Cough in Health and Disease

Cough is an important defense mechanism that clears the airways of secretions and prevents entry of foreign bodies and irritants to the lower respiratory tract. It is a universal experience in health but also a nonspecific presenting feature of most respiratory conditions and a number of nonrespiratory conditions. Acute cough is one of the most common presenting symptoms in the patient population encountered by the general practitioner. In most cases, cough results from viral and bacterial upper respiratory tract infection, is a self-limiting problem, and does not require further evaluation, but a small proportion of patients will have persistent cough that necessitates specialist opinion.

Chronic cough is arbitrarily defined as presence of cough for longer than 8 weeks. It affects 3% to 10% of the general population and is responsible for between 10% and 20% of respiratory outpatient referrals. Chronic cough with significant sputum production (i.e., more than a tablespoonful per day) is likely to be due to intrapulmonary disease such as chronic bronchitis or bronchiectasis. A chronic dry or minimally productive cough may be related to extrapulmonary factors; the cough is likely to be the result of abnormal sensitization of the cough reflex secondary to the effects of local inflammation on sensory nerve endings or an intrinsic abnormality of airway nerves. Most patients complain of an abnormal sensation in the laryngeal area such as a tickle in the throat (laryngeal paresthesia). Chronic cough often is perceived as a trivial annoyance but can be a disabling problem responsible for impairment of quality of life and associated with distressing symptoms such as musculoskeletal chest pains, syncope, incontinence, disturbed sleep, and social embarrassment.

The key to successful management is establishing a clear diagnosis and applying effective treatment for long enough to reset the activity of cough receptors at a more physiologic level. Important pitfalls include atypical presentations, the presence of multiple pathologic conditions, and inadequate therapy of the underlying disorder. Further difficulty arises from the fact that evidence for the efficacy of specific therapies in chronic cough is largely based on expert opinion or uncontrolled trials, as well as the paucity of randomized controlled trials with well-validated outcome measures to guide the clinician. Nevertheless, a systematic approach based on the so-called anatomic diagnostic protocol, which focuses on disease processes within the anatomic distribution of vagal afferent nerves, seems to be successful, and various studies have reported a high rate of treatment success even in tertiary referral populations. The general consensus is that in most cases of chronic cough in patients with no other respiratory symptoms or signs and normal findings on spirometry and chest radiography, the underlying cause is asthma, eosinophilic bronchitis, gastroesophageal reflux, or rhinitis, or a combination of these. Many of these conditions can be recognized clinically, and successful diagnosis and management often are possible without recourse to expensive or invasive investigations.

This chapter focuses primarily on isolated chronic cough, because it is a common condition not dealt with elsewhere in this book. In addition, an isolated chronic cough often is a difficult diagnostic problem for both primary and secondary care physicians. This category of cough is thought to involve a primary abnormality of the cough reflex leading to a heightened response to known tussive stimuli.

The Cough Reflex

Cough is a reflex that occurs when afferent nerve receptors are stimulated by inhaled, aspirated, or endogenous substances. The most sensitive sites for initiating cough are the larynx, the carina, and the points of bronchial branching. Cough receptors also are present in extrapulmonary structures, including the esophagus, diaphragm, and stomach. A broad group of rapidly adapting “irritant” receptors (RARs) found in the larynx and tracheobronchial tree can be stimulated by a wide range of stimuli, including cigarette smoke, ammonia, ether vapor, acid and alkaline solutions, hypotonic and hypertonic saline, and mechanical stimulation by direct contact, mucus, or dust; all such stimuli can provoke cough. Another closely related fiber is the slowly adapting stretch receptor (SAR), which terminates inspiration and initiates expiration when the lungs are at an adequate level of inflation. SARs also may influence cough. C-fiber receptors, which have thin, nonmyelinated vagal afferent fibers, are found in the laryngeal, bronchial, and alveolar walls. They are relatively insensitive to mechanical stimulation and lung inflation but are exquisitely sensitive to chemicals such as bradykinin, capsaicin, prostaglandins, and acid pH. Stimuli that are known to cause cough in human subjects such as capsaicin, bradykinin, and citric acid activate C-fiber afferents, particularly those located in the bronchi. Afferent nerve fibers pass to a central cough receptor in the medulla, triggering a forced expiratory maneuver against a closed glottis, followed by glottal opening and high-velocity expiration (Figure 18-1).

Figure 18-1 Representative scheme of afferent and efferent pathways that regulate cough, and of the pathophysiology of the enhanced cough reflex. Laryngeal and pulmonary receptors, such as rapidly adapting receptors (RARs), C-fibers, and slowly adapting fibers (SARs), and putative cough receptors provide input to the brain stem medullary central cough generator through the intermediary of the relay neurons in the nucleus tractus solitarius (nTS). The central cough generator then decides and coordinates the efferent output to the muscles that causes the cough effort. Also present is an efferent output to airway smooth muscle and mucosal glands (not shown). The cerebral cortex may control the motor output of cough volitionally or influence the “urge-to-cough” sensation. Potential factors involved in the enhancement of the cough reflex both in the upper airways and at the brain stem level are illustrated. Inflammatory responses with expression of mediators, neuropeptides, and vanilloid receptors (e.g., TRPV1) may influence the cough response and brain stem modulation of the afferent pathways. CGRP, calcitonin gene–related peptide; LTD₄, leukotriene D₄; PGE₂, prostaglandin E₂; TNF-α, tumor necrosis factor-α; TRPV1, transient receptor potential cation channel subfamily V member 1 [i.e., vanilloid receptor 1 or capsaicin receptor].

Differential Diagnosis of Cough

The causes of cough can be conveniently divided into acute and chronic (Box 18-1 and Table 18-1). An acute cough is arbitrarily defined as a cough of less than 3 weeks’ duration. Infectious and allergic conditions are by far the most common etiologic disorders. Most acute coughs related to viral upper respiratory tract infection resolve by 3 weeks, but a small proportion become persistent and require further evaluation.

Most pulmonary conditions implicated in causing chronic cough, such as chronic obstructive pulmonary disease, lung cancer, an inhaled foreign body, pulmonary tuberculosis, sarcoidosis, idiopathic pulmonary fibrosis, and heart failure, will be obvious on clinical assessment, spirometry, and chest radiography. Assessment and management of these conditions are dealt with elsewhere in this book. Thus, a majority of patients referred for investigation of chronic cough are nonsmokers with normal findings on physical examination and chest radiography. Most present with a nonproductive or minimally productive cough, and 60% to 75% are female. A recognized tendency is for cough to manifest initially around the time of menopause. The most common conditions implicated in aggravating or causing chronic cough in these patients are listed in Table 18-1.

Table 18-1 Common Conditions Implicated in Causing Chronic Cough

Clinical Assessment

An initial assessment of a patient with chronic cough is directed at finding a specific cause, assessing severity, and initiating trials of treatment. A careful history and physical examination are paramount in the evaluation of a patient with chronic cough (Table 18-2). Details of the factors surrounding the onset of cough and associated symptoms and a careful assessment of the upper airways and the respiratory system are particularly important. Basic initial investigations should include up-to-date chest radiography, spirometry, and tests of bronchodilator reversibility, if appropriate. An abrupt onset of coughing while eating or chewing should raise the possibility of an inhaled foreign body, and the onset of cough shortly after introduction of angiotensin-converting enzyme (ACE) inhibitor therapy suggests ACE inhibitor associated cough. The presence of significant quantities of sputum, hemoptysis, systemic symptoms, prominent breathlessness, wheeze, or abnormal physical signs increases the probability of intrinsic lung disease and should trigger appropriate investigations, which may include a CT scan of the chest and bronchoscopy even in the absence of suggestive findings with more simple investigations. The onset of cough with symptoms suggesting an upper or lower respiratory tract infection raises the possibility of a postinfectious cough; prominent whoops, a very troublesome nocturnal cough, and cough associated with vomiting all are associated with pertussis, a condition that is increasingly recognized in both school-age children and adults. Otherwise, little evidence is available to suggest that information on the timing, nature, complications, and potential aggravating factors is predictive of the underlying cause of the cough.

Table 18-2 Initial Evaluation of the Patient with Chronic Cough

Findings on history and physical examination often are unremarkable, in which case the patient evaluation should focus on the recognition of corticosteroid-responsive conditions (i.e., asthma and eosinophilic bronchitis) and extrapulmonary factors that may be aggravating the cough, such as rhinitis and gastroesophageal reflux. One approach to the assessment of patients with chronic cough is outlined in Figure 18-2

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