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Methods of Assessing Cough and Antitussives in Man
Pulmonary Pharmacology (1996) 9, 373–377 PULMONARY PHARMACOLOGY
Summing Up Methods of Assessing Cough and Antitussives in Man K. Fan Chung National Heart & Lung Institute, Imperial College School of Medicine, Royal Brompton Hospital, Dovehouse Street, London SW3 6LY, U.K.
INTRODUCTION
QUANTITATIVE DESCRIPTION OF THE COUGH SOUND
Cough is a normal protective reflex essential for the clearance of the respiratory tract, but in disease it may become pathological such that it impairs bodily functions and becomes an embarrassment for the patient. Thus, intensive and frequent cough may impair breathing and cardiac circulation, increase oxygen consumption and interfere with eating, sleep and rest. While one would not wish to completely suppress cough, in such cases suppression or restraint would be more beneficial than harmful. The control of cough, particularly acute virus-induced cough and chronic dry cough associated with hyperreactivity of the cough reflex often with no obvious cause, remains difficult. Clinically, cough is one of the most frequent presenting symptom of many diseases affecting the airways and lungs, and is often an early symptom of disease. Excluding diseases such as carcinoma of the lung, the common conditions that are associated with a chronic dry cough include post-nasal drip associated with chronic sinusitis/rhinitis, asthma, gastro-oesophageal reflux and sometimes following an upper respiratory tract virus infection.1 Often, there is no associated cause that can be found for a chronic dry cough. Other causes of cough are those associated with the production of mucus such as chronic bronchitis and bronchiectasis, in whom the cough reflex is not increased.2 It is in this context of the clinical problem of cough that this session of the Symposium focused on the evaluation of cough in man, with respect to what can be learnt about analysis of the cough sound profile, continuous recording of the cough sound, the measurement of cough responsiveness using tussive agents, and on the assessment of cough in therapeutic trials. Much of the emphasis has therefore been rightly placed on what can be learnt in terms of clinical diagnosis and assessment of cough both clinically and therapeutically. 0952–0600/96/5/60373+05 $25.00/0
The description and characterization of the cough sounds has long been considered to be diagnostically useful. Clinically, certain types of cough have diagnostic value such as the ‘bovine cough’ of laryngeal palsy. Methods for quantifying the characteristics of the cough sound have been described,3–7 ranging from the ‘tussiphonogram’ which integrates cumulatively the cough sound intensity to spectrographic analysis of the cough sound using Fourier analysis. The work of Korpas in the genesis of the cough sounds indicated that while the first sound originated at the level of the tracheal bifurcation or below, the second sound was probably arising from the vocal cords.8,9 The second cough sound was most often absent in some normal subjects, in patients following a chordectomy and in patients with a cough due to psychological reasons. Korpas reviewed what was known in this area. Abnormalities of the first cough sound such as prolongation of the first cough sound is characterized by tracheobronchial collapse. The presence of mucus in the airways could lead to doubling or tripling the first (or even the second) cough sound. Changes in airway calibre resulting from pharmacological drugs do not appear to change the sound of cough significantly. Various other characteristics have been described in terms of the cough sounds and its intensity for bronchitis, laryngitis and tracheitis, that could distinguish between these conditions, but these have never been put to the test in the clinical situation. Quantitative aspects of cough sound analysis include the following: the number of coughs over a period of time and its frequency, and the intensity of the cough which could be evaluated from the maximum expiratory and inspiratory efforts. Some work has been done regarding the cough sounds of patients with asthma, mostly with regard to diagnosis. Overall cough intensity is reported to be significantly less in asthma with relatively low upper 373
1996 Academic Press Limited
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K. Fan Chung
frequency limit of sound and low-end expiratory coughs3,7 while cough sound duration was found to be more prolonged for spontaneous asthmatic coughs than for coughs of other respiratory illnesses.7 It has been proposed that this sort of analysis could be helpful in diagnosing asthma in children.4,10 One of the difficulties of classifying cough sounds into different ‘types’ corresponding to different diseases is that the sounds vary in many different ways, not all of which are relevant to the changes induced by that disease. Spectral analysis of cough sounds induced by different tussive agents such as capsaicin, prostaglandin F2a and zero chloride-content solutions showed no marked differences within the same subject with more variation between subjects (Chung & Stoneman, unpublished).
SHORT-TERM RECORDING OF COUGH SOUNDS Quantitative recording of cough over a period of time is necessary for objective evaluation of cough associated with different diseases and of the efficacy of different treatments for chronic cough. However, most assessments of cough severity have usually depended on asking the patient for his own perception of the cough. Over the years, a variety of methods has been developed for assessing the frequency and intensity of cough. The methods that have previously been described to record cough have mostly been nonambulatory, and usually limited to short periods of time using visible and auditory changes.11–16 Intensity and duration of cough has been examined by recording of the pneumogram onto a kymograph,17 but the most common method has been to record the coughs onto a tape-recorder either fixed on the wall of the patient’s room or placed in close contact with the patient’s throat.18,19 Cough sounds have also been recorded with a dynamic microphone placed in the acoustic focus of a paraboloid mirror.20 Cough intensity has also been measured using an integrated surface abdominal electromyogram.21 More recent developments have given rise to ambulatory methods of monitoring cough over many hours. We devised a 24-h ambulatory system using a solid-state, multiple channel recorder to measure the number of coughs. Coughs were measured as the simultaneous cough sound recorded by a microphone and the electromyographic signals from the lower respiratory muscles. Our first study examined the cough frequency in fully-ambulant patients with chronic dry cough of unknown cause and in wellcontrolled asthmatics complaining of a dry cough.22 We found that most of the coughs occurred during the awake hours with very little activity during sleeping hours. In chronic coughers but not in the asthmatics, a good correlation between day-time coughs and the
self-assessment scores of cough. However, this method of cough recording did not allow for a measurement of intensity but is currently being used to assess the efficacy of potential antitussives. The work presented by Rajagopalan23 has been ongoing for the last 10 years and represents an important advance in the area of cough recording. Coughs were recorded on digital audiotape recorder and analysed in terms of their counts, intensity and total effort expended over time, thanks in great part to the availability of powerful computers nowadays. With an inbuilt calibration of the intensity of sound, it is possible to make comparisons between patients. The system is also fully portable. Such devices can be used to study the day-to-day variability of cough within the usual surroundings of the patient and the effects of anti-tussive drugs. Eccles24 also described a less sophisticated method that used a microphone attached to the throat with measurement of cough sound pressure levels (as an index of intensity) and cough frequency. The studies of Rajagopalan23 and Parvaz25 indicate that other measures apart from frequency such as intensity of cough are useful, and that examination of the quality of sound may give us a measure of the ‘clearability’ of sputum in coughers with sputum (e.g. in bronchiectasis). What remains unresolved is the significance of ‘throat-clearing’ and whether coughs should be measured as an epoch of cough (an episode of successive coughs) or as individual coughs. In our hands, we find an excellent correlation between the epochs and the actual number of cough events.22 This would indicate that a series of coughs is initiated by one stimulation. The study of Eccles24 indicate that the cough counts of patients during acute upper respiratory tract infections appear to fall off when recorded from non-ambulatory patients, which would suggest that these observations should be done in ambulatory patients.
ASSESSING COUGH RESPONSES TO TUSSIVE AGENTS Cough in response to inhaled agents has long been used in the testing of antitussive agents, and more recently in studies of patients with a chronic cough in order to elucidate mechanisms. The enhanced cough response to capsaicin that has been reported in conditions such as post-nasal drip and some patients with asthma presumably relates to sensitization of cough receptors in the upper airways, including the larynx, perhaps through the effects of mediators. This notion is supported by studies that demonstrate that prostaglandins PGF2a and E2 can enhance the cough response to capsaicin and low-chloride content solutions.26,27 Limited studies on the airway pathology of patients
Cough and Antitussives in Man
with chronic dry cough have pointed to some degree of inflammatory responses such as epithelial desquamation and mononuclear cell infiltration,28 and increased number of neutrophils in induced sputum (Lalloo, Jakatanon & Chung, unpublished), but these changes could equally result from the effects of chronic cough. The basis for the cough and enhanced cough reflex of patients on angiotensin converting enzyme (ACE) inhibitors remain intriguing. Studies in guineapigs implicate bradykinin as an important mediator of enhancement of the cough reflex.29 For cough associated with gastro-oesophageal acid reflux, it is possible that direct acid stimulation into the upper airway may sensitize the cough reflex.30 The observation that there are increased nerve profiles staining for substance P and calcitonin gene-related peptide in the airways of patients with a chronic dry cough and an enhanced cough reflex to capsaicin31 indicates that an increased number of cough receptors may be responsible for the cough hyperreactivity. Several agents have been used to measure the cough reflex in man, with citric acid being the most commonly used particularly in the assessment of antitussives, while more recently capsaicin and low-chloride solutions have become more established. In patients with denervated lungs such as those after a heart–lung transplant, the response to capsaicin and low-chloride content solutions is blunted.32 Are there differences in response between these different tussive stimuli and do these stimuli give us different information about the cough reflex? Animal studies indicate that low-chloride and non-isoomotic stimuli stimulate rapidly-adapting irritant receptors on the laryngeal mucosa, while citric acid and capsaicin may stimulate C-fibres33–35 The differential inhibition of inhaled frusemide on lowchloride cough versus capsaicin-cough may support differential cough receptor activation.36 The study presented by Morice37 in laryngectomized subjects indicating that capsaicin-sensitive cough receptors were mostly intrapulmonary while the cough receptors mediating citric acid cough were also in the larynx may point to different classes of receptors. Capsaicin-sensitive cough receptors appear to be more plentiful in the airways below the larynx,38 and the observation that bilateral blockade of the superior laryngeal nerves in man does not alter the threshold to citric acidinduced cough implies that the larynx is not an exclusive tussigenic zone for citric acid.39 Nishino40 presented vivid and impressive video images of the strong expiratory and cough responses induced by stimulation of the larynx (and trachea) by water, while stimulation of second and third generation bronchi elicited little or no response.41 Thus, one can also infer that water stimulation is most effective in the larynx and trachea. It is not known at present whether there is any advantage in studying more than one tussive agent (most
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investigators now use the capsaicin challenge) in studies in man. In using the cough reflex in the assessment of the patient with cough, several areas still need to be clarified. With the possibility of measuring cough intensity and frequency, it would be important to evaluate the relationship between the cough reflex and the cough frequency and intensity, in addition to the relationship between various tussive agents. In the assessment of therapy, a reduction in the cough reflex may well be reflected by the disappearance or control of cough, and this has been used to monitor therapy.42
EVALUATION OF ANTI-TUSSIVES Antitussives have been mainly evaluated by examining responses on the cough reflex or by asking patients about their responses. Earlier reviewers have highlighted the paucity of objective effects of antitussives agents reported in clinical practice.43 Most studies have not been placebo-controlled. The notion that testing of antitussives should be made on a heightened cough reflex (as found in patients with a chronic dry cough or as can be enhanced by certain mediators such as PGF2a) with the aim of returning the cough reflex to a normal range, rather than studying antitussives to suppress a normal cough response is very important. Comparative data should be obtained. Evaluation of antitussives on cough frequency after all is only possible in patients. In normal humans, oral administration of codeine or dextrometorphan cause only a small reduction in the cough reflex to capsaicin and citric acid. High doses of opiates administered parenterally reduce the sensitivity of the cough reflex stimulated by capsaicin.44 To study these antitussives in patients, one should resort to human ‘models’ of enhanced cough reflex such as during upper respiratory virus infections which is usually very transient over days and those with a chronic dry cough which is usually more sustained. The effect of antitussives on the frequency and intensity of the cough should be the primary assessment, and this should be correlated with the response of the cough reflex to tussive agents in the same study. This would give some indication of the value of using only the cough reflex as the primary outcome measure, as has been frequently done in the past. The studies presented by Eccles24 and Parvez25 are probably the first of their kind that attempt to answer whether the currently-available antitussives can inhibit the cough of common cold using these recorders. Eccles24 reported no effect of codeine at doses up to 50 mg per day on recorded cough frequency and intensity in patients with the common cold observed in the laboratory when compared to placebo. On the
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other hand, Parvez25 showed that dextromethorphan (20 mg) compared to placebo decreased cough numbers but not intensity while 30 mg was also effective in decreasing the effort of coughing within 2–3 h of administration again in non-ambulatory subjects. She emphasized that the patients were randomized according to several weighted factors relating to the characteristics of the cough. In the study involving patients with bronchiectasis, expectorants such as bromhexine decreased cough intensity but not cough numbers, associated with a reported ease of expectoration. In chronic cough associated with mucus production, it is probably beneficial to reduce the intensity of cough thereby reducing the work of cough, while at the same time maximizing mucus clearance. Clearly, these continuous recordings of cough sounds will provide useful information regarding various parameters of cough that would be valuable in understanding cough and its therapy, particularly in ambulant patients. Other types of chronic dry cough should be studied. With the possibility of recording frequency and intensity of cough, the work of coughing and the real effectiveness of current and novel antitussives can be evaluated in double-blind placebocontrolled studies.
5. 6. 7. 8. 9. 10. 11.
12.
13. 14. 15. 16.
CONCLUSION 17.
The session on cough in man has highlighted the recent progress in cough in terms of potential diagnostic evaluation of cough sound (less so regarding the origin of the cough sound), continuous ambulatory recording, use of tussive agents to assess the cough reflex in health and disease, and the evaluation of antitussives. We now have the tools to evaluate cough properly in man. There are still many other unresolved issues concerning cough and its accompanying phenomena. However, with the progress in the understanding of disease processes inducing chronic cough, we now have the tools to evaluate new tussive agents and to apply a lot of what has been learnt from animal physiology and pharmacology to the problem of persistent cough in the clinic. The future should bring exciting new data and possibly new agents that are really effective against various aspects of cough.
18. 19. 20.
21.
22.
23. 24.
REFERENCES 1. Chung KF, Lalloo UG. Diagnosis and management of chronic persistent dry cough. Postgrad Med J 1996; 72: 594–598. 2. Choudry NB, Fuller RW. Sensitivity of the cough reflex in patients with chronic cough. Eur Respir J 1992; 5: 296–300. 3. Salat D, Korpas J, Salatova V, Korpasova Sadlonova J, Palecek D. The tussiphonogram during asthmatic attack. Acta Physiol Hung 1987; 70: 223–225. 4. Thorpe VW, Toop LJ, Dawson KP. Towards a quantitative
25. 26. 27.
28.
description of asthmatic cough sounds. Eur Respir J 1992; 5: 685–692. Debreczeni LA, Korpas J, Salat D, et al. Spectra of the voluntary first cough sounds. Act Physiol Hung 1990; 75: 117–131. Debreczeni LA, Korpas J, Salat D. Spectral analysis of cough sounds recorded with and without a nose clip. Bull Eur Physiopathol Respir 1987; 23 Suppl 10: 57s–61s. Piirila P, Sovijarvi AR. Differences in acoustic and dynamic characteristics of spontaneous cough in pulmonary diseases. Chest 1989; 96: 46–53. Korpas J, Sadlonova J, Salat D, Masarova E. The origin of cough sounds. Bull Eur Physiopathol Respir 1987; 23 Suppl 10: 47s–50s. Korpas J, Sadlonova J, Vrabac M. Analysis of cough sound: an over view. Pulm Pharmacol 1996; 9: 261–268. Toop LJ, Dawson KP, Thorpe CW. A portable system for the spectral analysis of cough sounds in asthma. J Asthma 1990; 27: 393–397. Barach AL, Bickerman HA, Beck GJ. Clinical and physiological studies on the use of metacortandracin in respiratory disease. 1. Bronchial asthma. Dis Chest 1955; 27: 515–522. Bickerman HA, Borach AL. The experimental production of cough in human subjects induced by citric acid aerosols. Preliminary studies on the evaluation of antitussive agents. Am J Med Sci 1954; 228: 156–163. Morris DJ, Shane SJ. Human bioassay of a new antitussive agent. Can Med Assoc J 1960; 83: 1093–1095. Prime FJ. The assessment of antitussive drugs in man. Br Med J 1961; 1: 1149–1151. Calesnik B, Christensen JA, Munch JC. Antitussive action of L-propoxyphene in citric acid-induced cough response. Am J Med Sci 1961; 242: 560–564. Chernish SM, Lewis G, Kraft B, Howe J. Clinical evaluation of a new antitussive preparation. Ann Allergy 1963; 21: 677–682. Gravenstein JS, Devloo RA, Beecher HK. Effect of antitussive agents on experimental and pathological cough in man. J Appl Physiol 1954; 7: 119–139. Woolf CR, Rosenberg A. The cough suppressant effect of heroin and codeine: a controlled clinical study. Can Med Assoc J 1962; 87: 810–814. Sevelius H, Colmore JP. Objective assessment of antitussive agents in patients with chronic cough. J New Drugs 1966; 6: 216–233. Salmi T, Sovijarvi ARA, Brander P, Piirila P. Long-term recording and automatic analysis of cough using filtered acoustic sign movements on static charge sensitive bed. Chest 1988; 94: 970–975. Cox ID, Wallis PJW, Apps MCP. et al. An electromyographic method of objectively assessing cough intensity and use of the method to assess effects of codeine on the dose-response curve to citric acid. Br J Clin Pharm 1984; 18: 377–382. Hsu J, Stone RA, Logan-Sinclair R, Worsdell M, Busst C, Chung KF. Coughing frequency in patients with persistent cough using a 24-hour ambulatory recorder. Eur Resp J 1994; 7: 1246–1253. Subburaj S, Parvez L, Rajagopalan TG. Methods of recording and analysing cough sounds. Pulm Pharmacol 1996; 9: 269–279. Eccles R. Codeine, cough and upper respiratory inflation. Pulm Pharmacol 1996; 9: 293–297. Parvez L, Vaidya M, Sakhardande A, Subburaj S, Rajagopalan TG. Evaluation of antitussive agents in man. Pulm Pharmacol 1996; 9: 299–308. Stone R Barnes PJ, Fuller RW. Contrasting effects of prostaglandins E2 and F2a on sensitivity of the human cough reflex. J Appl Physiol 1992; 73: 649–653. Nichol GM, Nix A, Barnes PJ, Chung KF. Enhancement of capsaicin-induced cough by inhaled prostaglandin F2a: modulation by beta-adrenergic agonist and anticholinergic agent. Thorax 1990; 45: 694–698. Boulet LP, Milot J, Boutet M, St Georges F, Laviolette M.
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29.
30.
31.
32.
33.
34.
35.
36.
Airway inflammation in non-asthmatic subjects with chronic cough. Am J Respir Crit 1994; 149: 482–489. Fox AJ, Lalloo UG, Bernareggi M, Belvisi MG, Chung KF, Barnes PJ, Bradykinin and captopril-induced cough in guinea-pigs. Nature Medicine 1996; 2: 814–817. Ing AJ, Ngu MC, Breslin AB. Pathogenesis of chronic persistent cough associated with gastroesophageal reflux. Am J Respir Crit Care Med 1994; 149: 160–167. O’Connell F, Springall DR, Krausz T, et al. Abnormal intraepithelial airway nerves in persistent unexplained cough? Am J Resp Crit Care Med 1995; 152: 2068–2075. Higenbotham TW, Jackson M, Woolman P, Lowry R, Wallwork J. The cough response to ultrasonically nebulised distilled water in heart-lung transplant patients. Am Rev Respir Dis 1989; 140: 58–61. Anderson JW, Sant’Ambrogio FB, Mathew OP, Sant’Ambrogio G. Water-responsive laryngeal receptors in the dog are not specailized endings. Respir Physiol 1990; 79: 33–44. Lalloo UG, Fox AJ, Belvisi MG, Chung KF, Barnes PJ. Inhibition by capsazepine of cough induced by capsaicin and citric acid, but not by hypertonic saline in awake guinea-pigs J Appl Physiol 1995; 79: 1082–1087. Forsberg K, Karlsson J, Theodorosson E, Lundberg JM, Persson CGA. Cough and bronchoconstriction mediated by capsaicin-sensitive sensory neurons in guinea-pigs. Pulm Pharmacol 1988; 1: 33–39. Ventresca P, Nichol GM, Barnes PJ, Chung KF. Inhaled furosemide inhibits cough induced by low chloride content
37. 38. 39.
40. 41.
42.
43.
44.
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solutions and not by capsaicin. Am Rev Respir Dis 1990; 142: 143–146. Morice AH. Inhalation cough challenge in the investigation of the cough reflex and antitussives. Pulm Pharmacol 1996; 9: 281–284. Hansson L, Wollmer P, Dahlback M, Karlsson JA. Regional sensitivity of human airways to capsaicin-induced cough. Am Rev Respir Dis 1992; 145: 1191–1195. Stockwell M, Lang S, Yip R, Zintel T, White C, Galagher CG. Lack of importance of the superior laryngeal nerves in citric acid cough in humans. J Appl Physiol 1991; 75: 613–617. Nishino T, Fagaito Y, Isono S. Cough and other reflexes on irritation of airway mucosa in man. Pulm Pharmacol 1996; 9: 285–292. Nishino T, Hiraga K, Mizuguchi T, Honda Y. Respiratory reflex responses to stimulation of tracheal mucosa in enflurance-anesthetized humans. J Appl Physiol 1988; 65: 1069–1074. O’Connell F, Thomas VE, Pride NB, Fuller RW. Capsaicin cough sensitivity decreases with successful treatment of chronic cough. Am J Resp Crit Care Med 1994; 150: 374–380. Eddy NB, Friebel H, Hahn KJ, Halbach H. Codeine and its alternates for pain and cough relief. 3. The intitussive action of codeine-mechanism, methodology and evaluation. Bull World Health Organ 1969; 40: 425–454. Fuller RW, Karlsson J, Choudry NB Pride NB. Effect of inhaled and systemic opiates on responses to inhaled capsaicin in human. J Appl Physiol 1988; 65: 1125–1130.
Summing Up Methods of Assessing Cough and Antitussives in Man K. Fan Chung National Heart & Lung Institute, Imperial College School of Medicine, Royal Brompton Hospital, Dovehouse Street, London SW3 6LY, U.K.
INTRODUCTION
QUANTITATIVE DESCRIPTION OF THE COUGH SOUND
Cough is a normal protective reflex essential for the clearance of the respiratory tract, but in disease it may become pathological such that it impairs bodily functions and becomes an embarrassment for the patient. Thus, intensive and frequent cough may impair breathing and cardiac circulation, increase oxygen consumption and interfere with eating, sleep and rest. While one would not wish to completely suppress cough, in such cases suppression or restraint would be more beneficial than harmful. The control of cough, particularly acute virus-induced cough and chronic dry cough associated with hyperreactivity of the cough reflex often with no obvious cause, remains difficult. Clinically, cough is one of the most frequent presenting symptom of many diseases affecting the airways and lungs, and is often an early symptom of disease. Excluding diseases such as carcinoma of the lung, the common conditions that are associated with a chronic dry cough include post-nasal drip associated with chronic sinusitis/rhinitis, asthma, gastro-oesophageal reflux and sometimes following an upper respiratory tract virus infection.1 Often, there is no associated cause that can be found for a chronic dry cough. Other causes of cough are those associated with the production of mucus such as chronic bronchitis and bronchiectasis, in whom the cough reflex is not increased.2 It is in this context of the clinical problem of cough that this session of the Symposium focused on the evaluation of cough in man, with respect to what can be learnt about analysis of the cough sound profile, continuous recording of the cough sound, the measurement of cough responsiveness using tussive agents, and on the assessment of cough in therapeutic trials. Much of the emphasis has therefore been rightly placed on what can be learnt in terms of clinical diagnosis and assessment of cough both clinically and therapeutically. 0952–0600/96/5/60373+05 $25.00/0
The description and characterization of the cough sounds has long been considered to be diagnostically useful. Clinically, certain types of cough have diagnostic value such as the ‘bovine cough’ of laryngeal palsy. Methods for quantifying the characteristics of the cough sound have been described,3–7 ranging from the ‘tussiphonogram’ which integrates cumulatively the cough sound intensity to spectrographic analysis of the cough sound using Fourier analysis. The work of Korpas in the genesis of the cough sounds indicated that while the first sound originated at the level of the tracheal bifurcation or below, the second sound was probably arising from the vocal cords.8,9 The second cough sound was most often absent in some normal subjects, in patients following a chordectomy and in patients with a cough due to psychological reasons. Korpas reviewed what was known in this area. Abnormalities of the first cough sound such as prolongation of the first cough sound is characterized by tracheobronchial collapse. The presence of mucus in the airways could lead to doubling or tripling the first (or even the second) cough sound. Changes in airway calibre resulting from pharmacological drugs do not appear to change the sound of cough significantly. Various other characteristics have been described in terms of the cough sounds and its intensity for bronchitis, laryngitis and tracheitis, that could distinguish between these conditions, but these have never been put to the test in the clinical situation. Quantitative aspects of cough sound analysis include the following: the number of coughs over a period of time and its frequency, and the intensity of the cough which could be evaluated from the maximum expiratory and inspiratory efforts. Some work has been done regarding the cough sounds of patients with asthma, mostly with regard to diagnosis. Overall cough intensity is reported to be significantly less in asthma with relatively low upper 373
1996 Academic Press Limited
374
K. Fan Chung
frequency limit of sound and low-end expiratory coughs3,7 while cough sound duration was found to be more prolonged for spontaneous asthmatic coughs than for coughs of other respiratory illnesses.7 It has been proposed that this sort of analysis could be helpful in diagnosing asthma in children.4,10 One of the difficulties of classifying cough sounds into different ‘types’ corresponding to different diseases is that the sounds vary in many different ways, not all of which are relevant to the changes induced by that disease. Spectral analysis of cough sounds induced by different tussive agents such as capsaicin, prostaglandin F2a and zero chloride-content solutions showed no marked differences within the same subject with more variation between subjects (Chung & Stoneman, unpublished).
SHORT-TERM RECORDING OF COUGH SOUNDS Quantitative recording of cough over a period of time is necessary for objective evaluation of cough associated with different diseases and of the efficacy of different treatments for chronic cough. However, most assessments of cough severity have usually depended on asking the patient for his own perception of the cough. Over the years, a variety of methods has been developed for assessing the frequency and intensity of cough. The methods that have previously been described to record cough have mostly been nonambulatory, and usually limited to short periods of time using visible and auditory changes.11–16 Intensity and duration of cough has been examined by recording of the pneumogram onto a kymograph,17 but the most common method has been to record the coughs onto a tape-recorder either fixed on the wall of the patient’s room or placed in close contact with the patient’s throat.18,19 Cough sounds have also been recorded with a dynamic microphone placed in the acoustic focus of a paraboloid mirror.20 Cough intensity has also been measured using an integrated surface abdominal electromyogram.21 More recent developments have given rise to ambulatory methods of monitoring cough over many hours. We devised a 24-h ambulatory system using a solid-state, multiple channel recorder to measure the number of coughs. Coughs were measured as the simultaneous cough sound recorded by a microphone and the electromyographic signals from the lower respiratory muscles. Our first study examined the cough frequency in fully-ambulant patients with chronic dry cough of unknown cause and in wellcontrolled asthmatics complaining of a dry cough.22 We found that most of the coughs occurred during the awake hours with very little activity during sleeping hours. In chronic coughers but not in the asthmatics, a good correlation between day-time coughs and the
self-assessment scores of cough. However, this method of cough recording did not allow for a measurement of intensity but is currently being used to assess the efficacy of potential antitussives. The work presented by Rajagopalan23 has been ongoing for the last 10 years and represents an important advance in the area of cough recording. Coughs were recorded on digital audiotape recorder and analysed in terms of their counts, intensity and total effort expended over time, thanks in great part to the availability of powerful computers nowadays. With an inbuilt calibration of the intensity of sound, it is possible to make comparisons between patients. The system is also fully portable. Such devices can be used to study the day-to-day variability of cough within the usual surroundings of the patient and the effects of anti-tussive drugs. Eccles24 also described a less sophisticated method that used a microphone attached to the throat with measurement of cough sound pressure levels (as an index of intensity) and cough frequency. The studies of Rajagopalan23 and Parvaz25 indicate that other measures apart from frequency such as intensity of cough are useful, and that examination of the quality of sound may give us a measure of the ‘clearability’ of sputum in coughers with sputum (e.g. in bronchiectasis). What remains unresolved is the significance of ‘throat-clearing’ and whether coughs should be measured as an epoch of cough (an episode of successive coughs) or as individual coughs. In our hands, we find an excellent correlation between the epochs and the actual number of cough events.22 This would indicate that a series of coughs is initiated by one stimulation. The study of Eccles24 indicate that the cough counts of patients during acute upper respiratory tract infections appear to fall off when recorded from non-ambulatory patients, which would suggest that these observations should be done in ambulatory patients.
ASSESSING COUGH RESPONSES TO TUSSIVE AGENTS Cough in response to inhaled agents has long been used in the testing of antitussive agents, and more recently in studies of patients with a chronic cough in order to elucidate mechanisms. The enhanced cough response to capsaicin that has been reported in conditions such as post-nasal drip and some patients with asthma presumably relates to sensitization of cough receptors in the upper airways, including the larynx, perhaps through the effects of mediators. This notion is supported by studies that demonstrate that prostaglandins PGF2a and E2 can enhance the cough response to capsaicin and low-chloride content solutions.26,27 Limited studies on the airway pathology of patients
Cough and Antitussives in Man
with chronic dry cough have pointed to some degree of inflammatory responses such as epithelial desquamation and mononuclear cell infiltration,28 and increased number of neutrophils in induced sputum (Lalloo, Jakatanon & Chung, unpublished), but these changes could equally result from the effects of chronic cough. The basis for the cough and enhanced cough reflex of patients on angiotensin converting enzyme (ACE) inhibitors remain intriguing. Studies in guineapigs implicate bradykinin as an important mediator of enhancement of the cough reflex.29 For cough associated with gastro-oesophageal acid reflux, it is possible that direct acid stimulation into the upper airway may sensitize the cough reflex.30 The observation that there are increased nerve profiles staining for substance P and calcitonin gene-related peptide in the airways of patients with a chronic dry cough and an enhanced cough reflex to capsaicin31 indicates that an increased number of cough receptors may be responsible for the cough hyperreactivity. Several agents have been used to measure the cough reflex in man, with citric acid being the most commonly used particularly in the assessment of antitussives, while more recently capsaicin and low-chloride solutions have become more established. In patients with denervated lungs such as those after a heart–lung transplant, the response to capsaicin and low-chloride content solutions is blunted.32 Are there differences in response between these different tussive stimuli and do these stimuli give us different information about the cough reflex? Animal studies indicate that low-chloride and non-isoomotic stimuli stimulate rapidly-adapting irritant receptors on the laryngeal mucosa, while citric acid and capsaicin may stimulate C-fibres33–35 The differential inhibition of inhaled frusemide on lowchloride cough versus capsaicin-cough may support differential cough receptor activation.36 The study presented by Morice37 in laryngectomized subjects indicating that capsaicin-sensitive cough receptors were mostly intrapulmonary while the cough receptors mediating citric acid cough were also in the larynx may point to different classes of receptors. Capsaicin-sensitive cough receptors appear to be more plentiful in the airways below the larynx,38 and the observation that bilateral blockade of the superior laryngeal nerves in man does not alter the threshold to citric acidinduced cough implies that the larynx is not an exclusive tussigenic zone for citric acid.39 Nishino40 presented vivid and impressive video images of the strong expiratory and cough responses induced by stimulation of the larynx (and trachea) by water, while stimulation of second and third generation bronchi elicited little or no response.41 Thus, one can also infer that water stimulation is most effective in the larynx and trachea. It is not known at present whether there is any advantage in studying more than one tussive agent (most
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investigators now use the capsaicin challenge) in studies in man. In using the cough reflex in the assessment of the patient with cough, several areas still need to be clarified. With the possibility of measuring cough intensity and frequency, it would be important to evaluate the relationship between the cough reflex and the cough frequency and intensity, in addition to the relationship between various tussive agents. In the assessment of therapy, a reduction in the cough reflex may well be reflected by the disappearance or control of cough, and this has been used to monitor therapy.42
EVALUATION OF ANTI-TUSSIVES Antitussives have been mainly evaluated by examining responses on the cough reflex or by asking patients about their responses. Earlier reviewers have highlighted the paucity of objective effects of antitussives agents reported in clinical practice.43 Most studies have not been placebo-controlled. The notion that testing of antitussives should be made on a heightened cough reflex (as found in patients with a chronic dry cough or as can be enhanced by certain mediators such as PGF2a) with the aim of returning the cough reflex to a normal range, rather than studying antitussives to suppress a normal cough response is very important. Comparative data should be obtained. Evaluation of antitussives on cough frequency after all is only possible in patients. In normal humans, oral administration of codeine or dextrometorphan cause only a small reduction in the cough reflex to capsaicin and citric acid. High doses of opiates administered parenterally reduce the sensitivity of the cough reflex stimulated by capsaicin.44 To study these antitussives in patients, one should resort to human ‘models’ of enhanced cough reflex such as during upper respiratory virus infections which is usually very transient over days and those with a chronic dry cough which is usually more sustained. The effect of antitussives on the frequency and intensity of the cough should be the primary assessment, and this should be correlated with the response of the cough reflex to tussive agents in the same study. This would give some indication of the value of using only the cough reflex as the primary outcome measure, as has been frequently done in the past. The studies presented by Eccles24 and Parvez25 are probably the first of their kind that attempt to answer whether the currently-available antitussives can inhibit the cough of common cold using these recorders. Eccles24 reported no effect of codeine at doses up to 50 mg per day on recorded cough frequency and intensity in patients with the common cold observed in the laboratory when compared to placebo. On the
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K. Fan Chung
other hand, Parvez25 showed that dextromethorphan (20 mg) compared to placebo decreased cough numbers but not intensity while 30 mg was also effective in decreasing the effort of coughing within 2–3 h of administration again in non-ambulatory subjects. She emphasized that the patients were randomized according to several weighted factors relating to the characteristics of the cough. In the study involving patients with bronchiectasis, expectorants such as bromhexine decreased cough intensity but not cough numbers, associated with a reported ease of expectoration. In chronic cough associated with mucus production, it is probably beneficial to reduce the intensity of cough thereby reducing the work of cough, while at the same time maximizing mucus clearance. Clearly, these continuous recordings of cough sounds will provide useful information regarding various parameters of cough that would be valuable in understanding cough and its therapy, particularly in ambulant patients. Other types of chronic dry cough should be studied. With the possibility of recording frequency and intensity of cough, the work of coughing and the real effectiveness of current and novel antitussives can be evaluated in double-blind placebocontrolled studies.
5. 6. 7. 8. 9. 10. 11.
12.
13. 14. 15. 16.
CONCLUSION 17.
The session on cough in man has highlighted the recent progress in cough in terms of potential diagnostic evaluation of cough sound (less so regarding the origin of the cough sound), continuous ambulatory recording, use of tussive agents to assess the cough reflex in health and disease, and the evaluation of antitussives. We now have the tools to evaluate cough properly in man. There are still many other unresolved issues concerning cough and its accompanying phenomena. However, with the progress in the understanding of disease processes inducing chronic cough, we now have the tools to evaluate new tussive agents and to apply a lot of what has been learnt from animal physiology and pharmacology to the problem of persistent cough in the clinic. The future should bring exciting new data and possibly new agents that are really effective against various aspects of cough.
18. 19. 20.
21.
22.
23. 24.
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