(1993) 87,249-25 1
Chronic cough - mechanisms and management The cough reflex is initiated by the stimulation of sensory nerve endings situated beneath and between the epithelium of the larynx and tracheobronchial tree, although recruitment of receptors throughout the distribution of the vagus and superior laryngeal nerves can also induce cough (1). Afferent impulses travel centrally to the dorsal medulla where the reflex is then subject to considerable cortical control. There are thus a number of sites at which the reflex may be influenced and which may be relevant to both the aetiology and management of chronic cough. Two different mechanisms are probably responsible for pathological coughing, the first whereby receptors on sensory nerves are stimulated directly by airway secretions, foreign bodies and tumours, and the second in which an abnormal increase in the sensitivity of receptors leads to persistent cough or a reduced threshold for coughing. The latter mechanism, termed ‘sensitization of the cough reflex’, has been recognized since the description of cough associated with angiotensin converting enzyme (ACE) inhibitors (2). Up to 15% of patients on these drugs develop a sensitized cough reflex that may be demonstrated by increased responsesto tussivechallenge (3). Although the abnormality usually reverses upon their withdrawal (2), coughing becomes intractable in some cases,leading to the idea that persistent abnormalities of the cough reflex may arisein susceptible individuals. The causeof such abnormalities remains poorly understood, but the phenomenon is not confined to patients taking ACE inhibitors. Several studies now show that heightened responses to tussive agents such as capsaicin or low chloride-content solutions are seen in association with viral infections, oesophageal reflux, cough-variant asthma and ‘idiopathic cough’ (4,5). A sensitized cough reflex is suggested clinically by the persistent presence of a tickling sensation in the throat that is associated with profound paroxysms of coughing. Coughing tends to be exacerbated by factors such as change in air temperature, aerosol sprays and irritants such as perfumes and cigarette smoke. Intercurrent viral infections cause marked distress to such patients. Coleridge noted that the persistent tickling of the sensitized cough reflex is similar in nature to the sensation described by patients with sensoryhyperalgesia of the skin (6). This observation, together with the description of ACE inhibitor cough, has implicated neuroactive inflammatory mediators such as prostaglandins E, and F,, and bradykinin in the sensitization of the cough reflex. These agents are of 0954-611 l/93/040249+03
documented importance in the genesisof skin hyperalgesia (7,8) and both prostaglandins are powerful tussive agents (9) that have discrete effects on the sensitivity of the human cough reflex in the experimental situation (IO,1 1). The exaggeration of tussive responsesin patients with chronic cough is not merely a reflection of bronchial hyperreactivity, since the sensitivity of the cough reflex in patients with stable asthma is normal (5,12), and the majority of patients with a sensitizedcough reflex have a negative histamine response and no evidence of asthma (4). While it is important to recognize that cough may persist because of a sensitized reflex it is equally necessaryto understand that patients may continue to cough because they have been investigated inadequately. There is no uniformly accepted proforma for the investigation of chronic cough, but Irwin advocates the rigid application of a protocol designed to exclude anatomically all known causes of cough (13,14). The order of investigations and the extent to which they are pursued is dictated by the clinician’s view of each case, but tests should continue until a cause is identified. Once identified a potential cause should be treated. Irwin stresses,importantly, that more than one association of chronic cough occurs commonly in the same individual; if treatment of the first cause is unsuccessful, investigations should continue until another is found. Thus, based upon the sites that are known to influence the cough reflex, investigation of the upper airway (full ENT inspection + sinus X-rays +possible sinus CT), the lungs (atopy testing + CXR + full lung function + reactivity testing + possible bronchoscopy and biopsy, V/Q scanning, fine cut CT), the GI tract (ambulatory oesophageal pH monitoring + possible barium swallow), the heart (ECG + echo + possible stresstesting) and the mind (hyperventilation testing + possible psychometric testing, psychiatric appraisal) should be combined. The complete protocol is rather weighty, and as several studies suggest the commonest associations of undiagnosed cough are chronic sinusitis with postnasal drip, oesophageal reflux and cough-variant asthma (4,14,15) it would seem sensible to exclude these conditions before looking further afield. Oesophageal reflux may occur despite a normal barium swallow and the absence of symptoms (16), and ambulatory pH monitoring is advocated. Similarly, direct reactivity testing with histamine or methacholine may be the only positive investigation in @ 1993 Baillitre
cough-variant asthma. I would therefore suggest that all patients with recalcitrant cough should undergo the minimum of full ENT inspection, oesophageal pH monitoring and bronchial reactivity testing, remembering that these conditions may occur together, and recognition of one but not another will lead to treatment failure. Cough challenge is useful in the study of basic mechanisms and to demonstrate a sensitized reflex, but its clinical role in the follow-up of patients with cough has yet to be established. The development of ambulatory tussivemonitoring devicesmay provide a better means for the clinical assessmentof cough in the future. Sensitization of the cough reflex may causemuch of the therapeutic difficulty encountered in patients with recalcitrant cough. Although a thorough search for treatable associations such as sinusitis or reflux is advocated, lengthy medication may be required before symptomatic relief is obtained (14), and even then coughing may still persist. Thus, any potential cause of coughing should be treated aggressively with the appropriate drugs. This means high-dose nasal corticosteroids with antihistamines and anticholinergic spray for sinusitis/rhinitis, proton pump inhibitors for oesophageal reflux and high-dose inhaled corticosteroids for cough-variant asthma. Treatment of the sensitizedcough reflex itself is very difficult, largely because of the lamentable number of safe yet effective antitussive medications available for everyday use. Patients usually avoid situations that provoke extreme coughing and many find that cold drinks terminate coughing bouts. Demulcent preparations and cough sweetsare of soothing value largely because of their sugar content which probably coats sensory endings in the hypopharynx. They provide protection against tussive agents for a few minutes (17). Local anaesthetics such as bupivocaine are very effective at reducing traffic in sensory nerves, and their nebulized use may be of great value to some patients with recalcitrant cough (18). However, their beneficial effect seemsto be idiosyncratic and is offset by their ability to remove all other upper airway and pulmonary protective reflexes.The gold standard of the antitussive agents remains morphine. Together with its weaker opiate derivatives, it will reduce the sensitivity of the cough reflex to tussive challenge when given in sufficient doses (19). However, such doses are usually accompanied by intolerable side-effects.There is little to choose between the numerous proprietary remedies, which have similar side-effects at doses that are truly antitussive. The challenge therefore lies in understanding how the cough reflex becomes sensitized and in the subsequent development of novel antitussives. There is
recent evidence to suggest that neurotransmitters besidesopiates impinge on the sensitivity of the cough reflex (2&22) and it is encouraging to note that serotonergic agents have been shown to protect against cough challenge in both the experimental animal and man (22,23). R. STONE Department of Respiratory Medicine St. Bartholomew’s Hospital WestSmithjield London ECIA 7BE. U.K. References
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Editorial 15. Poe RH, Harder RV, Israel RH, Kallay MC. Chronic persistent cough: experience in diagnosis and outcome using ana anatomic diagnostic protocol. Chest 1989; 95: 123-128. 16. Irwin RRS, Zawacki JK, Curley FJ, French CL, Hoffman PJ. Chronic cough as the sole presenting manifestation of gastrooesophageal reflux. Am Rev Respir Dis 1989; 140: 1294-1300. 17. Packman EW, London SJ. The utility of articiallyinduced cough as a clinical model for evaluating the antitussive effects of aromatics. Eur J Respir Dis 1980; 110: lOlllO9. 18. Karlsson J-A. Airway anaesthesia and the cough reflex. Bull Eur Physiopathol Respir 1983; 23, Suppl 10: 29s-36s. 19. Fuller RW, Karlsson J-A, Choudry NB, Pride NB. Effect of inhaled and systemic opiates on responses to inhaled capsaicin in humans. J Appl Physioll988; 65: 1125-l 130.
20. Kamei J, Ogawa M, Kasuya Y. Effects of GABA antagonists on the pentobarbital-induced depression of respiration and cough in rats. Pharmacol Biochem Behav 1989; 32: 357-360. 21. Kamei J, Tanihara H, Igarishi H, Kasuya Y. Effects of n-methyl o-aspartate antagonists on thecough reflex. Eur J Pharmacoll989; 168: 1533158. 22. Kamei J, Mori T, Igarashi H, Kasuya Y. Effects of 8-hydroxy-2-(di-n-propylamino) tetralin, a selective agonist of S-HT,, receptors, on the cough reflex in rats. Eur J Pharmacoll991; 203: 253-258. 23. Stone RA, Worsdell Y-M, Fuller RW, Barnes PJ. Effects of 5-hydroxytryptamine and 5-hydroxytryptophan infusion on the human cough reflex. J Appi Physioll993; 74: (in press).