Chronic cough: a respiratory viewpoint Megan M. Cornere

Purpose of review This article reviews the common causes and investigation of chronic cough and explores unexplained cough and its relationship to cough hypersensitivity. Recent findings Cough plays a critical role in airway protection and clearance of secretions. Chronic cough, however, is a debilitating symptom that can significantly interfere with quality of life. Despite their limitations cough guidelines have raised the awareness of chronic cough as an important problem and provided a framework for a logical care pathway. The use of a systematic approach to diagnosis and management in a specialist clinic can result in successful identification as to the cause, with subsequent relief of symptoms. In a proportion of patients no diagnosis is reached or treatment fails. A common finding among these patients is cough reflex hypersensitivity and this is an important feature irrespective of the underlying diagnosis. The majority of patients referred to tertiary cough clinics are females. Women appear to have an intrinsically heightened cough response with augmented cough challenge and a high frequency of ACE-inhibitor cough. Summary The way in which we review cough has undergone radical change in the last decade. A distinct population of patients with chronic idiopathic cough is emerging in whom cough reflex hypersensitivity is a feature. Extended co-operation between clinicians, scientists and the pharmaceutical industry is required to better understand the pathophysiology of the enhanced cough reflex and the development of more effective antitussive therapies. Keywords antitussive therapy, capsaicin, chronic cough, cough guidelines, cough reflex, extrapulmonary, idiopathic cough, refractory cough

INTRODUCTION Chronic cough has had several definitions in the past but is generally defined in respiratory circles as cough lasting for greater than 8 weeks. It is a common and distressing symptom frequently encountered by physicians in both primary and secondary care. It is often perceived as a trivial problem. Although the impact on health status can be variable it can result in markedly impaired quality of life. It has the ability to affect physical, social and psychological domains, and incur significant healthcare costs from medical consultations and medication use. Although cough does not necessarily imply disease it is often the key symptom of chronic respiratory illness and may be the sole presenting feature of a number of extrapulmonary conditions. Chronic cough is often viewed as associated with little diagnostic or treatment success. Chronic cough may be successfully treated when associated with the common causes such as asthma, eosinophilic

bronchitis, gastroeosophageal reflux disease (GERD) and post nasal drip (PND) or rhinosinusitis [1–3]. Unfortunately, there is a proportion of patients in whom there is an associated diagnosis but treatment specifically directed at the associated cause does not lead to an improvement in the cough. There is some controversy as to whether these conditions are causes or aggravants of cough. It is also important to remember that the majority of patients with these conditions do not complain of cough. Unexplained chronic cough may be because of a failure to recognize that cough is often provoked from sites outside the airway, poor compliance with North Shore Hospital, Westlake, Auckland, New Zealand Correspondence to Dr Megan M. Cornere, MBChB, FRACP, PhD, Clinical Director Respiratory Medicine, North Shore Hospital, Shakespeare Road, Takapuna, Private Bag 93-503, Takapuna Auckland 0740, New Zealand. E-mail: [email protected] Curr Opin Otolaryngol Head Neck Surg 2013, 21:530–534 DOI:10.1097/MOO.0000000000000001 Volume 21  Number 6  December 2013

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Chronic cough: a respiratory viewpoint Cornere

KEY POINTS  Chronic cough may be defined as cough lasting for greater than 8 weeks.  Cough can often be successfully treated when associated with common causes.  Unexplained cough appears to be a distinct clinical entity.

also challenged those involved in research and drug development to explore potential new treatments and effective cough therapies that are able to control the symptom yet preserve this crucial defensive reflex.


therapy and ineffective therapy. The term idiopathic cough is often used in these cases [4–6]. Cough hypersensitivity syndrome has also been used to identify these patients and suggests an abnormality of the cough reflex [7,8]. Other terms used throughout the literature include nonspecific cough and refractory cough. Cough should only be considered idiopathic or unexplained following a specialist review in cough clinic. General consensus as to the terminology used to depict unexplained cough may be useful. It is unclear why some patients develop a chronic cough and it is most likely the result of upregulation of the cough reflex by multiple factors. Some individuals are troubled with cough that appears to serve no useful physiological purpose. A heightened cough reflex is an important feature in most patients irrespective of the diagnosis [9] and can be considered reversible or persistent in patients with chronic cough.

Cough can be measured subjectively using symptom scores and specific quality-of-life measures, and objectively by measuring cough numbers and intensity and by assessing the cough response to capsaicin and citric acid. Cough-specific healthrelated quality-of-life questionnaires coupled with a simple cough scoring system or a visual analogue scale is the easiest way of assessing the severity of cough in the clinic setting. Baseline evaluation should include a number of investigations that reflect the pulmonary and extrapulmonary conditions known to commonly cause cough. A plain chest X-ray is mandatory as a significant abnormality will alter the diagnostic algorithm dramatically. Spirometry may demonstrate airway reversibility. Bronchial provocation testing should also be considered in patients without a clinically obvious cause for chronic cough and with normal spirometry, as a negative test will exclude cough variant asthma (CVA) [10]. Bronchoscopy should be undertaken if foreign body inhalation is suspected. The diagnostic yield of bronchoscopy in the routine evaluation of chronic cough is low [7]. It can have significant diagnostic potential in selected patients in whom other more targeted investigations are normal [11]. Computerized tomography of the chest can be useful in selected patients.



Clinical guidelines are becoming more commonplace and have evolved from the need to follow protocol in managing certain medical conditions appropriately and efficiently. In the last decade, the American College of Chest Physicians, European Respiratory Society and British Thoracic Society to name a few, have each endorsed their own set of guidelines on management of cough but there remains considerable debate and criticism regarding their content and breadth. What is clear, however, is that a systematic multidisciplinary approach to diagnosis and treatment is required. Despite their obvious limitations cough guidelines have raised the awareness of cough and chronic cough as an important clinical problem and highlighted the common reasons for treatment failure. They have

Cough is a physiologic mechanism that protects against thermal, chemical or mechanical insult. There are however elements of voluntary control. It is generally reduced during sleep and under anaesthetic [12] and is susceptible to placebo suppression [13]. Our current understanding of the neurophysiology of the cough reflex is largely derived from animal work with limited data in humans. Cough is a reflex activity that dramatically enhances clearance of secretions and foreign material by narrowing the airways and increasing the turbulence and velocity of airflow. The cough reflex is a complex event. It occurs when airway afferent or sensory nerves are present in the larynx and tracheobronchial tree, especially, the carina and the points of bronchial branching are

 Chronic idiopathic cough is often associated with cough reflex hypersensitivity.  The need remains for more effective antitussive therapies.

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stimulated by a variety of inflammatory or mechanical changes or irritants present in the airways. The cerebral cortex also appears to exert higher voluntary control over these processes and may be involved in the sensation of the urge to cough [14]. There are at least five vagal afferent nerve subtypes. These include small unmyelinated c-fibres that comprise two groups and are sensitive to chemical stimuli, in particular capsaicin [15–17,18 ]. These appear to co-operate with rapidly adapting receptors (RARs) in mediating cough. RARs and slowly adapting receptors respond to both mechanical stimuli, alterations in airway compliance and chemical stimuli such as cigarette smoke and acidic pH. There is also evidence for a putative cough receptor that has no specific features typical of RAR and c-fibres, and mediates the immediate cough reflex to aspiration. Both peripheral and central sensitization may be important mechanisms in chronic cough and are under active investigation. It is becoming more apparent the need to understand the mechanisms underlying sensitization, how they interact with triggers and their relationship with the sensations that drive the urge to cough. &

COUGH REFLEX SENSITIVITY Measurement of the cough reflex has been studied most often using inhalation of citric acid or capsaicin. Both techniques have been well validated and methods well standardized. Capsaicin cough sensitivity is probably the most widely utilized as it induces cough reliably and assessment of the cough reflex with capsaicin is reproducible [19,20]. An increase in cough sensitivity has been reported in most conditions associated with chronic cough. However, there is considerable overlap between capsaicin cough reflex sensitivity and conventional cough challenge techniques in normal individuals. This suggests that there are other important mechanisms that are yet to be determined. Cough reflex sensitivity is more heightened in females than males and may be why chronic cough is more prevalent in females [21]. Cough reflex sensitivity can be considered to be reversible or persistent and is noticeably absent in patients with chronic productive cough associated with pulmonary conditions such as bronchiectasis or chronic obstructive pulmonary disease [22]. The role of heightened cough reflex sensitivity has been studied mostly in patients with ACEinhibitor (ACE-I) associated chronic cough. Literature suggests that approximately 10% develop a protracted cough. The reason why some patients 532

develop a chronic cough is unclear. It is postulated that the higher levels of Substance P, bradykinin and prostaglandin concentrations found in the airway secretions of these patients increase cough reflex sensitivity [23]. It is well known that withdrawal of the ACE-I leads to cessation of cough or at least a reduction in the cough severity. Reintroduction of the ACE-I invariably leads to cough recurrence. This reversibility is not unique to ACE-I cough and is seen in patients with eosinophilic bronchitis, CVA and upper respiratory tract infections.

ASTHMA Glauser [24] first described cough as the only presentation in asthma in 1972. In CVA, the cough is described as episodic and associated with other features more typical for asthma such as expiratory wheeze or exertional dyspnoea. Several prospective studies have demonstrated asthma to be among the most common causes of chronic cough and seen in 24–29% of nonsmoking adults [10,25,26]. Patients with CVA often present a diagnostic challenge as the physical examination and standard pulmonary function studies are normal. The diagnosis can be confirmed by spirometry with a positive bronchodilator response or a positive bronchial provocation challenge. Treatment involves education, self-management and the use of medication according to current asthma guidelines. Recent studies suggest that leukotriene receptor antagonists may be particularly effective in treating CVA. Treatment may result in an improvement in cough and appears to inhibit objectively measured cough sensitivity in these patients [27]. Little is known about the natural history of CVA, in particular, what proportion progresses to a more classic syndrome of dyspnoea wheeze and airflow obstruction. Current literature suggests that progression of this nature may be attenuated by inhaled corticosteroids [28–30].

EOSINOPHILIC BRONCHITIS Eosinophilic bronchitis is a common cause of cough and presents as an isolated chronic cough. It includes nonasthmatic eosinophilic bronchitis, eosinophilic asthma and atopic cough. A distinguishing feature of this syndrome is the absence of airway hyperresponsiveness or variable airflow obstruction. Eosinophilic bronchitis has been shown to be the cause of chronic cough in up to 15% of patients referred to specialist cough clinics [31]. Eosinophilic bronchitis is characterized by chronic eosinophilic inflammation of the lower airway that can be recognized from an induced sputum Volume 21  Number 6  December 2013

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Chronic cough: a respiratory viewpoint Cornere

(eosinophils > 3% of nonsquamous cells) or bronchoalveolar lavage (eosinophils > 2%) and suggested by an elevated fractional exhaled nitric oxide (FeNO) level (>47 ppb) [32 ]. This type of cough responds well to inhaled corticosteroids. If access to eosinophil markers is limited, an empirical trial of inhaled corticosteroids can be considered where appropriate. &

refractory cough. Nonspecific cough is a chronic cough that is not associated with any of the usual cough-associated diagnoses or cough pointers. In these cases, investigation with chest X-ray and spirometry yield no obvious cause. Refractory cough is a cough that persists after a trial of therapy. Some centres suggest that a cause for cough can be identified and successfully treated in up to 98% of cases [42,43,44 ]. The term idiopathic must be used with care, as in some cases treatment failure may be due to noncompliance, trials of therapy that are of inadequate dose or duration and a failure to appreciate coexisting causes. Truly idiopathic cough is likely to represent a distinct clinical entity and although it is likely to consist of a variety of disorders, a pattern in the characteristics of these patients is slowly emerging. Many patients with idiopathic or nonspecific cough report an upper respiratory tract infection as the initial trigger for the cough. As the infection subsides the cough persists. This may last for months and in some cases years. It is possible that chronic idiopathic cough may be a variation of postviral cough but with an extremely prolonged clinical course. Although the mechanisms are currently unknown, most patients have cough reflex hypersensitivity and markedly increased sensitivity to capsaicin. It is plausible that the sensory nerve may be damaged during some respiratory tract infections resulting in a reduction in sensory nerve threshold to stimulation [45,46]. &

COUGH AND GASTROEOSOPHAGEAL REFLUX DISEASE Chronic cough may represent an oesophageal manifestation of GERD although there is controversy to its cause and effect. Multiple studies have implicated GERD as one of the commonest causes of chronic cough [8,26,33–35]. The reflux theory suggests that cough is precipitated by gastric refluxate into the airways. The reflex theory postulates that the cough is a vagally mediated oesophageal –tracheobronchial reflex caused by acid perfusion onto the distal oesophageal [36]. In adults, an empirical trial of high dose proton pump inhibitor therapy is indicated if there is reasonable suspicion that GERD is contributing to the chronic cough. Although widely used, oesophageal pH monitoring has very poor predictive value in identifying patients likely to respond to acid suppression [37]. Nonacid reflux is a recognized condition that is associated with extraeosophageal symptoms including cough. This may explain the lack of satisfactory treatment response in some patients with documented GERD. A proportion of patients may require prokinetic agents and elimination of medications that can potentially worsen GERD should be identified. Laparoscopic fundoplication may be effective in treating certain causes; however, the timing and indications for surgery remain undefined.

UPPER AIRWAYS DISEASE These syndromes include chronic rhinosinusitis and what has previously been termed PND. The contribution of PND to chronic cough is particularly controversial as it often coexists without cough [38]. It has been suggested that nasal or sinus secretions dripping into the hypopharynx or larynx stimulate local cough receptors [39 ]. Current recommendations include an empirical trial of antihistamine/ decongestant or intranasal steroids [40,41]. Investigation can involve nasal endoscopy and CT sinuses, particularly, if the diagnosis is uncertain or the patient does not respond to treatment. &&

UNEXPLAINED CHRONIC COUGH With an unexplained cough it is important to make the differentiation between nonspecific and

CONCLUSION Chronic cough continues to be a frustrating problem to both patients and clinicians. Chronic cough is socially debilitating with considerable impact on quality of life. It is becoming more obvious that unexplained chronic cough should be considered a distinct entity and not just a symptom. There is certainly a distinct trend towards a population of patients who are female, middle aged and who report an initiating upper respiratory tract infection and have cough reflex hypersensitivity. It is likely that the presence of multiple factors may be necessary to maintain a sensitized cough reflex and these include both pulmonary and extra pulmonary factors. A major unmet need in chronic cough is the availability of effective antitussives. It is becoming more evident the need for the exploration and development of more effective agents. Furthermore, clinical research into chronic idiopathic cough may provide important information regarding the pathophysiological mechanisms of cough and the

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development of antitussive drugs that downregulate cough reflex sensitivity. Acknowledgements None. Conflicts of interest The author has no conflicts of interest to declare.

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Chronic cough: a respiratory viewpoint.

This article reviews the common causes and investigation of chronic cough and explores unexplained cough and its relationship to cough hypersensitivit...
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