Lung (2008) 186 (Suppl 1):S17S22 DOI 10.

1007/s00408-007-9031-0

The Current State of Cough Research: The Clinicians Perspective

Louis-Philippe Boulet

Received: 28 July 2007 / Accepted: 15 August 2007 / Published online: 3 October 2007 Springer Science+Business Media, LLC 2007

Abstract Cough is one of the most common reasons for medical consultation and it is responsible for a large human and socioeconomic burden. Current guidelines provide a useful framework for cough management and summarize current knowledge of causes and optimal testing sequences and treatments of cough. However, research is needed on the role of noninvasive airway inammation measurement in assessing etiology; optimal treatment of postinfectious cough or cough due to gastroesophageal reux disease; protussive treatment; causes of chronic cough in immunocompromised hosts; and characteristics and management of psychogenic cough. The effects of the use or nonuse of evidence-based guidelines should be documented. An empiric, integrative approach to management of chronic cough also needs further validation. Keywords Chronic cough Clinical management Airway diseases Management of cough

Introduction Cough is a common symptom of many other diseases and conditions. Cough may be a defense mechanism, particularly for the elimination of foreign bodies and excess bronchial secretions. It can also be severe and acute, related to a life-threatening condition or, most often, troublesome and persistent, affecting daily activities and reducing quality of life. Persistent cough is responsible for signicant absenteeism at work or school [1, 2].
L.-P. Boulet (&) Hopital Laval, 2725, chemin Sainte-Foy, G1V 4G5 Quebec City, Quebec, Canada e-mail: lpboulet@med.ulaval.ca

In one study, 373 individuals (mean age = 65.3 years [range = 988 years], 73% female, 2% current smokers, 24% reporting having asthma) who requested information following a national radio broadcast on cough completed a questionnaire on cough and its consequences [3]. Overall, 91% had consulted a general practitioner for cough, and 61% had seen at least one hospital specialist. Common symptoms reported were breathlessness (55%), wheeze (37%), fatigue (72%), disturbed sleep (70%), incontinence (in 55% of women), anger or frustration (83%), anxiety (69%), and depression (55%); 64% felt that the cough interfered with their social life. Median duration of cough was 6.5 years. Various other complications and reduced quality of life have been reported for chronic cough sufferers [3, 4]. The human and socioeconomic burden of persistent cough is therefore high. Possible explanations include the unsystematic evaluation of specic causes of cough and frequent use of nonspecic cough therapy, insufcient knowledge and translation of guidelines by physicians into current care, insufcient knowledge among patients of current recommendations, and lack of recognition of multiple causes [5]. The American College of Chest Physicians guidelines suggest that the clinician with a patient with an unexplained cough needs a systematic, integrated approach to treatment [6]. The guidelines also recommend that the patients response to specic treatment be the gold standard for assessing diagnostic accuracy and effectiveness of cough management. The use of empiric treatment directed at the most likely causes of cough is an important component of successful diagnosis and treatment. In this article we discuss how clinical cough research is useful to the clinician, what gaps remain in cough management, and what the future of cough research may be.

123

S18

Lung (2008) 186 (Suppl 1):S17S22

How Can Clinicians Use Cough Guidelines? Several consensus guidelines have been produced in the last two decades on most major diseases and conditions, including cough [1, 69]. These guidelines help the clinician, currently facing an exponential increase in scientic publications and information, sort out the important ndings and decide how to offer the best care according to current knowledge. The cough guidelines summarize data on the most frequent causes according to cough duration and suggest a systematic diagnostic approach based on probable etiology. Furthermore, they stress that chronic cough frequently has more than one cause. The guidelines offer evidence-based recommendations for effective management of cough, while identifying areas that require more research (Table 1) [68, 10]. The surprisingly high morbidity and health care costs associated with cough may be related largely to the lack of translation of current guidelines into current care. Many guidelines for other diseases remain largely unknown or unused among physicians, particularly in primary care [11]. This is despite the broad dissemination of information among patients and the public. Frequent use of nonspecic cough therapy, as shown by high yearly sales of such medications, along with lack of systematic evaluation of specic causes of cough, inadequate therapeutic approaches, and lack of recognition of the sometimes complex etiology of cough demonstrate this problem. Irwin and Madison [12] have reviewed common pitfalls in managing the most common causes of chronic cough, the most prominent being lack of recognition of its various causes and comorbidities (Table 2). As an example of noncompliance with guideline recommendations, despite current recommendations, a chest radiograph is often not performed when pneumonia is clinically suspected in patients presenting with cough [14]. Similarly, data reported by Everett et al. [3] showed that 60% of patients with chronic cough reported no improvement of cough symptoms with the prescribed therapy while it is generally considered that over 90% of persistent cough should resolve with appropriate treatment [6, 12, 13].

While major efforts have been made to disseminate cough guidelines, the lack of broad implementation indicates that targeted interventions are required. These may include the development of multifaceted programs involving case-based interactive learning, practice aids, various incentives, and feedback/audits [15]. Patients should also be aware of the main recommendations about the treatment of this symptom and should be offered the excellent documents produced for this purpose, along with other educational tools. Such interventions have been quite successful for other chronic diseases and should be tried for cough as well [16, 17].

Research Needs Regarding Cough: The Clinicians Perspective General Needs Although various authors have suggested specic questions and examinations for cough patients, recommendations are largely based on expert opinion and thus it is not clear what is the best evidence-based approach.

Upper Airway Cough Syndrome (UACS) Although UACS is one of the most common causes of persistent cough, its underlying mechanisms and patterns of response to medications and the contributing environmental factors are not well known [6]. Allergy-based UACS may be treated by inhaled nasal corticosteroids with or without nonsedating antihistamines while nonallergenic UACS may be treated with rst-generation antihistamines and decongestants. However, further evaluation is needed [6, 18]

Sinusitis It is not clear from the literature whether there is any advantage gained from using sinus tomograms in an attempt to establish the contribution of sinus disease to the etiology of cough [20]. One report suggested that sinus tomography is no better than ear, nose, and throat examination in the identication of upper airway disease as a cause of cough [21]. Furthermore, the role of bacterial infections in chronic sinusitis-related cough should also be examined, as should the effects of nasal corticosteroids on cough with acute or chronic sinusitis [19]. Finally, the best methods to assess this condition and predict responses to therapy remain to be documented. It would be particularly instructive to closely examine the role of noninvasive markers of airway inammation.

Table 1 How has research on cough been useful to the clinician? Provided data on the most frequent causes of cough, based on its duration Suggested a systemic diagnostic approach according to the probability of various etiologies Shown that there is frequently more than one cause of chronic cough Provided evidence-based recommendations on the optimal management of cough Identied need for more research in specic areas

123

Lung (2008) 186 (Suppl 1):S17S22

S19

Asthma There should be more examination of the evaluation and optimal management of cough-variant asthma. Airway inammation (usually eosinophilic) and remodeling have been reported in this condition [22]. However, the prevalence of noneosinophilic or pauci-granulocytopenic inammation in this condition remains to be evaluated. Furthermore, up to one third of patients with cough-variant asthma may develop classic asthma symptoms, particularly during periods of increased airway responsiveness [23]. Current treatment can suppress cough, but prevention of more severe asthma and long-term changes in airway function remains a greater challenge. Assessment of noninvasive airway inammation could identify not only the mechanisms underlying cough in asthma but also cases of nonasthmatic origin. One possible clinical marker is exhaled nitric oxide (NO) which has been shown to be lower in coughers without asthma than in people with comorbid cough and asthma [24]. The inuence of smoking on asthmas clinical features and response to therapy has also recently been examined. Surveys have shown that about 25% of the asthmatic population currently smokes [25]. Smoking is associated with poorer asthma control, greater declines in pulmonary function, changes in the type of airway inammation (more neutrophilic), and reduced response to asthma medications such as inhaled corticosteroids [25, 26]. In this context, cough may not necessarily be due to an uncontrolled asthmatic process. Current criteria to assess asthma control and response to therapy in the context of smoking-related bronchitis should be re-examined, as should the specic criteria for cough symptoms in these patients and the optimal therapeutic approach. Of course, smoking-cessation programs should be part of asthma management, and patients should also be offered help in alleviating respiratory symptoms during the weaning process.

Eosinophilic and Other Types of Bronchitis Nonasthmatic chronic eosinophilic bronchitis (CEB) is now recognized as a common cause of persistent cough [29]. This condition has probably been under-recognized because it is confused with asthma-related cough. This is largely because CEB responds well to inhaled corticosteroids, which are often offered in this circumstance, and also because airway responsiveness is infrequently assessed in primary care. The prevalence of this condition in various populations, its etiology, including the role of environmental factors, and why it does not translate into typical asthma with associated airway hyperresponsiveness, despite some interesting recent observations in this regard, remain unknown [30]. Evaluation of the long-term impact of CEB on airway structure and function will help determine the optimal long-term management of this condition.

Chronic Bronchitis, Bronchiolitis, and Bronchiectasis Studies are needed to specically assess the effects of treatment on cough in chronic bronchitis and in acute exacerbations of chronic bronchitis. However, for these conditions, as for bronchiectasis or cystic brosis, cough is a protective mechanism that eliminates bronchial secretions; therefore, strategies need to be developed to reduce the volume of secretions and/or increase their elimination [31]. Furthermore, the prevalence of chronic cough as a manifestation of bronchiolitis should be further assessed.

Unexplained and Psychogenic Cough Idiopathic cough, now called unexplained cough, is an exclusion diagnosis. It usually responds poorly to all forms of therapy. The characteristics of patients with unexplained cough remain undened, particularly in children and adolescents. Markers need to be developed to differentiate psychogenic cough from other etiologies [32].

Gastroesophageal Reux Disease (GERD) A therapeutic trial of proton pump inhibitors is suggested for GERD-related cough, although the optimal treatment modality and response time have not been clearly established [27]. Nonacid reux has often been reported and optimal management of this condition remains to be explored. Multichannel intraluminal impedance and pH monitoring are increasingly available and may help better characterize this problem, although their role in the evaluation of chronic cough remains to be determined [28] Table 2. Other Conditions Lung cancer may be associated with a troublesome cough, which is usually treated with opiates. However, the effects of chemotherapy or other treatments, including new nonopioid agents with fewer side effects, on the cough and on the effectiveness of the treatment for cough remain unexamined. Furthermore, bronchial aspiration is common but often underdiagnosed. The characteristics of patients at risk of

123

S20 Table 2 Common pitfalls in managing the most common causes of chronic cough Postnasal-drip syndrome j Failing to recognize that it can present as a syndrome of cough and phlegm j Assuming that all H1 antagonists are the same j Failing to consider sinusitis because it is not obvious

Lung (2008) 186 (Suppl 1):S17S22

j Failing to consider allergic rhinitis and failing to recommend the avoidance of allergens because symptoms are perennial Asthma j Failing to recognize that it can present as a syndrome of cough and phlegm j Failing to recognize that inhaled medications may exacerbate cough j Assuming that a positive result of methacholine challenge alone is diagnostic of asthma Gastroesophageal reux disease j Failing to recognize that it can present as a syndrome of cough and phlegm j Failing to recognize that silent reux disease can be the cause of cough, that 23 months of intensive medical therapy is usually required before cough starts to improve, and 56 months usually elapse before cough resolves j Assuming that cough cannot be due to gastroesophageal reux disease because cough remains unchanged when gastrointestinal symptoms improve j Failing to recognize that cough may fail to improve with the most intensive medical therapy and that the adequacy of therapy and the need for surgery can be assessed by means of 24-h monitoring of esophageal pH j Failing to recognize the effects of coexisting diseases (e.g., obstructive sleep apnea or coronary artery disease) or their treatment (e.g., nitrates) j Failing to treat adequately coexisting causes of cough that perpetuate the cycle of cough and reux Postnasal drip, asthma, and gastroesophageal reux disease j Failing to consider that more than one of these conditions may be contributing simultaneously to cough j Failing to consider these common conditions because of another obvious cause (e.g., chronic interstitial pneumonia). From [12] (reproduced with permission)

this complication, its incidence, and the optimal approach to its treatment all should be evaluated [33]. Cough is a common side effect of certain drugs, including angiotensin-converting enzyme inhibitors. The potential of medications to cause this undesirable side effect should be evaluated and communicated to clinicians and patients. Furthermore, optimal treatment for patients who cannot discontinue such medications should be determined as only anecdotal reports are available on these choices [34]. Finally, cough may be associated with interstitial diseases. However, the spectrum and frequency of this problem and what the best way to manage cough in these patients remain undetermined.

Cough, Smoking, and the Environment Various environmental exposures can induce a cough. One of the most frequent is cigarette smoke. Thus, smoking cessation should be promoted in chronic coughers who smoke, although such individuals rarely consult for this symptom. Second-hand smoke may produce a cough in normal subjects but even more so in those with an underlying airway disease.

Cough may also result from various environmental exposures following either sensitization, as is the case for occupational asthma (OA), or the irritant effect of various substances in subjects with normal or increased airway tussive responses [35]. However, it has not yet been documented what role cough may play in the early identication of OA or in susceptibility to develop OA. Recently, new ways, such as induced sputum analysis, have been developed to investigate the potential of environmental sensitizers to induce airway inammation [36]. These methods might also be used to identify environmentally based CEB. Another important target of future research may be the role of occupational upper airway disease in persistent cough. Reactive airway dysfunction syndrome (RADS), initially described by Brooks et al. [37], may result in a highly troublesome cough, as may lower-grade exposures to high levels of irritants in the workplace. The optimal management of these conditions remains to be determined. Finally, the inuence of airborne contaminants, pollutants, and cold air on outdoor workers or athletes has yet to be explored. The potential of these factors to cause a troublesome or persistent cough also remains unstudied.

123

Lung (2008) 186 (Suppl 1):S17S22

S21 (2006) Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest 129(1 Suppl):1S23S Morice AH, Fontana GA, Belvisi MG, Birring SS, Chung KF, Dicpinigaitis PV, Kastelik JA, McGarvey LP, Smith JA, Tatar M, Widdicombe J, European Respiratory Society (2007) ERS guidelines on the assessment of cough. Eur Respir J 29:1256 1276 Committee for the Japanese Respiratory Society Guidelines for Management of Cough, Kohno S, Ishida T, Uchida Y, Kishimoto H, Sasaki H, Shioya T, Tokuyama K, Niimi A, Nishi K, Fujimura M, Matsuse H, Suzaki H (2006) The Japanese Respiratory Society guidelines for management of cough. Respirology 11(Suppl 4):S135S186 Irwin RS (2007) Guidelines for treating adults with acute cough. Am Fam Physician 75:476, 479, 482 Boulet LP (2006) Future directions in the clinical management of cough: ACCP evidence-based clinical practice guidelines. Chest 129:287S292S Boulet LP, Becker A, Bowie D, McIvor A, Hernandez P, Rouleau M, Bourbeau J, Graham I, Legare F, Ward T, Cowie R, Drouin D, Harris SB, Tamblyn R, Ernst P, Tan WC, Partridge M, Godard P, Herrerias C, Wilson J, Stirling L, Rozitis EB, Garvey N, Lougheed D, Labrecque M, Rea R, Holroyde M, Fagnan D, Dorval E, Pogany L, Kaplan A, Cicutto L, Allen M, Moraca S, Fitzgerald M, Borduas F, Logan J (2006) Implementing Practice Guidelines: A workshop on guidelines dissemination and implementation with a focus on asthma and COPD. Can Respir J 13(Suppl A):547 Irwin RS, Madison JM (2000) The diagnosis and treatment of cough. N Engl J Med 343:17151721 Chung KF (2007) Effective antitussives for the cough patient: an unmet need. Pulm Pharmacol Ther 20:438445 Aagaard E, Maselli J, Gonzales R (2006) Physician practice patterns: chest x-ray ordering for the evaluation of acute cough illness in adults. Med Decis Making 26:599605 Grol R, Grimshaw J (2003) From best evidence to best practice: Effective implementation of change in patients care. Lancet 362:12251230 Cote J, Bowie DM, Robichaud P, Parent JG, Battisti L, Boulet LP (2001) Evaluation of two different educational interventions for adult patients consulting with an acute asthma exacerbation. Am J Respir Crit Care Med 163:14151419 Sigurdardottir AK, Jonsdottir H, Benediktsson R (2007) Outcomes of educational interventions in type 2 diabetes: WEKA data-mining analysis. Patient Educ Couns 67:2131 Members of the Workshops (2004) ARIA in the pharmacy: Management of allergic rhinitis symptoms in the pharmacy. Allergic rhinitis and its impact on asthma. Allergy 59:373387 Fokkens W (2007) Role of steroids in the treatment of rhinosinusitis with and without polyposis. Clin Allergy Immunol 20:241250 Tatli MM, San I, Karaoglanoglu M (2001) Paranasal sinus computed tomographic ndings of children with chronic cough. Int J Pediatr Otorhinolaryngol 60:213217 McGarvey LP, Heaney LG, Lawson JT, Johnston BT, Scally CM, Ennis M, Shepherd DR, MacMahon J (1998) Evaluation and outcome of patients with chronic non-productive cough using a comprehensive diagnostic protocol. Thorax 53:738743 American Thoracic Society (1987) Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. This ofcial statement of the American Thoracic Society was adopted by the ATS Board of Directors, November 1986. Am Rev Respir Dis 136:225244 Koh YY, Jeong JH, Park Y, Kim CK (1999) Development of wheezing in patients with cough variant asthma during an increase in airway responsiveness. Eur Respir J 14:302308

Assessment of Cough and Effects of Treatments Patients may adapt to symptoms so subjective or patient reports of cough severity are often unreliable. The use of diary cards, various scales, and ambulatory monitoring have been proposed [38, 39]. New instruments that collect objective data on the frequency and characteristics of cough will allow better assessment of cough severity and the effects of treatments.
7.

8.

Assessment of New Therapies A number of agents are under investigation as antitussive therapies and may be particularly useful in specic contexts (e.g., lung cancer, irritant-induced, or postinfectious cough). They include neurokinin receptor antagonists, gamma-aminobutyric acid receptor antagonists, cannabinoid receptor agonists, local anaesthetics, transient receptor potential channels, potassium channel openers, and opioid derivatives [7, 40].

9. 10.

11.

12.

Conclusion
13.

Cough remains a signicant challenge for the clinician [41, 42]. Recent guidelines have provided valuable data and guidance on the assessment and treatment of cough. Nevertheless, more research is needed on various aspects of this common complaint, including its causes in various populations, optimal methods of assessment, specic tools for the determination of treatment efcacy, and approaches to increase implementation of cough guidelines.

14.

15.

16.

17.

References
18. 1. Irwin RS, Boulet LP, Cloutier MM, Fuller R, Gold PM, Hoffstein V, Ing AJ, McCool FD, OByrne P, Poe RH, Prakash UB, Pratter MR, Rubin BK (1998) Managing cough as a defense mechanism and as a symptom. A consensus panel report of the American College of Chest Physicians. Chest 114:133S181S 2. Irwin RS (2006) Complications of cough: ACCP evidence-based clinical practice guidelines. Chest 129:54S58S 3. Everett CF, Kastelik JA, Thompson RH, Morice AH (2007) Chronic persistent cough in the community: A questionnaire survey. Cough 3:5 4. Kuzniar TJ, Morgenthaler TI, Afessa B, Lim KG (2007) Chronic cough from the patients perspective. Mayo Clin Proc 82:5660 5. Irwin RS, Madison JM (2002) The persistently troublesome cough. Am J Respir Crit Care Med 165:14691474 6. Irwin RS, Baumann MH, Bolser DC, Boulet LP, Braman SS, Brightling CE, Brown KK, Canning BJ, Chang AB, Dicpinigaitis PV, Eccles R, Glomb WB, Goldstein LB, Graham LM, Hargreave FE, Kvale PA, Lewis SZ, McCool FD, McCrory DC, Prakash UB, Pratter MR, Rosen MJ, Schulman E, Shannon JJ, Smith HC, Tarlo SM, American College of Chest Physicians

19.

20.

21.

22.

23.

123

S22 24. Chatkin JM, Ansarin K, Silkoff PE, McClean P, Gutierrez C, Zamel N, Chapman KR (1999) Exhaled nitric oxide as a noninvasive assessment of chronic cough. Am J Respir Crit Care Med 159:18101813 25. Lemiere C, Boulet LP (2005) Cigarette smoking and asthma: a dangerous mix. Can Respir J 12:7980 26. Boulet LP, Lemiere C, Archambault F, Carrier G, Descary MC, Deschesnes F (2006) Smoking and asthma: clinical and radiologic features, lung function, and airway inammation. Chest 129:661668 27. Irwin RS, Madison JM (2002) Diagnosis and treatment of chronic cough due to gastro-esophageal reux disease and postnasal drip syndrome. Pulm Pharmacol Ther 15:261266 28. Wise JL, Murray JA (2007) Utilising multichannel intraluminal impedance for diagnosing GERD: A review. Dis Esophagus 20:8388 29. Dicpinigaitis PV (2004) Cough. 4: Cough in asthma and eosinophilic bronchitis. Thorax 59:7172 30. Thomson NC, Chaudhuri R (2004) Why is eosinophilic bronchitis not asthma? Am J Respir Crit Care Med 170:45 31. McCool FD, Rosen MJ (2006) Nonpharmacologic airway clearance therapies: ACCP evidence-based clinical practice guidelines. Chest 129:250S259S 32. Linz AJ (2007) The relationship between psychogenic cough and the diagnosis and misdiagnosis of asthma: A review. J Asthma 44:347355

Lung (2008) 186 (Suppl 1):S17S22 33. Smith Hammond CA, Goldstein LB (2006) Cough and aspiration of food and liquids due to oral-pharyngeal dysphagia: ACCP evidence-based clinical practice guidelines. Chest 129:154S168S 34. Babu KS, Marshall BG (2004) Drug-induced airway diseases. Clin Chest Med 25:113122 35. Tarlo SM (2006) Cough: Occupational and environmental considerations: ACCP evidence-based clinical practice guidelines. Chest 129:186S196S 36. Menzies D, Nair A, Lipworth BJ (2006) Non-invasive measurement of airway inammation in asthma. J Asthma 43:407415 37. Brooks SM, Weiss MA, Bernstein IL (1985) Reactive airways dysfunction syndrome (RADS). Persistent asthma syndrome after high level irritant exposures. Chest 88:376384 38. Chang AB, Newman RG, Carlin JB, Phelan PD, Robertson CF (1998) Subjective scoring of cough in children: parent-completed vs child-completed diary cards vs an objective method. Eur Respir J 11:462466 39. Chang AB, Newman RG, Phelan PD, Robertson CF (1997) A new use for an old Holter monitor: An ambulatory cough meter. Eur Respir J 10:16371639 40. Dicpinigaitis PV (2006) Current and future peripherally-acting antitussives. Respir Physiol Neurobiol 152:356362 41. Rank MA, Kelkar P, Oppenheimer JJ (2007) Taming chronic cough. Ann Allergy Asthma Immunol 98:305313 42. Morice AH, Kastelik JA (2003) Cough. 1: Chronic cough in adults. Thorax 58:901907

123

Copyright of Lung is the property of Springer Science & Business Media B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.