Chronic cough in non-smokers: diagnostic approach
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Chronic cough in non-smokers: diagnostic approach
Márcia JacomelliI (TE SBPT); Rogério SouzaI (TE SBPT); Wilson Leite Pedreira JúniorI (TE SBPT)
Pulmonology Department of the Faculdade de Medicina da Universidade de São Paulo
Cough is the main physiological mechanism responsible for the clearance of secretions from airways, acting as an important defense mechanism. However, the presentation of chronic cough is one of the most important causes for patients to seek medical attention all over the world, thus the significance of the correct recognition of all the factors related to the process of cough.
Among those factors, some are of extreme importance, since they may be present in almost 95% of the cases: post-nasal drip syndrome, asthma and gastroesophageal reflux disease.
The main step for a successful therapy for chronic cough is a rational and progressive diagnostic approach, narrowing the list of possible diagnosis and allowing the institution of a treatment with a better cost-effectiveness. The proposal of an algorithm focusing on the most common causes of chronic cough may be helpful in this initial approach.
Key words: Chronic cough. Diagnostic algorithm. Asthma. Postnasal drip syndrome. Gastroesophageal reflux
Abbreviations used in this paper:
CB Chronic bronchitis
ACE Angiotensin-converting enzyme
CT Computed tomography
FEV1 Forced expiratory volume in one second
Cough is the primary physiological mechanism responsible for clearing secretions from airways. However, persistent cough leads to a series of complications such as life-style changes, general malaise, insomnia, hoarseness, headache, musculoskeletal pain, excessive sweating, urinary disturbances and even syncope.(1) Due to these complications, cough is the fifth most common complaint for which patients seek medical attention worldwide. In nonsmoking adults, the incidence of persistent cough varies from 14 to 23%.(2,3)
Cough can be caused by a multiplicity of disorders. Therefore, it is important to define a cough as either acute or chronic in order to reduce the number of possible diagnoses.(4) Despite some controversy,(1,4) most studies define chronic cough as lasting for more than 3 weeks.(1,2,4-10)
Clinical experience suggests that the most common causes of acute cough are upper respiratory tract infections (mainly caused by common colds), bacterial sinusitis, allergies, pneumonia and complications resulting from asthma or chronic obstructive pulmonary disease.(4) On the other hand, in 90% to 95% of cases, chronic cough is due to one or more components of the postnasal drip-asthma-gastroesophageal reflux triad.(1,2,5-7,11) Prospective studies have shown that, 38% to 82% of the time, chronic cough may be due to a single causal factor and that 18% to 62% of cases have multiple causes.(2,5,7,11) Palombini et al.(6) reported multiple causal factors in 48 (61.5%) of the 78 cases studied.
Thus, in nonsmokers who are not taking an angiotensin converting enzyme (ACE) inhibitor and whose chest radiographs appear normal, chronic cough is due to one of the factors in the symptomatic triad in 90% to 99.4% of cases. Other causes reported in the literature include chronic bronchitis, bronchiectasis, bronchogenic carcinoma, reaction to medication, parenchymal diseases, cardiovascular disease, foreign bodies in the airways and tracheobronchial compression.
A systematic evaluation, taking into consideration the knowledge of the physiopathological mechanisms of cough, its clinical and laboratory manifestations, together with its most frequent causes allows a causal diagnosis in 88% to 100% of cases and therapeutic success in 84% to 98%.(1) It is important to stress that the gold standard in the diagnosis of chronic cough is a satisfactory response to therapy.
In this review, we will give special attention to the diagnosis, physiopathology and treatment of the primary causes of chronic cough.
According the results of four prospective studies undertaken since the 1980s, postnasal drip is the most common cause of chronic cough.(2,5,7,8) The clinical history and the physical examination provide useful information for the diagnostic investigation. The main symptoms reported are a sensation of something dripping into the throat, nasal congestion or nasal discharge. Few patients are asymptomatic. The physical examination may show inflammation of the nasal and pharyngeal mucosa (swelling and red or pallid areas), with or without secretion. However, these findings alone are not enough to characterize a specific disease. To make a definitive diagnosis, radiological examination, fiber optic endoscopy(7) and, finally, a positive response to the prescribed medication are required.(1,2,5,12)
The most common causes of cough secondary to postnasal drip are seasonal or perennial allergic rhinitis, vasomotor rhinitis, postinfectious rhinitis, sinusitis, drug-related rhinitis and environmental irritants.(1,9,12)
Among the diseases presenting postnasal drip, sinusitis is responsible for approximately 30% of the dry cough cases and for 60% of the productive cough cases.(1)
When diagnosis based only on clinical symptoms is not possible, when response to treatment is unsatisfactory or when there is a suspicion of involvement of neighboring structures, conventional radiographs play a role in the initial investigation of patients suspected of having acute sinusitis.(13) Radiographs are more useful in evaluating the maxillary, sphenoid and frontal sinuses. Opacification of the paranasal cavity, air-fluid levels or mucosal thickening greater than 6 to 8 mm (in children and adults, respectively) are suggestive of sinusitis.(14)
Conventional radiographs may be taken from the following perspectives:
1) Waters, or occipitomental, view (preferred to assess the maxillary sinuses)
2) Caldwell, or occipitofrontal, view (to assess the frontal and anterior ethmoidal sinuses)
3) Hirtz, or submentovertex, view (to study the posterior ethmoidal and the sphenoid sinuses)
4) Lateral view (allows the evaluation of all the sinuses, especially the frontal and sphenoid, the floor and posterior wall of the maxillary sinuses, the nasal fossae and also the rhinopharynx(15)
Radiological findings must be interpreted in light of the clinical history, of the fact that abnormalities observed in conventional radiographs may be related to multiple bone projections in each sinus and of the fact that some patients may be asymptomatic.(13) The importance of the clinical-radiological correlation has also been documented in a prospective study of 31 healthy subjects who presented common cold-like symptoms.(16) Using computerized tomography (CT), the authors observed significant alterations to the ostiomeatal complex and paranasal cavities, including obstruction of the ethmoidal infundibulum (due to mucosal inflammatory reaction, congestion and thickening), in 77% of the cases studied. In addition, changes were found in one or more paranasal cavities (maxillary sinuses, 87%; ethmoidal, 65%; frontal, 32%; sphenoidal, 39%), which were characterized by densely radiopaque fluid inside the sinus and mucosal thickening. The authors monitored the 14 patients for 13 to 20 days after the initial symptoms and found that 11 (79%) presented spontaneous regression of the symptoms without specific treatment for sinusitis.
Some authors refer to the low sensitivity of radiographs in comparison to CT, to technical or interpretation problems, or even to the fact that the radiographs are not performed from the various perspectives that seem to facilitate analysis of the paranasal cavities and upper-airway components.(2,7,12,17,18) One study performed on patients with chronic cough, based upon favorable responses to sinusitis therapy and evaluating the diagnostic value of conventional radiographs, showed that, in cases of productive cough, sinus radiographs have a positive predictive value of 81% and a negative predictive value of 95%(7) and that, in cases of non productive chronic cough,(2) conventional radiographs have positive and negative predictive values of 57% and 100%, respectively.
The method of choice in evaluating the paranasal cavities, especially regarding the ostiomeatal complex and ethmoidal sinuses, is CT scan involving 3- to 4-mm coronal sections, which is more sensitive than conventional radiographs.(14) Such CT scans are especially indicated in cases of complicated acute sinusitis or chronic sinusitis and are quite useful for preoperative evaluation, as well.
In order to determine anatomical causes as well as the extent of diseases with nasal obstruction, secretion clearance and other inflammatory processes in patients with chronic symptoms, endoscopy of the nasal cavity, pharynx and larynx is indicated. It complements CT and it is fundamental in the planning of a therapy regime.(14,19)
Some authors have suggested that postnasal drip treatment should be based upon clinical presentation and symptoms, leaving extensive diagnostic work-up for refractory cases.(4)
However, even considering all the clinical and complementary diagnostic tests, the gold standard in establishing the diagnosis, once the causal relationship between posterior nasal dripping and chronic cough is established, is the improvement of symptoms after therapy (Table 1).
Asthma, cough-variant asthma and eosinophilic bronchitis
Asthma is the second most common cause of chronic cough. Clinical history, when positive (wheezing, dyspnea, chest tightness and worsening with the use of a b-blocker) and combined with a favorable response to therapy with b2 agonist, is indicative of this diagnosis (Table 1).(1) Variable airflow obstruction is characteristic of bronchial asthma. The obstruction can be evaluated through the spirometric measurement of forced expiratory volume in the first second (FEV1) before and after inhalation of a b2 agonist. An FEV1 > 7% in relation to the predicted values and of at least 200 ml (Brazilian Society of Pulmonology and Phthisiology, SBPT) or > 12% in relation to basal values and also of at least 200 ml (American Thoracic Society, ATC) is accepted as an indication of significant response to bronchodilators. However, it is known that some patients with severe airflow obstruction do not present significant variations in FEV1 measurements and that patients with cough-variant asthma may not present this variation. In such cases, simple morning and evening measurements of peak expiratory flow over time (for some weeks) should be made to monitor response to treatment.
Inhalation challenge with methacholine or histamine has a high sensitivity and negative predictive value, and is mostly used to rule out a diagnosis of asthma.(20) Some prospective studies on chronic cough confer a negative predictive value of approximately 100% on such treatment.(2,7,21,22) False-positive results have been reported in up to 22% of cases.(2) An official SBPT publication on pulmonary function testing stresses that this test determines airway responsiveness status, that false-positive and false-negative results may occur and that the results should therefore be interpreted according to clinical findings.(23)
Chronic cough as an isolated symptom of asthma, known as cough-variant asthma, can occur in 6.5 to 57% of cases.(1) The difference between this variation and the classic presentation of asthma is the fact that a patient with no history of bronchial obstruction and presenting no signs of such upon physical examination may be suffering from cough-variant asthma, despite presenting symptom improvement with b2 agonists. Although the mechanism responsible for cough-variant asthma has not been well defined, it can be characterized as bronchial hyperresponsiveness to methacholine challenge.(24,25) This condition evolves into bronchial asthma in only 25% to 45% of patients.(23)
Among the diseases that should be considered in the differential diagnosis of asthma, eosinophilic bronchitis deserves special attention. It may present as chronic cough and increased numbers of eosinophils and metachromatic cells in the sputum, similar to the findings in asthma. Nevertheless, the absence of variable airflow obstruction, airways hyperresponsiveness and mast cell infiltration of the smooth muscles in the airways allows it to be distinguished from asthma.(26) Brightling et al.(27) studied 91 patients with chronic cough and identified eosinophilic bronchitis in 13% of the cases, with an incidence greater than that of gastroesophageal reflux (7.7%). The patients in that study obtained clinical benefit from oral or inhaled corticosteroids.(28)
Even in light of the positive results from the previous studies cited above, symptom improvement after b2-agonist use is a key factor in the diagnosis of asthma as the cause of cough. Corticosteroid therapy cannot be considered in the same way since it can also effect marked improvement in other diseases, such as chronic bronchitis, eosinophilic bronchitis, postinfectious cough and rhinitis.(1,4)
Gastroesophageal reflux is the third most frequent cause of chronic cough (6% to 10% of cases).(1,2,5) Despite the fact that the physiopathological mechanisms are not being completely understood, some theories(22) have been proposed:
acid and enzymatic stimulation of the pharynx and larynx
pulmonary aspiration syndrome
In 50% to 75% of cases, dyspeptic symptoms are absent.(1) Barium-contrast examination of the esophagus may be normal.(2,5,7) Esophageal endoscopy may be an initial method of investigation, and is very useful in grading esophagitis. However, a normal endoscopy does not rule out the disease. Twenty-four-hour outpatient monitoring of esophageal pH is highly sensitive and specific, although false-negatives may occur.(4) In two prospective studies investigating chronic cough, 24-hour esophageal pH monitoring reached positive predictive values of 89 to 100% and negative predictive values of approximately 100%.(2,7) Such pH monitoring is important in quantifying esophageal exposure to acid and in documenting the temporal relationship between clinical symptoms and reflux.(1) Nevertheless, a causal relationship can only be established after a satisfactory response to therapy.(4) according to the American Gastroenterological Association (AGA) provides the following guidelines:
Esophageal pH monitoring is:
useful in documenting reflux in patients who present normal endoscopic exams, are refractory, will undergo anti-reflux surgery or are under investigation for chest pain (after cardiac evaluation).
useful in evaluating recurrence of reflux after surgical treatment.
useful in evaluating refractory cases of pharyngitis, laryngitis or chronic cough.
useful in documenting reflux in adults with recent-onset asthma when there is a suspicion that the asthma is reflux-induced, although positive esophageal pH does not confirm a causal relationship.
not useful in evaluating alkaline reflux and esophagitis.
Among the reported symptoms of gastroesophageal reflux are hoarseness, choking, spasms, a sensation of pain or burning in the pharynx, globus sensation and the need to constantly clear the throat due to sputum. Direct laryngoscopy allows the detection and grading of acute and chronic inflammatory alterations(29-31) that affect the posterior structures of the larynx (the posterior third of the vocal folds, the arytenoids and the interarytenoid and retrocricoid regions). These alterations can be characterized by edema, enanthema, hypertrophy, mucosal thickening or contact granulomas. Together, they are defined as posterior laryngitis and have been the object of several studies for the past last decades, especially in correlation with the results of 24-hour esophageal pH monitoring. Structural alterations (cysts, nodules and polyps on the vocal folds) and functional alterations (cleavages and asymmetries) may be found.(30,31)
Even in patients who test positive for reflux through any of the above methods, symptom improvement after anti-reflux therapy (Table 1) is what establishes a causal diagnosis in patients with chronic cough.(1)
Chronic bronchitis (CB) is defined by the presence of productive cough on most days over a period of 3 months for at least 2 consecutive years. Approximately 5% of patients who seek medical attention for cough are eventually diagnosed with CB.(2,5) Most CB patients are smokers and their coughing is therefore generally attributed to smoking.
In various prospective studies, bronchiectasis has been found to be the cause of chronic cough in approximately 4% of the cases studied.(2,7) The diagnosis is indicated when there is a clinical history of cough, and sputum production can be associated with dyspnea. Chest auscultation may reveal varying degrees of crackles, ronchi and wheezing. In the diagnosis of bronchiectasis, chest CT has a 60 to 100% sensitivity and a 92 to 100% specificity.(33) Bronchoscopy is not useful for the diagnosis of bronchiectasis, but can be performed to locate bleeding sites, orient the therapy, identify associated infections, determine immunoglobulin levels and detect the presence of foreign bodies in the airways (localized bronchiectasis). In the study of 78 chronic cough patients performed by Palombini et al.,(6) bronchiectasis was the fourth most common causative factor (17.9%).
Centralized tumors occur most commonly in smokers and induce coughing with 70 to 90% frequency over the course of the disease.(1) However, less than 2% of these patients seek medical care(2,5) since they tend to attribute the cough to smoking. On the other hand, coughs that change in character, that persist even after 4 weeks of smoking cessation or that produce hemoptysis deserve detailed diagnostic work-ups, even when conventional chest radiography appears normal.
In evaluating bronchogenic carcinoma as the cause of cough, chest radiographs, sputum cytology and bronchoscopy are the initial tests indicated.(1) Chest radiographs have a positive predictive value of 36 to 38% and, when they are normal in nonsmokers or do not present signs of new infiltrate or change in relation to a previous pattern, bronchogenic carcinoma is unlikely(1,2,7) and other causes of cough, such as the triad previously described, chronic bronchitis and eosinophilic bronchitis should be considered.(4)
Bronchoscopy can be used in the diagnostic work-up when there is doubt about the cause of cough in patients of a susceptible group or when there is a suspicion based on radiographs. It is advisable to perform a visual endoscopic analysis (of endobronchial lesions, synchronous or metastatic tumors) and obtain a sample for pathological diagnosis.(33)
Despite a variable sensitivity (22 to 77%) depending upon the method of collection, sputum samples for cytology obtained through spontaneous or induced expectoration can be alternatives for the diagnosis of inflammatory or neoplastic pulmonary diseases when bronchoscopy or other invasive methods are contra-indicated.(34,35) It is important to keep in mind that patients with tumors of the upper airways (mouth, pharynx and larynx) can present sputum contamination by neoplastic cells.
Angiotensin-converting enzyme inhibitors
The use of angiotensin-converting enzyme (ACE) inhibitors has been implicated in 0 to 3% of coughs that motivate patients to seek medical advice.(2,7,8) The cough may develop hours or months after the ACE inhibitor is started and is likely due to accumulation of substance P, bradykinin and prostaglandins, all of which stimulate the C fibers in the respiratory mucosa. Cough has been reported by 3 to 20% of the patients who take this medication, is not dose-dependent and can occur with any kind of ACE inhibitor (captopril, enalapril, lisinopril, ramipril, benazepril, fosinopril and others). The improvement after the drug is discontinued can take up to four weeks and is a key factor to establish the diagnosis.(1) Angiotensin II receptor inhibitors, especially those (such as losartan and valsartan) that inhibit type 1 receptors, do not act directly on kininase (angiotensin-converting enzyme) and thus do not cause kinin accumulation. Therefore, they cause a much lower incidence of cough than do ACE inhibitors, as has been shown in controlled studies.(36,37)
A chronic, uncontrollable cough, together with a choking sensation was described in a group of patients studied by Palombini et al.,(6) and, known as tracheobronchial compression, is the fifth most common cause of chronic cough. Diagnosis is made by observation of expiratory distal airway compression through flexible bronchoscopy.
Postinfectious cough, although commonly considered acute cough, can persist and evolve into a case of chronic cough. In such cases, clinical history is compatible and chest radiographs are normal. This occurs mainly after Mycoplasma pneumoniae, Chlamydia pneumonia and Bordetella pertussis infections.(1,38) Viral infections can also trigger coughing after an upper-airway infection. Persistent inflammatory processes of the respiratory mucosa (rhinitis, tracheobronchitis),(4) bronchial hyperresponsiveness(39) or infective complications such as bacterial sinusitis(22) may be the mechanisms responsible for the persistence of coughing in these cases. When there is no bacterial infection, the cough improves spontaneously or with corticosteroid use.
Cough due to aspiration of food can occur in the elderly, in patients with neuromuscular diseases or in those who have suffered cerebrovascular accidents. Sensitivity or motility disturbances of the pharynx, larynx and esophagus can be the main responsible factors. In these cases, cough usually occurs during eating. Voice changes, weight loss or recurrent pneumonia can occur. Evaluation using videofluoroscopy or flexible videoendoscopy is useful in the diagnosis of anatomical and functional causes, as well as in the documentation of aspiration episodes.(40)
Cough can occur together with progressive dyspnea in cases of left ventricular insufficiency, hemoptysis, pleural effusion, or chest pain due to pulmonary embolism. Clinical history and physical examination are fundamental in the diagnostic work-up.(41) Dyspnea can also be combined with cough in patients with interstitial diseases. Therefore, interstitial disease has not been reported as a motive for patients to seek medical advice due to cough alone.(1)
External compression of the airways by tumors or arterial-venous malformations occurs but is a less frequent cause of cough.(42)
Other infrequent causes of cough are Arnolds nerve reflex cough syndrome, involving the auricular branch of the vagus nerve, which is partially responsible for external ear canal sensitivity. Simple otoscopy(43) can be used to establish the diagnosis when there is a clinical suspicion (foreign bodies or wax in the external ear canal).
Psychogenic cough is rare in adults(1) and should be considered only after all other possible diagnoses have been ruled out.
Chronic cough in children
In children, cough accounts for 2 to 3% of office visits. Asthma (at 39%), sinusitis (at 23%) and gastroesophageal reflux (at 15%) are the most frequent causes.(44) Less common causes of chronic cough, such as anomalous innominate artery, cardiac malformations, foreign bodies in the airways and aspiration should also be considered. Postinfectious cough in children seems to be related more frequently to respiratory syncytial virus, parainfluenza virus, Mycoplasma pneumonia, Chlamydia pneumonia and Bordetella pertussis.(1)
Using an algorithm for diagnosing chronic cough based on the clinical history, physical examination, most frequent causes and complemented by specific exams for the probable causes (Figure 1), it is possible to determine the etiology of chronic cough in almost 100% of the cases, thereby allowing a satisfactory response to therapy in 86 to 98% of the cases.(2,6,7,8,11,12) Postnasal drip syndrome, asthma and gastroesophageal reflux are the most frequent causes of cough in otherwise healthy, nonsmoking patients who do not use ACE inhibitors and who have normal chest radiographs. Nevertheless, the gold standard for definitive diagnosis is a positive response to therapy.
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