INTERNAL MEDICINE

Diagnosis and Management of Chronic Cough due to Extrapulmonary Etiologies KN MOHAN RAO

ABSTRACT Cough remains one of the chief complaints for which patients seek medical attention. It has been estimated that at least 25% of chronic cough cases are caused by multiple, simultaneous causes. Cough is also an important presenting feature of a number of extrapulmonary conditions, such as cardiac diseases, upper airway diseases, gastroesophageal reflux diseases and neurological/ psychological conditions. The diagnosis of extrapulmonary causes of cough is quite challenging and the management is complicated by poor treatment response if underlying etiological mechanisms are overlooked. The intention of this article is to highlight the importance and consequences of nonpulmonary etiologies of cough such as drug-induced vocal cord dysfunction, gastroesophageal reflux disease, laryngeal reflux and neuropathic disorders and to discuss about management strategies for each etiology.

Keywords: Chronic cough, extrapulmonary causes, mechanisms, management options

C

ough is a vital physiological reflex, which protects the airways from entry of harmful substances.1,2 Acute cough (8 weeks) may be a key symptom of several chronic respiratory conditions.4 Multiple aggravates have been linked to the pathogenesis of cough and it has been estimated that in at least 25% of chronic cough cases, cough is due to the presence of multiple, simultaneous causes.4,5 Apart from respiratory causes, cough is also an important presenting feature of a number of extrapulmonary conditions, such as those involving upper airways, cardiac, neurological/ psychological diseases and gastroesophageal reflux disease (GERD).4,6,7 In a study involving 1,332 patients with chronic persistent cough who attended a chest clinic, nonpulmonary causes such as rhinosinusitis and gastroesophageal reflux were found to contribute to 60% and 9% of cases, respectively.8 Additionally, patients with chronic cough also present with an array of sensory symptoms associated with laryngeal neural dysfunction.9 Diagnosing cough due to extrapulmonary cases can present as an intimidating challenge to physicians since cough can arise from practically anywhere the

vagus nerve travels.10 Analogous to the chronic pain syndrome both peripheral and central sensitizations are implicated in chronic cough; and cough due to extrapulmonary sites such as the esophagus has been linked to visceral hypersensitivity occurring as a result of central sensitization.11 Difficult-to-treat cough is often considered to be functional or psychogenic, often overlooking extrapulmonary causes of cough such as GERD and this can lead to treatment failure with available agents.12 Uncontrolled chronic cough can considerably affect patients’ quality-of-life and precipitate anxiety, physical distress and social and personal discomfiture.13 The objective of this article is to highlight the importance and consequences of extrapulmonary etiologies of cough. This article also addresses the effective diagnosis and management of cough induced by drugs, vocal cord dysfunction (VCD), GERD, laryngeal reflux, cardiac diseases and neurological disorders. In preparing this article, PUBMED was searched for studies/guidelines published in the English language using the MeSH terms: Cough, causes of cough, etiology of cough, nonpulmonary causes and extrapulmonary causes of cough. COMMON EXTRAPULMONARY CAUSES OF CHRONIC COUGH

Professor and Head Dept. of Chest Disease Raja Rajeswari Medical College and Hospital, Bangalore E-mail: [email protected]

In the vast majority of patients, airway disorders such as asthma, nonasthmatic eosinophilic bronchitis, bronchiectasis, atopic cough, chronic bronchitis,

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INTERNAL MEDICINE Table 1. Extrapulmonary Causes of Chronic Cough6,13 Drugs Angiotensin-converting enzyme inhibitors and β-blockers Upper airway diseases Postnasal drip syndrome, vocal cord dysfunction, obstructive sleep apnea Esophageal causes Gastroesophageal reflux disease, laryngopharyngeal reflux and tracheoesophageal fistula Cardiac diseases Chronic heart failure, pulmonary congestion and endocarditis, etc. Neurological/psychological causes Psychogenic (habit) cough

sarcoidosis, aspiration and airway foreign bodies as well as benign and malignant tumors involving the airways and parenchyma are considered as the common etiological factors for chronic cough.13 However, the importance of extrapulmonary causes of cough cannot be disregarded and these causes have been listed in Table 1.6,13 CHRONIC COUGH DUE TO VARIOUS EXTRAPULMONARY ETIOLOGIES

Drug-induced Cough Drugs, as a cause of a myriad of pulmonary diseases, have been in focus for many years. Contrary to a review published in 1972, which has reported that 19 drugs have the potential to cause pulmonary diseases, recent estimates have indicated that more than 350 drugs have the potential role in causing pulmonary diseases including chronic cough.14 Drugs are being increasingly recognized as a cause of chronic cough particularly drugs belonging to the angiotensin-converting enzyme (ACE) inhibitor class. Between 5% and 35% of people suffer from chronic nocturnal cough with the use of ACE inhibitors (ACEIs). The mechanism is thought to be through the release of bradykinin by ACEIs, which is otherwise metabolized by ACE in the lungs. This results in a characteristic tickling, scratchy or itchy sensations in the throat.15 Beta-blockers are also known to produce cough, which may be an initial manifestation of drug-related airway hyper-responsiveness or bronchoconstriction. Apart from cough, wheeze and dyspnea may occur with the use of β-blockers. Calcium channel antagonists

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are known to induce reflux cough by relaxing the lower esophageal sphincter pressure and also by a dose-dependent impairment of esophageal clearance. Bronchoconstriction has been observed with the use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) in 5% of people with asthma. This could be due to the production of cysteinyl leukotriene and inhibition of cyclooxygenase-1 enzyme.15 Clinical, radiological and histological findings are generally nonspecific and make the diagnosis of druginduced cough difficult. A careful consideration of drug history and ruling out other causes of cough can help in diagnosing drug-induced cough. Management includes discontinuation of the relevant drug that is implicated to produce cough.14

Upper Airway Diseases and Cough Postnasal Drip Syndrome Postnasal drip is part of upper airway cough syndrome, which includes rhinitis and rhinosinusitis. It is generally associated with chronic cough and patients typically present with symptoms such as frequent throat clearing, hoarseness, nasal congestion and sensation of dripping at the back of throat.1 Therapy with proton pump inhibitors may also be beneficial in patients with postnasal drip syndrome apart from regular medications such as antihistamines, nasal steroids and decongestants.13 Vocal Cord Dysfunction Vocal cord dysfunction is characterized by periodic involuntary paradoxical adduction of the vocal cords, which can lead to acute severe dyspnea that is nonresponsive to conventional asthma therapy.16 Females have a higher preponderance to develop VCD compared to males with an estimated incidence of 40:1.17 There are three presentations of VCD as follows:17 ÂÂ

Exercise-induced VCD: The symptoms are linked to exercise.

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Spontaneous VCD: Indicates a sudden onset of symptoms without exercise.

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Persistent VCD: Indicates adduction of vocal cords during both inspiration and expiration.

Apart from exercise, certain other triggers are implicated for VCD, such as psychological conditions, airborne irritants, rhinosinusitis, GERD or use of certain drugs. Cough is one of the characteristic features observed in patients with VCD, which presents with recurrent episodes of subjective respiratory distress. Diagnosis

INTERNAL MEDICINE of VCD can be made with pulmonary function testing with a flow-volume loop and flexible laryngoscopy.18 In acute cases, reassurance and breathing instructions can relieve VCD; however, in the long-term, elimination of precipitating factors may be useful. Evidence suggests that a number of patients with VCD, which is commonly diagnosed as a mimic of asthma, receive overtreatment with inhaled corticosteroids and consequently have considerable adverse effects. Hence, appropriate diagnosis and management of VCD is crucial to avoid iatrogenic complications.16 Apart from these upper airway diseases, patients with sleep apnea also complain of chronic cough.6

Gastroesophageal Reflux Disease Chronic cough is a prominent feature in GERD and is the sole symptom in up to 75% of cases. In adults with microaspiration, cough follows symptoms of heartburn, regurgitation, sour taste, dysphonia, hoarseness and throat pain.19 GERD has also been implicated in several other pulmonary diseases, such as bronchial asthma, chronic bronchitis and diffuse pulmonary fibrosis that have cough as a presenting symptom. In more than 90% of patients with chronic persistent cough, GERD, bronchial asthma and postnasal drip syndrome either alone or in combination has been implicated as a causative factor. The principal mechanisms of cough caused by GERD include aspiration of gastric contents, autonomic dysfunction and vagally-mediated distal esophagealtracheobronchial reflexes. A self-perpetuating positive feedback cycle between cough and esophageal reflux has been proposed recently whereby cough originating from any cause may precipitate further reflux, which may worsen the cough (see Fig. 1).20

Cough

Increased transient lower esophageal sphincter relaxation and transdiaphragmatic pressure

Proton pump inhibitors

The following features help in predicting chronic cough due to GERD:21 ÂÂ

Complaints of a dry or productive cough for a period of at least 2 months

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Cough observed in nonsmokers and those not exposed to other environmental irritants

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Cough in individuals not taking an ACEI

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A normal or near-normal chest radiograph

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No evidence of symptomatic asthma or cough not improving with asthma medications

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No evidence of postnasal drip syndrome due to rhinosinusitis and the use of first-generation H1antagonists have failed to improve cough

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No evidence of eosinophilic bronchitis as confirmed by negative sputum studies or cough not improving with inhaled/systemic corticosteroids.

Empirical medical antireflux therapy with proton pump inhibitors may be useful in managing patients with GERD and cough but there is a significant failure rate associated with this in which case antireflux surgery may be useful.20

Laryngopharyngeal Reflux Chronic laryngitis occurs as a result of exposure to irritants. However, reflux-induced laryngitis or laryngopharyngeal reflux (LPR) may be observed in patients not exposed to irritants.22 The differentiating features between GERD and LPR are described in Figure 2.21 Laryngoscopy and 24-hour pH monitoring are the most common tests used for the diagnosis of reflux-related laryngitis.23 In a study by Patterson et al involving 19 patients with asthma and 18 patients with chronic cough, nonacid  reflux  episodes  reaching  the  pharynx  was found to be an important factor associated with cough that was assessed using multi-channel intraluminal impedance and pH monitoring in the esophagus and hypopharynx.24 Use of acid suppressive drugs have produced insufficient treatment response in patients with LPR.23

Distal esophageal and tracheobronchial reflux

GERD

Figure 1. Positive feedback cycle between cough and esophageal reflux.

Gastroesophageal reflux

Laryngopharyngeal reflux

yy Heartburn yy Acid reflux symptom yy Aggravated at night and when lying down

yy Dry cough yy Voice change, throat clearing yy Aggravated when eating, standing

Figure 2. Differentiating features between GERD and LPR.21

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INTERNAL MEDICINE Cardiac Causes Cough is one of the presenting features of heart failure with pulmonary congestion; therefore, a high index of suspicion for left ventricular heart failure should be maintained by the physicians in patients presenting with a new or worsening cough.22 Dry irritating cough, particularly nocturnal, is observed in patients with chronic heart failure and it is often mistaken for asthma, bronchitis or ACEI-induced cough.25 Nonproductive cough with shortness of breath may be observed in patients with acute pericarditis.26 Cough can also arise as a side-effect of medications used for the treatment of cardiac conditions, such as ACEIs, β-blockers and amiodarone. Therefore, a targeted diagnostic and

treatment approach should be undertaken for relieving cough in such patients.6

Neurological/Psychological Causes Cough due to Neuromuscular Causes Coughing and choking are frightening and distressing symptoms observed in patients with neuromuscular diseases and are generally a consequence of a need to cough but with impaired efficacy of the cough reflex. Coughing is precipitated by a variety of factors in patients with upper and lower motor neuron dysfunction who suffer from varying degrees of respiratory muscle weakness, dysphagia and laryngeal

Cough lasting more than 8 weeks History and physical examination Normal chest radiography findings

History of cough due to use of drug (angiotensinconverting enzyme inhibitor)

yy Heartburn, respiratory symptoms, water brash, regurgitation yy Symptoms worse when lying down yy Positive results of pH

yy Dry cough yy Voice change yy Frequent throat clearing

yy Upper respiratory tract signs and symptoms yy Cough worsened by allergens, temperature changes or pregnancy indicates rhinitis

Frequent involuntary paradoxical adduction of the vocal cords, and acute severe dyspnea

Cough related to cardiac diseases

Repeated throat clearing with no other cause of cough

GERD

Reflux-related laryngitis

Postnasal drip

Vocal cord dysfunction

Targeted diagnosis and treatment

Others (habit/ psychogenic cough)

Acid suppressant drug (?)

yy First-generation antihistamine, ipratropium bromide and nasal steroids yy Surgery for severe, recalcitrant cases

yy Reassurance and breathing instructions (short-term) yy Eliminating aggravating factors (long-term)

Drug-induced

Discontinue the relevant drug OR Adjust dose of angiotensinconverting enzyme inhibitor OR Consider using an angiotensinII–receptor inhibitor

Conservative options yy Weight loss yy Avoid exacerbating foods yy Smoking cessation Drugs yy H2 antagonists for 6 months yy Re-evaluate with pH probe and endoscopy yy Proton pump inhibitor yy Fundoplication for severe, recalcitrant cases

Figure 3. Algorithm for managing chronic cough due to extrapulmonary causes.16,19,29

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Specific therapy (behavior modification or psychiatric intervention)

INTERNAL MEDICINE dysfunction.27 In a small case series, cough was observed to be a presenting feature in patients with mononeuritis multiplex, diabetic autonomic neuropathy, HolmesAdie syndrome and hereditary sensory neuropathy 1.28 Habit or Psychogenic Cough Habit cough or psychogenic cough is associated with a throat clearing noise. The 2006 American College of Chest Physicians evidence-based clinical practice guidelines state that the diagnosis of habit cough can be made only after an extensive evaluation is undertaken to rule out tic disorders and uncommon causes of cough. This type of cough improves with specific therapy, which includes behavior modification or psychiatric intervention.29 GENERAL PRINCIPLES IN THE MANAGEMENT OF CHRONIC COUGH ASSOCIATED WITH EXTRAPULMONARY DISEASES

Evaluation and History Taking Patient evaluation and history taking are an important part of initial evaluation of patients presenting with cough caused by extrapulmonary factors. The nature, frequency, onset, duration, medication use and aggravating factors of chronic cough should be determined by proper history taking. In addition, details of response to previous treatment can also be derived from initial assessments.21

Diagnosis and Management Chest radiography forms an important initial investigation to help detect several ominous pulmonary diseases that may need specialist care. When results of chest radiographs are normal, pulmonary (asthma and postnasal drip), as well as extrapulmonary causes of cough such as drug-induced, GERD or postinfectious are probable etiologies. Specific treatment measures have been described in Figure 3.16,19,29 In some instances, additional investigations including methacholine challenge test, sinus radiography and an esophageal pH probe are needed to confirm the diagnosis. ANTITUSSIVE TREATMENT Treatment directed against aggravating factors of chronic cough often remains suboptimal; therefore, antitussive therapies are sometimes needed for symptomatic relief.30 Antitussives can be categorized as centrally or peripherally acting.31 Centrally acting antitussive agents have been used as antitussive agents of choice for decades and include codeine,

dextromethorphan, methadone and morphine.31,32 These agents inhibit cough primarily by their effect on the cough center in the brain.31 Most antitussives are combinations of dextromethorphan or codeine with antihistamines, expectorants, decongestants and/or antipyretics.33 These antitussives are useful in the symptomatic relief of dry or nonproductive cough. Codeine is one of the most commonly preferred centrally acting cough suppressants. Findings from a meta-analysis which included five studies on efficacy of dextromethorphan and codeine in adults with cough concluded that central antitussives have marginally superior efficacy when compared to placebo.31 CONCLUSION Chronic cough remains one of the most common complaints for which patients seek medical help. Chronic cough has a significant impact on patients’ quality-of-life and causes considerable social and psychological distress. Cough is not only a symptom of respiratory conditions but is also a key indicator of nonpulmonary pathologies such as gastroesophageal disease, infections, VCD, LPR, cardiac and neurological diseases. Management options for extrapulmonary cough are specific and directed towards managing the aggravating factors. However, the response to specific treatments for these conditions is unpredictable and there is a high incidence of treatment failure prompting the need for use of antitussives in such instances. Centrally acting antitussive agents such as codeine and dextromethorphan may have a role in the symptomatic relief of dry or nonproductive cough. REFERENCES 1. Singh N, Singh V. Combating cough - etiopathogenesis. J Assoc Physicians India 2013;61(5 Suppl):6-7. 2. Chung KF, Pavord ID. Prevalence, pathogenesis, and causes of chronic cough. Lancet 2008;371(9621):1364-74. 3. Morice AH. Epidemiology of cough. Pulm Pharmacol Ther 2002;15(3):253-9. 4. Morice AH, McGarvey L, Pavord I; British Thoracic Society Cough Guideline Group. Recommendations for the management of cough in adults. Thorax 2006;61 Suppl 1:i1-24. 5. Madison JM, Irwin RS. Cough: a worldwide problem. Otolaryngol Clin North Am 2010;43(1):1-13. 6. Kardos P. Management of cough in adults. Breathe 2010;7(2):122-33. 7. Albert NM, Davis M, Young J. Improving the care of patients dying of heart failure. Cleve Clin J Med 2002;69(4):321-8.

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INTERNAL MEDICINE 8. Al-Mobeireek AF, Al-Sarhani A, Al-Amri S, Bamgboye E, Ahmed SS. Chronic cough at a non-teaching hospital: Are extrapulmonary causes overlooked? Respirology 2002;7(2):141-6. 9. Chung KF, McGarvey L, Mazzone SB. Chronic cough as a neuropathic disorder. Lancet Respir Med 2013;1(5):414-22. 10. Simpson CB, Amin MR. Chronic cough: state-of-the-art review. Otolaryngol Head Neck Surg 2006;134(4):693-700. 11. Woodcock A, Young EC, Smith JA. New insights in cough. Br Med Bull 2010;96:61-73. 12. Jeyakumar A, Brickman TM, Haben M. Effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough resulting from postviral vagal neuropathy. Laryngoscope 2006;116(12):2108-12. 13. Iyer VN, Lim KG. Chronic cough: an update. Mayo Clin Proc 2013;88(10):1115-26. 14. Verma S, Mahajan V. Drug induced pulmonary diseases. Int J Pulmon Med 2007;9:2. 15. Medford AR. A 54 year-old man with a chronic cough Chronic cough: don’t forget drug-induced causes. Prim Care Respir J 2012;21(3):347-8. 16. Kenn K, Balkissoon R. Vocal cord dysfunction: what do we know? Eur Respir J 2011;37(1):194-200. 17. Varney V, Parnell H, Evans J, Cooke N, Lloyd J, Bolton J. The successful treatment of vocal cord dysfunction with low-dose amitriptyline - including literature review. J Asthma Allergy 2009;2:105-10. 18. Deckert J, Deckert L. Vocal cord dysfunction. Am Fam Physician 2010;81(2):156-9. 19. D’Urzo A, Jugovic P. Chronic cough. Three most common causes. Can Fam Physician 2002;48:1311-6. 20. Ing AJ. Cough and gastro-oesophageal reflux disease. Pulm Pharmacol Ther 2004;17(6):403-13. 21. Jeong JW. The causes of chronic cough: Chronic cough due to extrapulmonary etiologies. Korean J Med 2010;78(6):670-3.

22. W est LM. Causes of cough. J Malta Coll Pharm Pract 2010;16:23-6. 23. Moore JM, Vaezi MF. Extraesophageal manifestations of gastroesophageal reflux disease: real or imagined? Curr Opin Gastroenterol 2010;26(4):389-94. 24. Patterson N, Mainie I, Rafferty G, McGarvey L, Heaney L, Tutuian R, et al. Nonacid reflux episodes reaching the pharynx are important factors associated with cough. J Clin Gastroenterol 2009;43(5):414-9. 25. Guidelines for the prevention, detection and management of chronic heart failure in Australia. Updated Oct. 2011. National Heart Foundation of Australia. 26. Maisch B. Guidelines on the diagnosis and management of pericardial diseases. The Task Force on the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology. Eur Heart J 2004;1:1-28. 27. Hadjikoutis S, Wiles CM, Eccles R. Cough in motor neuron disease: a review of mechanisms. QJM 1999;92(9): 487-94. 28. Karur PS, Morjaria JB, Wright C, Morice AH. Neurological conditions presenting as airway reflux cough. Eur Respir Rev 2012;21(125):257-9. 29. Irwin RS, Glomb WB, Chang AB. Habit cough, tic cough, and psychogenic cough in adult and pediatric populations: ACCP evidence-based clinical practice guidelines. Chest 2006;129(1 Suppl):174S-179S. 30. Pavord ID, Chung KF. Chronic Cough 2: Management of chronic cough. Lancet 2008;371:1375-84. 31. De Blasio F, Virchow JC, Polverino M, Zanasi A, Behrakis PK, Kilinç G, et al. Cough management: a practical approach. Cough 2011;7(1):7. 32. Reynolds SM, Mackenzie AJ, Spina D, Page CP. The pharmacology of cough. Trends Pharmacol Sci 2004;25(11):569-76. 33. Padma L. Current drugs for the treatment of dry cough. J Assoc Physicians India 2013;61(5 Suppl):9-13.

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Treat dry cough the ~ way

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