- linergic activity and the common cold is not mediat- ed by histamine. On the other hand, when cough is due to a histamine-mediated condition such as allergic rhinitis (Table 1), it is significantly improved by the nonsedating antihistamines. 13 We do not recommend pharmacologic therapy as a substitute for the avoid- ance of offending allergens. The common cold is a viral rhinosinusitis 14 that of- ten cannot be distinguished clinically from bacterial sinusitis. 15 Because viral rhinosinusitis is the more com- mon of the two, we recommend giving antibiotics to patients with findings that are suggestive of acute si- nusitis only if their symptoms fail to show progressive improvement when treated with antihistamines and decongestants and if they have at least two of the fol- lowing signs and symptoms: a maxillary toothache; purulent nasal secretions; abnormal findings on trans- illumination of any sinus; and a history of discolored The New England Journal of Medicine Downloaded from nejm.org at WELCH MED LIB JHU-MCAULEY BLDG on January 16, 2013. For personal use only. No other uses without permission. Copyright © 2000 Massachusetts Medical Society. All rights reserved.
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1716 á December 7, 2000 The New England Journal of Medicine nasal discharge (Table 1). It is usually not necessary to perform imaging studies of the sinuses in order to begin antibiotic therapy. 16 It is not generally recognized that the common cold, like chronic postnasal-drip syndromes arising from a variety of rhinosinus conditions, can present as a syndrome of cough and phlegm. 17,18 Consequent- ly, physicians tend too frequently to diagnose such a syndrome as bacterial bronchitis and to prescribe an- tibiotics. 19 We do not diagnose bronchitis in patients with a syndrome of cough and phlegm along with acute upper respiratory tract symptoms, and with few exceptions we do not initially prescribe antibiotic ther- apy in these instances. We do prescribe antibiotics for patients with an exacerbation of chronic obstructive pulmonary disease (Table 1) if the acute cough is ac- companied by worsening shortness of breath, wheez- ing, or both. 20 We also prescribe antibiotics for pa- tients with acute upper respiratory tract symptoms who have had close contact with a patient with a known case of pertussis (Table 1) and for patients with coughing and vomiting suggestive of Bordetella per- tussis infection. 1 In the absence of chronic obstructive pulmonary disease, the failure to diagnose bronchitis when it is present will probably not adversely affect the patient, because most acute respiratory infections are viral. 21 Acute cough can be the presenting manifestation of pneumonia, left ventricular failure, asthma, or condi- tions that predispose patients to the aspiration of for- eign matter. 1,22 It is especially important to have a high index of suspicion for these disorders in elderly pa- tients, because classic signs and symptoms may be non- existent or minimal. SUBACUTE COUGH For diagnosing the cause of subacute cough, we rec- ommend a clinical approach based on trials of em- pirical therapies and limited laboratory testing. When cough is subacute and is not associated with an ob- vious respiratory infection, we evaluate patients in much the same way as those with chronic cough (see below). For a cough that began with an upper respi- ratory tract infection and has lasted for three to eight weeks, the most common conditions to consider are postinfectious cough, bacterial sinusitis, and asthma. Postinfectious cough is defined as cough that be- gins with an acute respiratory tract infection that is not complicated by pneumonia (i.e., the chest radio- graph is normal) and that ultimately resolves with- out treatment. 1 It may result from postnasal drip or clearing of the throat due to rhinitis, tracheobronchi- tis, or both, with or without transient bronchial hyper- responsiveness. If the patient reports hav ing a post- nasal drip or frequently clears his or her throat or if mucus is seen in the oropharynx, we recommend an *Specific drugs and doses are mentioned when their use is supported by double-blind, randomized, placebo-controlled studies. Pa O 2 denotes partial pressure of arterial oxygen, and SaO 2 arterial oxygen saturation. T ABLE 1. G UIDELINES FOR T REATING THE M OST C OMMON C AUSES OF A CUTE C OUGH IN A DULTS .* C AUSE T HERAPEUTIC O PTIONS C OMMENTS Common coldDexbrompheniramine, 6 mg, plus pseudoephedrine, 120 mg, twice daily for 1 wk, or naproxen, 500-mg loading dose, then 500 mg 3 times daily for 5 days, or ipratropium (0.06%) nasal spray, 2 42-µg sprays per nostril 3 to 4 times daily as needed for 4 days First-generation H 1 antagonists may be helpful, but the rel- atively nonsedating H 1 antagonists will most likely be in- effective. Ipratropium should be used in patients who can- not take or tolerate the other medicines. Allergic rhinitisAvoidance of offending allergens Loratadine, 10 mg once a day Other oral H 1 antagonists, nasal cromolyn, corticosteroids, and azelastine may also be helpful. Acute bacterial sinusitisDexbrompheniramine, 6 mg, plus pseudoephedrine, 120 mg, twice daily for 2 wk Oxymetazoline, 2 sprays twice daily for 5 days Antibiotic directed against Haemophilus influenzae and Strep- tococcus pneumoniae Choice of antibiotic depends on multiple factors, including cost, allergies, and local patterns of bacterial resistance. Although the appropriate duration of therapy is not well defined, we treat for 2 wk. Exacerbation of chronic obstructive pulmo- nary disease Antibiotic directed against H. influenzae and S. pneumoniae for 10 days Systemic corticosteroids tapered over 2-wk period Continuous oxygen if PaO 2 Ç55 mm Hg or SaO 2 Ç88%, or if PaO 2 Ç59 mm Hg and there is evidence of erythro- cythemia or cor pulmonale Ipratropium, 2 18-µg puffs, plus albuterol, 2 90-µg puffs, 4 times daily by metered-dose inhaler with spacer Cessation of smoking Choice of antibiotic depends on multiple factors (see above). If treatment is started in the hospital, give equivalent of methylprednisolone, 125 mg every 6 hr for 72 hr, then prednisone, 60 mg/day for 4 days, 40 mg/day for 4 days, and 20 mg/day for 4 days. Oxygen is prescribed to increase PaO 2 to 60Ð80 mm Hg at rest (SaO 2 >90%); an additional 1 liter/min is given dur- ing exercise and sleep. Need for continued oxygen is as- sessed after 1 mo. Bordetella pertussis infection Erythromycin, 500 mg 4 times daily for 14 days, or (if aller- gic) trimethoprimÐsulfamethoxazole, 160 mgÐ800 mg twice daily for 14 days Given their in vitro activity, other macrolides are also likely to be effective. These drugs and doses are appropriate for treatment and prophylaxis. Systemic corticosteroids have been beneficial in severely af- fected children. The New England Journal of Medicine Downloaded from nejm.org at WELCH MED LIB JHU-MCAULEY BLDG on January 16, 2013. For personal use only. No other uses without permission. Copyright © 2000 Massachusetts Medical Society. All rights reserved.
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PRIMARY CARE Volume 343Number 23 á 1717 initial course of treatment similar to that for the common cold (Table 2). If the cough has not disap- peared after one week of this therapy, we perform imaging studies of the sinuses to determine whether bacterial sinusitis is present. If these studies reveal a mucosal thickening of more than 5 mm, airÐfluid levels, or opacification, 23 we prescribe a nasal decon- gestant for five days and an antibiotic for three weeks (Table 2), and then reassess the patientÕs condition. When a patient presents with wheezes, rhonchi, or crackles on physical examination, a chest radiograph should be obtained. If it is normal, we prescribe in- haled bronchodilators and corticosteroids and con- sider antibiotics only if we suspect a recent B. pertussis infection. In such cases, improvement does not mean the diagnosis is asthma, because these drugs may have alleviated the cough by increasing mucociliary clear- ance and decreasing the production of mucus or by decreasing transient bronchial hyperresponsiveness after a viral infection. However, cough may be the sole presenting manifestation of asthma (as in so-called cough variant asthma). This diagnosis is suggested by the presence of bronchial hyperresponsiveness (e.g., a positive result on methacholine challenge) and is confirmed only when cough resolves during asthma therapy (Table 2) and follow-up proves the chronic nature of the disease. 1 If B. pertussis infections have recently been reported in the community, if there is a history of contact with a patient who has a known case, or if the patient pre- sents with the characteristic but infrequently heard whoop or with coughing and vomiting, empirical ther- apy for this infection should be considered (Tables 1 and 2). 1 The later in the illness antibiotics are pre- scribed, the less likely it is that they will be efficacious. The laboratory diagnosis of pertussis is difficult to es- tablish because there is usually a delay between the onset of cough and the suspicion of the disease and because there is no readily available, reliable serologic test for B. pertussis. 24,25 Cultures of nasopharyngeal secretions are usually negative after two weeks, and reliable, serologic confirmation of a recent B. pertussis infection requires evidence of an elevated level of an- tibodies against one of the various virulence factors of the organism, as revealed by an enzyme-linked immu- nosorbent assay. CHRONIC COUGH Although cough that lasts longer than eight weeks can be caused by many different diseases, 26 most cases are attributable to one of only a few diagnoses. Con- sequently, we recommend a systematic evaluation that initially assesses the likelihood of the most common causes by means of trials of empirical therapy and tri- als involving the avoidance of irritants and drugs, along with focused laboratory testing (e.g., chest radiog- raphy or methacholine challenge), followed by addi- tional testing and consultation with a specialist, if nec- essary. The definitive diagnosis of the cause of chronic cough is then established on the basis of an obser- vation of which specific therapy eliminates the cough. Because chronic cough can result simultaneously from *Specific drugs and doses are mentioned when their use is supported by double-blind, randomized, placebo-controlled studies. T ABLE 2. G UIDELINES FOR T REATING THE M OST C OMMON C AUSES OF S UBACUTE C OUGH IN A DULTS .* C AUSE T HERAPEUTIC O PTIONS C OMMENTS PostinfectionDexbrompheniramine plus pseudoephedrine for 1 wk, or ipratropium (0.06%) nasal spray for 1 wk Ipratropium, 4 18-µg puffs 4 times daily by metered-dose inhaler with spacer for 1Ð3 wk In case of postnasal drip and throat clearing, treat similarly to common cold (see Table 1). If partial or no response to therapy for the common cold. Systemic corticosteroids tapered over period of 2Ð3 wk Central antitussives If partial or no response to above therapy. Consider an ini- tial dose of prednisone, 30 to 40 mg/day (or equivalent) for 3 days. For protracted, troublesome cough, consider dextromethorphan and codeine. If postinfectious cough is associated with Bordetella pertussis infection, add antibiot- ic (see below); if associated with bronchial hyperrespon- siveness, treat similarly to asthma for 6Ð8 wk (see below). B. pertussis infectionErythromycin for 14 days, or (if allergic) trimethoprimÐ sulfamethoxazole Dose same as in Table 1. Always consider cough associated with B. pertussis to be postinfectious and consider adding the above therapy if protracted. Violent coughing can provoke gastroesophageal reflux. Subacute bacterial sinusitisDexbrompheniramine plus pseudoephedrine for 3 wk Oxymetazoline for 5 days Antibiotic directed against Haemophilus influenzae and Streptococcus pneumoniae Initial treatment is similar to that for acute bacterial sinusitis (see Table 1), but we recommend a 3-wk course of an an- tihistamineÐdecongestant and an antibiotic. AsthmaBeclomethasone, 4 42-µg puffs twice daily by metered-dose inhaler with spacer or other equivalent Albuterol, 2 90-µg puffs as needed, up to 4 times daily by metered-dose inhaler with spacer Equivalent doses of different agents should yield similar re- sults. Try different formulations if an inhaled agent pro- vokes coughing. If all inhaled agents fail, give oral corti- costeroids. The New England Journal of Medicine Downloaded from nejm.org at WELCH MED LIB JHU-MCAULEY BLDG on January 16, 2013. For personal use only. No other uses without permission. Copyright © 2000 Massachusetts Medical Society. All rights reserved.
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1718 á December 7, 2000 The New England Journal of Medicine more than one condition (as is the case in 18 to 93 percent of instances), 1,2 therapy that is partially suc- cessful should not be stopped but should instead be sequentially supplemented. Multiple studies 1,17,18,27-32 have shown that in approx- imately 95 percent of cases in immunocompetent patients, chronic cough results from postnasal-drip syndrome from conditions of the nose and sinuses, asthma, gastroesophageal reflux disease, chronic bron- chitis due to cigarette smoking or other irritants, bronchiectasis, eosinophilic bronchitis, or the use of an angiotensin-convertingÐenzyme inhibitor. In the remaining 5 percent of cases, chronic cough results from a variety of other diseases, such as bronchogen- ic carcinoma, carcinomatosis, sarcoidosis, left ven- tricular failure, and aspiration due to pharyngeal dys- function. In our experience, psychogenic, or Òhabit,Ó coughs are rare conditions best diagnosed by exclu- sion. 1,26 For example, a postnasal-drip syndrome with continual clearing of the throat can be misdiagnosed as a habit cough. 1 Diagnosis and Clinical Evaluation Physicians can narrow the list of possible diagnoses by reviewing the patientÕs history and physical exam- ination and focusing on the most common causes of chronic cough (i.e., postnasal-drip syndromes, asthma, and gastroesophageal reflux disease); obtaining a chest radiograph; and determining whether the symptoms conform to the clinical profile that is usually associ- ated with a diagnosis of postnasal-drip syndrome, asth- ma, gastroesophageal reflux disease, or eosinophilic bronchitis, alone or in combination. If the cough is productive of blood, the patient should be evaluated according to published guidelines for hemoptysis. 33 If the patient has a history of smoking or of expo- sure to other environmental irritants or is currently being treated with an angiotensin-convertingÐenzyme inhibitor, the first step in the evaluation of cough becomes straightforward; elimination of the irritant or discontinuation of the drug for four weeks should be encouraged because it will reveal whether the cough is partially or entirely due to chronic bronchitis or to the angiotensin-convertingÐenzyme inhibitor. Cough due to these factors should substantially improve or resolve within this time (Table 3). 1 A comprehensive review of cough due to angiotensin-convertingÐ enzyme inhibitors has been published elsewhere. 1 In the absence of exposure to irritants, a diagnosis of chronic bronchitis is untenable even if the cough is productive. The character of the cough (e.g., paroxys- mal, loose and self-propagat ing, productive, or dry), the quality of the sound (e.g., barking, honking, or brassy), and the timing of the cough (e.g., at night or with meals) have not been shown to be diagnostically useful. 18 Although a history of postnasal drip or clearing of the throat and physical findings of mucus, a cobble- stone appearance to the mucosa of the oropharynx, or both suggest postnasal-drip syndrome, these symp- toms and signs are not specific to this diagnosis 32 nor do they always appear even when this syndrome is the cause of cough. A minority of patients may have no upper respiratory symptoms or signs yet may have a favorable response to combination therapy with a first- generation H 1 antagonist and a decongestant (these patients have ÒsilentÓ postnasal-drip syndrome). 31 Al- though frequent heartburn and regurgitation suggest that gastroesophageal reflux disease is the cause of cough, these symptoms may be absent in up to 75 per- cent of cases (i.e., in patients with ÒsilentÓ gastro- esophageal reflux disease). 34 Because cough can be the sole manifestation of asth- ma in up to 57 percent of cases 35 (i.e., with cough vari- ant asthma or ÒsilentÓ asthma) and because the clini- cal diagnosis of asthma is unreliable even when there is a history of wheezing and a current physical finding of wheezing, 36 it is inadvisable to diagnose asthma on clinical grounds alone. Although the presence of oth- er abnormal sounds such as crackles and rhonchi sug- gests that testing for lower respiratory tract disease is indicated, these findings, with or without confirma- tory laboratory-test results (e.g., chest radiography showing chronic interstitial pneumonia), should not be relied on exclusively in the determination of the ultimate cause of cough. A definitive diagnosis can be made only when cough responds to specific therapy. Chest Radiography The chest radiograph is useful for the initial ranking of possible diagnoses and for guiding trials of empir- ical therapies and laboratory testing. 1 A normal radio- graph in an immunocompetent patient, or a radio- graph that shows no abnormality other than one consistent with an old and unrelated process, makes postnasal-drip syndrome, asthma, gastroesophageal reflux disease, chronic bronchitis, and eosinophilic bronchitis likely and bronchogenic carcinoma, sar- coidosis, tuberculosis, and bronchiectasis unlikely. If the chest radiograph is abnormal, the physician should next evaluate the possibility of the diseases suggested by the radiographic findings. The Most Common Causes The clinical profile associated with postnasal-drip syndrome, asthma, gastroesophageal reflux disease, eosinophilic bronchitis, or some combination of these conditions is that of a nonsmoking patient with a chronic cough who is not taking an angiotensin-con- vertingÐenzyme inhibitor and has a normal or near- normal and stable chest radiograph. Because there is no diagnostic test for postnasal- drip syndrome and because it is the most common cause of chronic cough, the patient should be evalu- ated for this condition first. The outcome of specific therapy will depend on the determination of the cor- The New England Journal of Medicine Downloaded from nejm.org at WELCH MED LIB JHU-MCAULEY BLDG on January 16, 2013. For personal use only. No other uses without permission. Copyright © 2000 Massachusetts Medical Society. 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PRIMARY CARE Volume 343Number 23 á1719rect cause and the choice of the correct specific ther- apy (Table 3). 1 The differential diagnosis of postna- sal-drip syndrome includes sinusitis and the following types of rhinitis, alone or in combination: nonallergic, allergic, postinfectious, vasomotor, drug-induced, and environmental-irritantÐinduced. If the specific ther- apy that is chosen fails, it does not necessarily mean that there is no postnasal-drip syndrome; cough may have failed to improve because the wrong antihista- mine was given. 1 The newer-generation H 1 antagonists do not appear to be effective when cough induced by postnasal drip is not mediated by histamine. 1Because a negative result of methacholine challenge rules out asthma as a cause of chronic cough (except soon after an exposure to toluene diisocyanate), 1 we recommend that the test be routinely performed. Although its positive predictive value ranges from 60 to 88 percent, 17,32,34,37 its negative predictive value is 100 percent. 17,32,34,37 Cough variant asthma should be treated the same way as asthma in general. 1 If cough *Specific drugs and doses are mentioned when their use is supported by double-blind, randomized, placebo-controlled studies. €The diet should be low in fat (approximately 45 g of fat per day); patients should eliminate foods and beverages that relax lo wer esophageal sphincter tone or are acidic (coffee, tea, soft drinks, citrus fruit, tomato, alcohol, chocolate, mint); they should eat three meals per day and no snacks; and they should have nothing to eat or drink except for taking medications for two hours before reclining. Once cough resolves, restrictions ca n be relaxed but not elimi- nated. Lifestyle changes include cessation of smoking and wearing clothes that are not constricting. The head of the bed should be elevated for the minority of patients who have reflux in the supine position. The great majority of patients who cough because of gastroesophageal reflux disease have reflux while upright, not while supine. TABLE 3. GUIDELINES FOR TREATING THE MOST COMMON CAUSES OF CHRONIC COUGH IN ADULTS.*CAUSETHERAPEUTIC OPTIONSCOMMENTSPostnasal-drip syndromes Nonallergic rhinitis Dexbrompheniramine plus pseudoephedrine for 3 wk, or ipratropium (0.06%) nasal spray for 3 wk Doses similar to those for common cold (see Table 1). Im- provement should start within 2Ð7 days. Initial therapy with nasal corticosteroids or second-generation H 1 antag- onists will probably yield poorer results. After cough re- solves, prescribe beclomethasone (or equivalent) nasal spray, 1 or 2 84-µg puffs per nostril daily for 3 mo. Flares may follow subsequent colds. Allergic rhinitisAvoidance of offending allergens Loratadine, 10 mg once a day See comments in Table 1. Vasomotor rhinitisIpratropium (0.06%) nasal spray for 3 wk and then as neededDoses similar to those for common cold. If necessa ry, add dexbrompheniramine plus pseudoephedrine. Chronic bacterial sinusitis Dexbrompheniramine plus pseudoephedrine for 3 wk Oxymetazoline for 5 days Antibiotic directed against Haemophilus influenzae, Strepto- coccus pneumoniae, and anaerobes in the mouth Initial treatment is similar to that for acute bacterial sinusitis (see Table 1) except for a 3-wk course of an antihista- mineÐdecongestant and an antibiotic. After cough re- solves, prescribe nasal corticosteroids (see above) for 3 mo. AsthmaBeclomethasone by metered-dose inhaler with spacer Albuterol by metered-dose inhaler with spacer as needed See comments in Table 2. Cough will start to improve within 1 wk and may take 6Ð8 wk to resolve. Long-term main- tenance therapy with an antiinflammatory drug may be necessary. Gastroesophageal reflux disease Modifications of diet and lifestyle€ Acid suppression Prokinetic therapy Initial medical therapy should be intensive (dietary changes, proton-pump inhibition, and a prokinetic agent such as metoclopramide). Long-term maintenance therapy will be necessary. If there is no improvement within 3 mo, do not assume that reflux disease has been ruled out. Assess the adequacy or failure of therapy by means of 24-hr monitoring of esophageal pH while patient is receiving therapy. Treat coexisting conditions (see Table 4). Chronic bronchitisElimination of irritant Ipratropium, 2 18-µg puffs 4 times daily by metered-dose inhaler with spacer Cough will improve or disappear in 94Ð100% of patients with cessation of smoking. In those who continue to smoke, ipratropium can be helpful. If cough temporarily worsens with cessation of smoking, ipratropium and cor- ticosteroids may be helpful. Angiotensin-convertingÐ enzyme inhibitors Discontinuation of drugThe cough is not dose-related; substitution of another drug in the same class will not help. With discontinuation, cough should improve or resolve within 4 wk. If these drugs must be continued, oral sulindac, indomethacin, nifedipine, and inhaled cromolyn sodium may provide re- lief. Therapy with angiotensin IIÐreceptor antagonists has not been complicated by cough. Eosinophilic bronchitisInhaled budesonide, 400 µg twice daily for 14 daysEquivalent doses of other inhaled corticosteroids are also ef- fective. Systemic corticosteroids (prednisone, 30 mg/day for 2Ð3 wk) are sometimes required. Long-term therapy may be necessary. If associated with an environmental ir- ritant (e.g., acrylic resin), avoidance is advised. The New England Journal of Medicine Downloaded from nejm.org at WELCH MED LIB JHU-MCAULEY BLDG on January 16, 2013. For personal use only. No other uses without permission. 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1720áDecember 7, 2000 The New England Journal of Medicine does not improve with asthma treatment (Table 3), the result of methacholine challenge can be considered to have been falsely positive. On the other hand, if methacholine challenge is not performed and cough disappears after the administration of systemic corti- costeroids, it should not be assumed on the basis of this empirical trial alone that the patient has asthma, because other inflammatory conditions (e.g., eosin- ophilic bronchitis and allergic rhinitis) also respond well to corticosteroids. 1We do not routinely recommend diagnostic test- ing for the evaluation of patients for ÒsilentÓ gastro- esophageal reflux disease, for the following reasons: although 24-hour monitoring of esophageal pH is the single most sensitive and specific test, it has a neg- ative predictive value of less than 100 percent and a positive predictive value as low as 89 percent 17,32,34 ;24-hour monitoring of esophageal pH is inconven- ient for patients and not widely available; and there is no consensus about the best way to interpret the results obtained through such monitoring in the di- agnosis of cough due to reflux disease. 1,33,34 Even if the attempted therapies (changes in lifestyle, acid sup- pression, and the addition of prokinetic drugs) do not improve cough (Table 3), it must not be assumed that gastroesophageal reflux disease has been ruled out as the cause. The therapy may not be intensive enough or may not have been sustained long enough, or the disease may not respond to even the most in- tensive medical therapy; in some cases, antireflux sur- gery may be successful. 1,38 The adequacy of the reg- imen of medical treatment and the need for antireflux surgery can be assessed by means of esophageal pH monitoring while medical therapy continues. 1,38 Eosinophilic bronchitis is a cause of chronic cough in up to 13 percent of cases. 30-32,35 Although an analy- sis of the sputum generally shows eosinophils and met- achromatic cells similar to those seen in asthma, this condition is distinct from asthma because it is not associated with bronchial hyperresponsiveness. 39 Eo- sinophilic bronchitis is responsive to inhaled and es- pecially systemic corticosteroids (Table 3). 30 It can be ruled out if eosinophils make up less than 3 percent of the nonsquamous cells in the induced-sputum sample as determined with the use of standard methods 30,39 or if cough fails to improve with empirical cortico- steroid therapy. PERSISTENTLY TROUBLESOME CHRONIC COUGH Because postnasal-drip syndrome, asthma, and gas- troesophageal reflux disease are the most common causes of chronic cough, the first step in managing a persistently troublesome chronic cough must be to consider the most common errors in management (Table 4). In our experience, 35 the failure to avoid these common pitfalls is often the reason chronic cough remains troublesome. Once potential errors in management have been addressed, additional lab- oratory studies 1 (e.g., studies of sputum, modified bar- ium esophagography, 24-hour monitoring of esoph- ageal pH, esophagoscopy, a study of gastric emptying, high-resolution computed tomography of the chest, bronchoscopy, 43 or noninvasive cardiac studies) and re- ferral to a cough specialist are indicated to assess the possibilities of intrathoracic processes (e.g., bronchi- ectasis, 44 bronchiolitis, 44 and left ventricular failure 35)that were not suggested by the chest radiograph. TABLE 4. COMMON PITFALLS IN MANAGING THE MOST COMMON CAUSES OF CHRONIC COUGH.Postnasal-drip syndrome Failing to recognize that it can present as a syndrome of cough and phlegm. 17Assuming that all H 1 antagonists are the same. 1Failing to consider sinusitis because it is not obvious. Failing to consider allergic rhinitis and failing to recommend the avoidance of allergens because symptoms are perennial. Asthma Failing to recognize that it can present as a syndrome of cough and phlegm. 17Failing to recognize that inhaled medications may exacerbate cough. 1Assuming that a positive result of methacholine challenge alone is diagnostic of asthma. 40Gastroesophageal reflux disease Failing to recognize that it can present as a syndrome of cough and phlegm. 17Failing to recognize that ÒsilentÓ reflux disease can be the cause of cough and that it may take 2Ð3 months of intensive medica l therapy before cough starts to improve and, on average, 5Ð6 months before cough resolves. 1Assuming that cough cannot be due to gastroesophageal reflux disease because cough remains unchanged when gastrointestinal symp toms improve. Failing to recognize that cough may fail to improve with the most intensive medical therapy and that the adequacy of therapy an d the need for surgery can be assessed by means of 24-hour monitoring of esophageal pH. 1Failing to recognize the effects of coexisting diseases (e.g., obstructive sleep apnea or coronary artery disease) or their tre atment (e.g., nitrates). 41,42 Failing to treat adequately coexisting causes of cough that perpetuate the cycle of cough and reflux. 1,38 Postnasal drip, asthma, and gastroesophageal reflux disease Failing to consider that more than one of these conditions may be contributing simultaneously to cough. 38Failing to consider these common conditions because of another ÒobviousÓ cause (e.g., chronic interstitial pneumonia). 1The New England Journal of Medicine Downloaded from nejm.org at WELCH MED LIB JHU-MCAULEY BLDG on January 16, 2013. For personal use only. No other uses without permission. Copyright © 2000 Massachusetts Medical Society. 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