Chronic cough

Chronic cough

COMMON MEDICAL PROBLEMS IN AMBULATORY CARE 0025-7125/95 $0.00 + .20 CHRONIC COUGH Herbert Patrick, MD, and Frank Patrick "What did one casket say t...

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COMMON MEDICAL PROBLEMS IN AMBULATORY CARE

0025-7125/95 $0.00 + .20

CHRONIC COUGH Herbert Patrick, MD, and Frank Patrick

"What did one casket say to the other casket?" "Is that you coffin?" ANONYMOUS

Cough is a sudden explosive force of air through the glottis in an effort to clear mucus or other matter from the large bronchi, trachea, or larynx. During cough, expiratory flow rates can exceed 12 L/ sec, resulting in a characteristic sound such as whooping cough or the brassy cough of tracheal compression. 29 ,31 Chronic cough is commonly defined as a persistent or recurrent cough exc~eding 3 weeks' duration. lo The prevalence of chronic cough is reported to range from 14% to 23% for nonsmoking adults. 39 Cough in adults is the fifth most common symptom in patients seen by outpatient physicians and accounts for 30 million office visits annually.39 Patients with chronic cough seek medical attention for reasons such as the following: concern that something is wrong; self-consciousness; hoarseness; fear of cancer, acquired immunodeficiency syndrome (AIDS), and tuberculosis. 16 In children, chronic cough is one of the most common reasons for an office visit to a pediatrician. 2 , 13, 23 PATHOPHYSIOLOGY

The function of cough is removal of foreign material from the respiratory tract. Cough is under both voluntary and involuntary, i.e., protective reflex, control in humans and many animals. Each cough is generated in four steps coordinated by the cough center in the brain-

From the Division of Pulmonary Medicine and Critical Care, Jefferson Medical College, Thomas Jefferson University (HP, FP); and the Department of Respiratory Care, Thomas Jefferson University Hospital (HP), Philadelphia, Pennsylvania MEDICAL CLINICS OF NORTH AMERICA VOLUME 79· NUMBER 2· MARCH 1995

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stem: (1) initial inspiratory gasp; (2) Valsalva maneuver with forceful contraction of the muscles of the chest wall, abdominal wall, and diaphragm against a closed glottis; (3) expiratory blast as the vocal cords abduct; and (4) posttussive prolonged inspiration. 11 , 20 The removal of foreign material is accomplished during the expiratory phase. 31 Spinal cord injury above C6-7 results in loss of chest wall, intercostal, and abdominal muscles necessary for cough, markedly reducing cough effort and efficacy.11 Chronic cough can result in a number of complications reflecting the physiology in each of the four generating steps. The Valsalva maneuver elevates intrathoracic pressure, causing decreased venous return and increased systemic blood pressure with reflex vasodilation and bradycardia. All of these, when combined with posttussive inspiration, can lead to tussive syncopeY The raised intrathoracic pressure can cause pneumothorax and retinal vessel rupture. High venous pressures in cerebral vessels raise intracranial pressure and may result in tussive headache.11,33 Stresses of coughing can cause chest wall and abdominal muscle strain or even rib fracture. 42 Path%gic cough refers to reflex cough activity caused by disease. This cough is beneficial if airway secretions need to be cleared; however, pathologic cough is futile when there is no abnormal material in the airways.l1 Such a dry cough, compared with a productive cough, may still discredit the patient sociallyY Pathologic cough also results from stimulation of the cough reflex independent of respiratory secretions, i.e., increased sensitivity of the cough reflex. The nerves that initiate cough are predominately in the upper airway offering the site of greatest initial protection of the airway.2,1O The larynx, with the greatest number of sensory innervations via the bilateral superior laryngeal nerves, has the greatest protection against the entry of foreign material.2' 10 The tracheobronchial tree has several types of sensory nerves: (1) slowly adapting receptors, also known as stretch receptors; (2) rapidly adapting receptors, also known as irritant receptors; (3) pulmonary C-fiber receptors, also known as J-type receptors; and (4) bronchial C-fiber receptors. 1• 27 It is well established by studying action potentials of the vagus nerve that both stretch and irritant receptors trigger the cough reflex. 1,27 Agents selective for Cfibers, such as inhaled capsaicin and sulfur dioxide, also trigger cough and sneezing. 25,27 Even receptors in the external auditory canal can cause cough after mechanical stimulation from cerumen or hair triggers an afferent signal along the auricular branch of the vagus known as Arnold's nerve. 6,9, 11

THERAPY Appropriate assessment of chronic cough begins with a careful history and physical examination to identify the cause or causes of chronic cough and to select specific therapy.lO, 15-17, 20, 23, 30

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Despite the array of antitussive pharmacologic agents available, each is nonspecific. 17 Pharmacologic agents that alter the cough reflex can be divided by the site of action along the cough reflex, i.e., peripherally acting on sensory receptors and centrally acting on the respiratory centers in the medulla and nucleus tractus solitarius. 32 Although hundreds of compounds have been synthesized as antitussive agents, few have been marketed successfully because of the proven antitussive action of oral codeine. 11, 16 Two of the effective central acting antitussives that increase the cough threshold are the nonopioid dextromethorphan and antihistamine diphenhydramine. ll , 17, 40, 41 All centrally acting opioid agents may be sedating and have the side effect of respiratory center depression. Peripheral acting expectorants, also known as mucus-clearing agents, theoretically stimulate the flow of fluid secretions from submucosal glands and thereby promote a decrease in sputum viscosity. Hydration has historically been a first-line agent for decreasing sputum viscosity because dehydrated patients have great difficulty clearing secretions. The most common oral expectorants after water are guaifenesin (glyceryl guaiacolate), terpin hydrate elixir, potassium iodide (saturated solution), and iodinated glycerolY' 16, 17 Unfortunately, there is no scientific evidence to suggest that any expectorant has a greater effect on reducing sputum viscosity compared with strongly favored foods such as garlic, horseradish, pepper, or chicken soup. Although the iodides are popular for treating cough associated with chronic bronchitis and bronchiectasis, sustained-release guaifenesin is well tolerated and is the most prescribed protussiveY Mucolytics are indicated in patients with high mucus viscosity and copious, thick secretions that make coughing ineffective despite use of expectorants. N-acetylcysteine is the only mucolytic marketed in the United StatesY' 16, 17 It is delivered by high-flow nebulizer, and because it may irritate the airways, a [3-agonist treatment should always precede the use of acetylcysteine. Peripheral-acting anesthetic agents that block stretch receptors and reduce afferent signals include oral benzonatate and inhaled lidocaine delivered by high-flow nebulizer. 11 , 17,40,41 These agents are minimally effective and are often used in conjunction with expectorants. Patients taking inhaled lidocaine must be cautioned to avoid eating for 1 to 2 hours after the treatment because the topical anesthetic effect on the epiglottis may persist for over an hour and encourage aspiration. Medicated lozenges and cough drops are popular over-the-counter items for cough relief. These products contain various combinations of benzocaine, honey, camphor, menthol, eucalyptus oil, and flavoring agents; there is no proven advantage over simple sucking candies. Common causes and selective treatment of chronic cough are listed in Table 1. The five most common causes are discussed subsequently. POSTNASAL DRIP

The postnasal drip syndrome is the most common cause of chronic cough, accounting for 87% of patients in one study.39 Postnasal drip

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Table 1. CAUSES AND TREATMENTS OF CHRONIC COUGH Cause Postnasal drip Cough-variant asthma Gastroesophageal reflux Chronic bronchitis or bronchiectasis Angiotensin converting enzyme inhibitor induced Miscellaneous Restrictive lung disease Postviral bronchial hyperresponsiveness Aspiration Psychogenic

Treatment Antihistamine, decongestant, expectorant, inhaled nasal corticosteroid, decongestant spray, antibiotic Remove allergens, inhaled corticosteroid, inhaled [3-agonist, theophylline, oral corticosteroid Antireflux diet with 3 meals/day, head of bed blocks, H2 antagonist; avoid smoking, caffeine, alcohol, chocolate Smoking cessation, inhaled [3-agonist, inhaled ipratropium bromide, expectorant, antibiotics Reduce dosage or switch to another family of medication Treat underlying disorder, expectorant, antitussive Inhaled corticosteroid, inhaled [3-agonist, oral corticosteroid Treat underlying disorder, modify diet and swallowing habits, consider enteral feedings Eliminate all other causes, counseling

commonly results from allergic perennial, nonallergic, and vasomotor rhinitis; acute nasopharyngitis; and less commonly sinusitis. 39 The symptoms of postnasal drip are a sensation of liquid moving down into the throat associated with a tickle in the back of the throat, cough, and clearing of mucopurulent secretions from the oropharynx. IS, 19, 39 The signs of postnasal drip are cobbles toning of the oropharygeal mucosa owing to chronic stimulation of submucosal lymphoid follicles. IS Pathophysiology

The stimulation of irritant receptors in the oropharynx and pharynx by mucus accounts for initiation of the cough reflex. 20 Treatment

Combinations of pharmacologic agents are needed, beginning with a sustained-action oral antihistamine and decongestant. If there is no initial improvement in the first week, nasal corticosteroids by inhaler are added for a second week. If improvement still has not occurred, sinusitis should be searched for by obtaining sinus radiographic films. Findings on sinus films suggesting sinusitis include sinus opacification, air-fluid levels, or mucosal thickening. If sinusitis is present, a nasal decongestant spray and antibiotics for up to 6 weeks are added. Sinusitis

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that fails to respond to this medical regimen for 6 weeks requires consultation with an otolaryngologist for possible surgery.!9,39 COUGH-VARIANT ASTHMA

Wheezing has always been a classic sign establishing the diagnosis of asthma. Patients with cough, however, may have asthma without wheezing and are defined as having cough-variant asthma; they account for 29% of patients with chronic cough. 26, 34, 39 Cough without wheezing, especially in older patients with bronchodilator-responsive pulmonary function tests, is often mistaken as a symptom of chronic bronchitis or congestive heart failure,34,36 The cough of patients with cough-variant asthma is dry, occurs around the clock, and is made worse by exacerbations of airway inflammation owing to upper respiratory tract viral infection, seasonal allergies, exercise, or cold air,22 On physical examination, wheezing may be absent, and standard spirometry with peak flows or forced expiratory volume in 1 second (FEV l ) may be normal. Bronchoprovocation pulmonary function testing, using increasing dosages of inhaled methacholine, is most valuable in establishing the diagnosis of airway hyperresponsiveness. 16, 37-39 Doubling the concentrations of inhaled methacholine until the FEV! falls 20% from baseline allows comparison between patients. Asthmatics respond to methacholine with greater bronchoconstriction at a smaller concentration than normals. Pathophysiology

Animal studies have shown that when hyperresponsive airways are present, less airway stimulation is necessary to produce cough. In humans, a cough stimulus and bronchoconstriction stimulus may act on different receptors simultaneously, although neither is completely dependent on the other for its action. 34 Mechanical changes in inflamed airways during bronchoconstriction may lead to stimulation of the cough reflex and subsequent cough-variant asthma. 22, 34 Possibly, significant inflammation in the large airways stimulates the abundant irritant receptors located there compared with peripheral airways. Because wheezing reflects peripheral airway bronchoconstriction, patients with coughvariant asthma who wheeze may have both large and small airway inflammation. 22,34 Treatment

Cough-variant asthmatics mistaken for having congestive heart failure do not respond to diuretics. If bronchodilators are prescribed for presumed chronic bronchitis, the cough should incidentally improve, although l3-agonists do not reduce bronchial reactivity. The newest

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definitions of asthma recognize chronic inflammation in the airways resulting in increased bronchial reactivity. Standard therapy for asthma consists of allergen removal, inhaled steroids to reduce inflammation, and inhaled [3-agonists for bronchodilation. 3 , 34, 39 The use of daily inhaled anti-inflammatory agents, such as twice-daily corticosteroids or cromolyn four times per day (or both), is aimed at reduction of bronchial reactivity. Long-term high-dose inhaled corticosteroids, which offer fewer side effects than oral corticosteroids, may be necessary, especially in combination with a spacer device to enhance drug delivery. Although a new 12-hour inhaled [3-agonist, salmeterol, may aid in the treatment of nocturnal asthma and cough owing to its prolonged action, airway inflammation and reactivity would not be reduced. Oral theophylline or a short course of oral corticosteroids (or both) may be necessary if inhaled anti-inflammatory and [3-agonist agents are ineffective. 39 Expectorants, mucolytics, or central-acting antitussives are generally not needed.

GASTROESOPHAGEALREFLUX Chronic cough is due to gastroesophageal reflux (GER) in 10% to 21 % of patients and can be the sole manifestation of gastroesophageal reflux disease (GERD).18 The mechanism of cough resulting from GER is repetitive stimulation of the distal esophagus, whereas less commonly, tracheal aspiration of gastric contents causes cough. 1R GERD can cause cough while silent from a gastrointestinal standpoint 75% of the time, complicating the establishment of a diagnosis. 14• 18 Patients who have GER and are nonsmokers with normal chest films should be considered more likely to have cough owing to GER.18 Diagnostic testing by esophageal pH monitoring for 24 hours has a sensitivity of 92% for GER, which is higher than esophagoscopy and barium esophagography.18 Confirming GER as the cause of chronic cough, however, can occur only when therapy for GER alone successfully treats the cough. 39 Pathophysiology

GER-induced cough appears to be triggered by stimulation of mucosal receptors in the distal esophagus rather than irritation in the upper respiratory tract from chronic aspiration. 14, 18 The stimulation of the distal esophageal receptors may be from acid alone without symptoms of reflux, just as acid infusion during the Bernstein and Baker test may fail to recreate chest pain in patients with pain accompanying GER.14 Experimental models of GERD have shown that proteolytic enzymes produce significantly more damage in the esophagus than acid alone. 18 Studies of airway inflammation in patients with chronic cough owing to GERD have shown increased bronchial inflammation compared with controls.3

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Treatment

Specific therapy for GER begins with 2 weeks of consuming a standard antireflux diet consisting of high-protein, low-fat meals three times each day; not eating or drinking for 2 to 3 hours before bedtime or lying down; and avoiding caffeine, alcohol, and chocolate. 1s,39 Additional therapies include daily use of H2 antagonists and metoclopromide, smoking cessation, and 20-cm elevation of the head of the bed using blocks. Lack of a response to this trial requires 24-hour esophageal pH monitoring of both the distal and the proximal esophagus to establish the diagnosis. 1s,39 A barium swallow, upper gastrointestinal study, or gastroenterology consultation for endoscopy should be considered for gastrointestinal complaints exceeding 8 weeks of anti reflux therapy.6,39 Pulmonary consultation for bronchoscopy to detect aspiration may also be necessary in patients unresponsive to antireflux therapy.

CHRONIC BRONCHITIS AND BRONCHIECTASIS

Pulmonary disorders with chronic airway irritation and inflammation account for 5% of patients with chronic cough. 39 Chronic bronchitis is characterized by chronic cough and sputum production for at least 3 months per year for 2 consecutive years. The major pathologic features of chronic bronchitis are the enlargement of the tracheobronchial mucous glands and hyperplasia of goblet cells in the small airways. Mucus is produced daily and may be discolored yellow, green, or brown. The most common patient characteristic is smoking of cigarettes, cigars, or pipes. 4 Tobacco smoke inhibits ciliary activity in both the nose and the tracheobronchial tree, decreasing mucociliary clearance. Smoke also increases mucus volume and viscosity. Pulmonary function tests usually disclose obstructive airways disease without bronchodilator responsiveness. Chest films may be abnormal with postobstructive atelectasis or dilated bronchioles with thickened walls or both features. In bronchitic patients with a hypersecretory state, cough becomes necessary to maintain mucus clearance and avoid infections from viruses, Mycoplasma, and Chlamydia. For patients with poor mucus clearance, the protussive agent iodinated glycerol has improved cough frequency, cough severity, ease of expectoration, and overall wellbeing, although the side effect of hypothyroidism has limited its clinical use. Bronchiectasis is the abnormal, irreversible dilation of bronchi, which change shape to become cylindric, varicose (irregular), or cystic. Most patients have a dry cough. The chest film may disclose thin parallel lines (tram tracks) representing airway walls in cylindric bronchiectasis. Bronchography has been replaced by high-resolution computed tomography (CT) scanning, which discloses the thick-walled airways.

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Treatment

A study of the relationship between respiratory symptoms and cessation of cigarette smoking disclosed that chronic cough and chronic phlegm were reduced by 50% in ex-smokers compared with subjects who continued to smoke. 28 Smoking cessation has a greater impact in reducing chronic cough than the combination of bronchodilator therapy, expectorants, and empiric antibiotics. 6 Ipratropium bromide, an inhaled anticholinergic available as a metered-dose canister or nebulizer solution, acts as both a bronchodilator and a peripheral antitussive and is preferred over ~-agonists.16, 17 Long-term antibiotics, selected according to sputum cultures, may help together with theophylline, chest physiotherapy, and postural drainage, Oral corticosteroid use, with little effect noted in spirometry, is controversial. ANGIOTENSIN CONVERTING ENZYME INHIBITOR INDUCED

Pharmacologic inhibition of angiotensin converting enzyme (ACE) provides for treatment of hypertension and congestive heart failure. 21 ,35 As the popularity of ACE inhibitors increased since their introduction in 1977, reports of chronic nonproductive cough also increased. 32 This cough appeared at various times after starting ACE inhibitors in 6% to 14% of patients. 24, 32 Establishing a definitive relationship of ACE inhibitors to cough is compounded by the variable onset of cough, being 3 to 4 weeks up to 1 year from the initiation of the drug. 24 ACE inhibitorinduced cough may be worse at night and in the supine position, mimicking GER.32,35 The cough is more common in females and in nonsmokers compared with smokers.24,32 Pathophysiology

ACE is a kininase localized to endothelial cells that cleaves terminal dipeptides, e.g., his-leu from angiotensin I to form angiotensin Ips Because ACE is also responsible for the breakdown of kinins, such as bradykinin, ACE inhibition allows kinins to accumulate. s,24 Bradykinin, together with local increases of histamine, substance P, neuropeptide Y, and prostaglandin synthesis, may play a role in ACE inhibitor-induced cough, rhinitis, angioedema, and possible asthma. 24,35 Treatment

The frequency of cough may diminish with a dose reduction of the ACE inhibitor as tolerated clinically.24 Switching among the various inhibitors does not affect the cough. 8 ,32 Addition of agents that interfere

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with prostaglandin synthesis, such as indomethacin or sulindac, has diminished the cough based on the fact that proinflammatory peptides stimulate afferent cough nerve fibers in the bronchial mucosa. 24 The use of oral theophylline 5 and sodium cromoglycate by inhalation 12 has also been effective in some patients. The only reliable remedy for ACE inhibitor-induced cough, however, is to withdraw the ACE inhibitor for several days and initiate treatment with a different family of antihypertensive compounds. H, 24

LESS COMMON CAUSES Pulmonary Tumors

The frequency of cough in patients with newly diagnosed lung cancer varies between 21 % and 87%, but chronic cough ultimately occurs in up to 90% of all lung cancer patients owing to endobronchial involvement or postobstructive atelectasis (or both).38 Although tumors such as bronchial adenomas may directly stimulate receptors initiating cough, the chest film may appear normal. Bronchoscopy is rarely helpful in the presence of a normal chest film. 6, 38 CT of the thorax is indicated at the time of bronchoscopy to search for pulmonary and pleural lesions if the more common causes of chronic cough have been eliminated and a follow-up chest film remains normal. 6

Restrictive Lung Disease

Diseases of the pleura, chest wall, diaphragm, neuromuscular apparatus, or pulmonary interstitium all result in reduced lung volumes. The resultant lack of stimulation to the stretch receptors during normal respirations initiates a nonproductive cough. In certain interstitial lung diseases, such as sarcoidosis, submucosal bronchial infiltration and inflammation are thought also to initiate the cough reflex. 38,40 Treatment of the underlying lung disease are necessary to control the cough.

Postviral Bronchial Hyperresponsiveness

Cough owing to an acute viral upper respiratory infection is extremely common and fortunately self-limiting? Chronic cough may folIowa viral respiratory infection, possibly owing to the establishment of chronic bronchial inflammation. 3 , 34, 39 If methacholine challenge pulmonary function testing demonstrates hyperresponsiveness, inhaled or oral corticosteroids with bronchodilators are required for treatment, analogous to cough-variant asthma. 34

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Aspiration

Cough during eating or drinking suggests aspiration. 6 A barium swallow, performed with the help of a speech pathologist, establishes the diagnosis if tracheal penetration is noted in the pharyngeal phase of swallowing. 6 Although instruction and changes in swallowing habits and food consistency may decrease cough frequency, gastric or jejunal feeding tubes may be indicated depending on the frequency of cough and respiratory distress. Psychogenic Cough

This rare psychiatric diagnosis can only be established after all other possible diagnoses have been eliminated. 6, 30 SUMMARY

Chronic cough is a common symptom presenting to all clinicians. Every effort should be made to determine the cause(s) of cough because specific therapy has a higher likelihood of success than empiric therapy. Evaluation begins with a complete history, physical examination, routine health screen laboratory testing, chest film, and pulmonary function testing. Further investigation should be guided by the response to treatment of the most likely diagnostic possibilities: postnasal drip, coughvariant asthma, gastroesophageal reflux, chronic bronchitis, bronchiectasis, and ACE inhibitor induced, The majority of each patient's workup can be performed and ordered by the primary care physician. ACKNOWLEDGMENT The authors thank Nina Chiles for her assistance in preparing the manuscript.

References 1. Adcock JJ: Peripheral opioid receptors and the cough reflex, Respir Med 85 (suppl A):43--46, 1991 2, Beardsmore CS, Simpson H: Cough in children, J Asthma 28:309-321, 1991 3. Boulet L-P, Milot J, Boutet M, et al: Airway inflammation in nonasthmatic subjects with chronic cough. Am J Respir Crit Care Med 149:482--489, 1994 4. Brown CA, Woodward M, Tunstall-Pedoe H: Prevalence of chronic cough and phlegm among male cigar and pipe smokers. Results of the Scottish Heart Health Study. Thorax 48:1163-1167,1993 5. Cazzola M, Matera MC, Liccardi C, et al: Theophylline in the inhibition of angiotensin converting enzyme inhibitor-induced cough. Respiration 60:212-215, 1993 6. Curley FJ, Irwin RS: Chronic cough. In Conn RB (ed): Current Diagnosis, ed 8. Philadelphia, WB Saunders, 1991, pp 16--20

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7. Curley FJ, Irwin RS, Pratter MR, et al: Cough and the common cold. Am Rev Respir Dis 138:305-311, 1988 8. Do TM, Wanders DL, Hart LL: Drug information analysis service, ACE inhibitorinduced cough. mcp, Ann Pharmacother 24:1059-1060,1990 9. Feldman JI, Woodworth WF: Cause for intractable chronic cough. Arnold's nerve [letter]. Arch Otolaryngol Head Neck Surg 119:1042, 1993 10. Fuller RW, Jackson OM: Physiology and treatment of cough [edit]. Thorax 45:425430, 1990 11. Hagen NA: An approach to cough in cancer patients. J Pain Symptom Manage 6:257-262, 1991 12. Hargreaves M: Sodium cromoglycate, a remedy for ACE inhibitor-induced cough. Brit J Clin Pract 47:319-320, 1993 13. Hatch RT, Carpenter CB, Smith LJ: Treatment options in the child with a chronic cough. Drugs 45:367-373, 1993 14. Ing AI, Ngu MC, Breslin AB: Pathogenesis of chronic persistent cough associated with gastroesophageal reflux. Am J Respir Crit Care Med 149:160-167, 1994 15. 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 123:413-417, 1981 16. Irwin RS, Curley FJ: The treatment of cough, a comprehensive review. Chest 99:14771484, 1991 17. Irwin RS, Curley FJ, Bennett FM: Appropriate use of antitussives and protussives. A practical review. Drugs 46:80-91, 1993 18. Irwin RS, French CL, Curley FJ, et al: Chronic cough due to gastroesophageal reflux. Chest 104:1511-1517,1993 19. Irwin RS, Pratter MR, Holland PS, et al: Post-nasal drip causes cough and is associated with reversible upper airway obstruction. Chest 85:346-352, 1984 20. Irwin RS, Rosen MJ, Braman SS: Cough, a comprehensive review. Arch Intern Med 137:1186-1191,1977 21. Israili ZH, Hall WO: Cough and angioneurotic edema associated with angiotensinconverting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med 117:234-242, 1992 22. Johnson 0, Osborn LM: Cough variant asthma: A review of the clinical literature. J Asthma 28:85-90, 1991 23. Kamei RK: Chronic cough in children. Pediatr Clin North Am 38:593-604, 199] 24. Karlberg BE: Cough and inhibition of the renin-angiotensin system. J Hypertens 11:S49-S52, 1993 25. Karlsson JA: A role for capsaicin sensitive, tachykinin containing nerves in chronic coughing and sneezing but not in asthma: A hypothesis. Thorax 48:396-400, 1993 26. Konig P: Cough variant asthma. J Asthma 28:83-84, 1991 27. Korpas I, Widdicombe JC: Aspects of the cough reflex. Respir Med 85:3-5, 1991 28. Krzyzanowski M, Robbins OR, Lebowitz MD: Smoking cessation and changes in respiratory symptoms in two populations followed for 13 years. Int J Epidemiol 22:666-673, 1993 29. Loudon RC: Cough: A symptom and a sign. Basics of RD 9:1-6,1981 30. Loudon RC: Finding the cause of cough. Ask, listen, and look. J Respir Dis 6:97-107, 1985 31. Mahajan RP, Singh P, Murty CE, et al: Relationship between expired lung volume, peak flow rate and peak velocity time during a voluntary cough manoeuvre. Br J Anaesth 72:298-301, 1994 32. Martinez El, Seleznick MJ: Respiratory tract side effects of angiotensin converting enzyme inhibitors, current knowledge. South Med J 84:1343-1346,1991 33. Moncada E, Craff-Radford SB: Cough headache presenting as a toothache, a case report. Headache 33:240-243, 1993 34. O'Connell EJ, Rojas AR, Sachs MI: Cough-type asthma, a review. Ann Allergy 66:278286, 1991 35. O'Hollaren MT, Porter CA: Angiotensin converting enzyme inhibitors and the allergist. Ann Allergy 64:503-506, 1990

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36. Pender ES, Pollack CV: Cough-variant asthma in children and adults: Case reports and review. J Emerg Med 8:727-731, 1990 37. Poe RH, Arter RV, Israel RH, et al: Chronic persistent cough, experience in diagnosis and outcome using an anatomic diagnostic protocol. Chest 95:723-728, 1989 38. Poe RH, Israel RH, Utell MJ, et al: Chronic cough, bronchoscopy or pulmonary function testing? Am Rev Respir Dis 126:160-162, 1982 39. Pratter MR, Bartter T, Akers S, et al: An algorithmic approach to chronic cough. Ann Intern Med 119:977-983, 1993 40. Sanders RV, Kirkpatrick MB: Prolonged suppression of cough after inhalation of lidocaine in a patient with sarcoid. JAMA 252:2456-2457, 1984 41. Trochtenberg S: Nebulized lidocaine in the treatment of refractory cough. Chest 105:1592-1593, 1994 42. Wynn-Williams N, Young RD: Cough fracture of the ribs including one complicated by pneumothorax. Tubercle 40:47-49, 1959

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