Abstract
Eosinophilic bronchitis presents with chronic cough and sputum eosinophilia, but without the abnormalities of airway function seen in asthma. It is important to know how commonly eosinophilic bronchitis causes cough, since in contrast to cough in patients without sputum eosinophilia, the cough responds to inhaled corticosteroids. We investigated patients referred over a 2-yr period with chronic cough, using a well-established protocol with the addition of induced sputum in selected cases. Eosinophilic bronchitis was diagnosed if patients had no symptoms suggesting variable airflow obstruction, and had normal spirometric values, normal peak expiratory flow variability, no airway hyperresponsiveness (provocative concentration of methacholine producing a 20% decrease in FEV1 ([PC20] > 8 mg/ml), and sputum eosinophilia ( > 3%). Ninety-one patients with chronic cough were identified among 856 referrals. The primary diagnosis was eosinophilic bronchitis in 12 patients, rhinitis in 20, asthma in 16, post-viral-infection status in 12, and gastroesophageal reflux in seven. In a further 18 patients a diagnosis was established. The cause of chronic cough remained unexplained in six patients. In all 12 patients with eosinophilic bronchitis, the cough improved after treatment with inhaled budesonide 400 μ g twice daily, and in eight of these patients who had a follow-up sputum analysis, the eosinophil count decreased significantly, from 16.8% to 1.6%. We conclude that eosinophilic bronchitis is a common cause of chronic cough, and that sputum induction is important in the investigation of cough.
Gibson and colleagues (1, 2) have described a group of patients with corticosteroid-responsive chronic cough who had sputum evidence of an eosinophilic bronchitis but normal spirometry, no evidence of airway hyperresponsiveness (AHR), and normal peak expiratory flow (PEF) variability. The features of this condition were distinct from those of asthma, and Gibson and colleagues suggested that it should be known as eosinophilic bronchitis. It is important to know how commonly eosinophilic bronchitis causes chronic cough, since in contrast to cough in patients without sputum eosinophilia (3), the cough responds well to inhaled corticosteroids (2). Current algorithms for investigating chronic cough do not include assessment of airway inflammation, and would not allow recognition of these patients.
We have modified a well-validated protocol (4, 5) for investigating chronic cough by adding a differential inflammatory cell count on induced sputum if a diagnosis has not been reached after a history, clinical examination, chest radiography, spirometry, serial measurement of PEF, and a methacholine inhalation test. We used this modified protocol to prospectively look for evidence of eosinophilic bronchitis in new patients with chronic cough of more than 3 wk duration who were seen by a single consultant between January 1996 to December 1997.
Patients with an isolated chronic cough lasting more than 3 wk were identified from new patient referrals made between January 1996 and December 1997 to a single respiratory physician by primary care physicians in both rural and urban areas. Patients were between 28 and 76 yr of age, and other than having a chronic cough, had no clinical or radiologic evidence of significant lung disease at the time of referral. Subjects gave full informed consent to participate in the study. The protocol was approved by the Leicestershire Health Authority ethics committee.
Spirometry was done with a rolling-seal spirometer (Vitalograph, Buckingham, UK), with recording of the greater of successive readings within a 200 ml range. If the FEV1/FVC ratio was < 70%, spirometry was repeated 15 min after inhalation of 200 μg salbutamol. Allergen skin sensitivity was measured by skin prick testing with Dermatophagoides pteronyssinus, cat fur, grass pollen, and Aspergillus fumigatus solutions, with controls consisting of normal saline and histamine (Bencard, Brentford, UK). PEF was measured twice daily as the best of three expirations, using a mini-Wright peak flow meter (Clement Clarke Ltd., London, UK). Airway responsiveness was measured according to the tidal breathing method (6). Sputum was induced and processed as suggested by Pizzichini and colleagues (7). Briefly, sputum was induced with 3%, 4%, and 5% saline inhaled in sequence for 5 min via an ultrasonic nebulizer (Medix, Harlow, UK; output: 0.9 ml/ min; mass median aerodynamic diameter: 5.5 μm). After each inhalation, patients blew their noses and rinsed their mouths to minimize nasal contamination, and expectorated sputum into a sterile pot. FEV1 was measured after each inhalation, and subjects were pretreated with inhaled salbutamol in a dose of 200 μg at 10 min before sputum induction in order to minimize bronchoconstriction. Sputum free of salivary contamination was selected and was mixed with four times its volume of 0.1% dithiothreitol. Mixing was achieved by shaking with a vortex machine for 15 s, gentle aspiration in and out of a Pasteur pipette, and rocking on a bench rocker for 15 min. The sample was further diluted with an equal amount of phosphate-buffered saline (PBS), before being filtered through a 48-μm-mesh gauze and centrifuged at 2,000 rpm (790 × g) for 10 min. The cell pellet was resuspended in PBS. A total cell count was taken and cell viability was assessed with a Neubauer hemocytometer and the trypan blue exclusion method. The cell suspension was readjusted to 1 × 106 cells/ml, and 75 μl was suspended in cytocentrifuge cups and centrifuged at 450 rpm (18 × g) for 6 min. After air drying, the cytospin preparation was stained with Romanowski's stain and a differential cell count was obtained by counting > 400 nonsquamous cells.
The cause of chronic cough in each subject was investigated according to the anatomic-diagnostic protocol suggested by Irwin and colleagues (4, 5), with modifications similar to those suggested by O'Connell and coworkers (8) (Table 1, Figure 1). All patients had an initial clinical assessment consisting of a history, physical examination, chest radiograph, allergen skin prick tests, twice-daily measurement of peak expiratory flow for at least 2 wk, and, if appropriate, spirometry with reversibility studies following inhalation of 200 μg of salbutamol (Figure 1). A trial of treatment was begun only if patients had one or more symptoms suggesting an underlying diagnosis, together with at least one positive finding on examination or investigation. The clinical features and abnormalities found in the study, and the investigations and therapies used, are outlined on Table 1. Patients were followed up after 6 to 8 wk and asked if their cough had improved. The primary diagnosis was accepted if pretreatment criteria were fulfilled and the cough improved with specific therapy. In situations in which more than one disease process was thought to be contributing to the cough, therapy aimed at all potential causes was begun and the most important cause in the opinion of the responsible clinician was designated the primary diagnosis. If no initial cause for the cough could be identified, or if the initial treatment did not alleviate the cough, the patient had a methacholine inhalation test followed by sputum induction. Other investigations were dictated by the individual clinical picture (Table 1, Figure 1). Eosinophilic bronchitis was diagnosed if a patient had a cough, no symptoms suggesting variable airflow obstruction, normal spirometric values, normal peak PEF variability (percent difference of the maximum within-day amplitude of < 20% from the mean over a 2-wk period [9]), a provocative concentration of methacholine causing a 20% decrease in FEV1 (PC20) > 8 mg/ml, and sputum eosinophilia of > 3% nonsquamous cells. We chose 3% in order to be consistent with Carney and colleagues' (10) definition of eosinophilic bronchitis, and because this is > 3SD outside the normal range in our laboratory (our normal range is 0 to 1%).
| Diagnosis | History | Examination | Investigations | Treatment | ||||
|---|---|---|---|---|---|---|---|---|
| Rhinitis | Rhinorrhea, nasal obstruction, sinus pain, sneezing, nasal itch, postnasal drip | Nasal secretions, nasal or pharyngeal mucosal inflammation | Sinus X-ray/CT showing mucosal thickening and/or fluid level | Topical budesonide/BDP 100 μg twice daily. In selected cases: topical ipratropium bromide 40 μg twice daily, topical xylometazoline HCL 0.1%, oral antibiotics, oral antihistamine | ||||
| Eosinophilic bronchitis | No wheezing, dyspnea | No signs of airflow obstruction | FEV1 > 80% pred. FEV1/FVC > 75%. Maximum within-day PEF variability over 2 wk < 20%. PC20 > 8 mg/ml. Sputum eosinophil count > 3% | Inhaled budesonide/BDP 400 μg twice daily with prednisolone 30 mg daily for 14 d in selected cases | ||||
| ACE inhibitor-induced cough | Cough onset temporarily related to starting ACE inhibitor | Drug withdrawal. Substitution of alternative if appropriate. | ||||||
| Gastroesophageal reflux | Heartburn, flatulence, waterbrash | Barium swallow, endoscopy, and 24 h esophageal manometry and pH in selected cases | Weight reduction, elevation of head of bed, avoidance of eating within 2 h of bedtime, acid supression. Prokinetic agent in selected cases | |||||
| Asthma | Episodic wheezing, dyspnea, and/or chest tightness | Polyphonic expiratory wheeze | One or more of the following: > 15% increase in FEV1 after inhaled salbutamol 200 μg, maximum within-day PEF variability over 2 wk > 20%, PC20 < 8 mg/ml | Inhaled budesonide/BDP 400 μg twice daily with prednisolone 30 mg daily for 14 d in selected cases. Inhaled β2-agonist as required | ||||
| Postviral | Onset following viral upper respiratory tract infection | Observation | ||||||
| Chronic bronchitis | Productive morning cough > 3 mo/yr for more than 1 yr. Smoking history | Coarse crackles | Cessation of smoking |
Methacholine PC20 was calculated by linear interpolation of the log dose–response curve. The sputum eosinophil count was not normally distributed, and was log transformed and described as a geometric mean. Changes in sputum eosinophil count were expressed as -fold differences with a 95% confidence interval (CI).
Ninety-one patients with chronic cough were identified from 856 new referrals seen between January 1996 and December 1997 (10.6%). A diagnosis leading to successful treatment was reached in 93% of cases. Fifty-one (56%) patients had findings at presentation suggestive of a primary diagnosis, which was successfully treated in 44 (48%) patients. Four of the remaining seven patients, and the 40 (44%) patients who did not have suggestive clinical features, had a methacholine challenge and sputum induction. This led to a diagnosis in a further 20 patients. The remaining 27 patients had further investigations, resulting in a diagnosis in 21 cases, and thus leaving six (7%) patients with unexplained cough (Figure 1). Ten patients (11%) were thought to have more than one explanation for their cough. In seven patients gastroesophageal reflux was one of the codiagnoses. Sputum suitable for processing was obtained from 40 of the 44 patients who had sputum induction. Of the four patients in whom sputum induction was unsuccessful, two had AHR and were diagnosed as having asthma. The other two patients had no explanation for their cough. All of the patients with unexplained cough had empirical treatment directed toward asthma, eosinophilic bronchitis, rhinitis, and gastroesophageal reflux, without clinical improvement in any case.
The causes of cough are shown in Table 2. Eosinophilic bronchitis was the primary diagnosis for cough in 12 (13.2%) patients. The characteristics of these patients are shown in Table 3. After treatment with budesonide 400 μg given via a turbohaler, cough improved in all 12 patients. In eight patients repeat sputum induction was performed from 4 to 8 wk after treatment was begun, and showed a significant decrease in the sputum eosinophil count, from a geometric mean of 16.8% to 1.6% (10.7-fold difference; 95% CI: 4.1 to 27.7; p < 0.01).
| Primary Cause of Cough | No. of Patients (%) | |
|---|---|---|
| Rhinitis | 20 (24%) | |
| Asthma | 16 (17.6%) | |
| Postviral | 12 (13.2%) | |
| Eosinophilic bronchitis | 12 (13.2%) | |
| Gastroesophageal reflux | 7 (7.7%) | |
| Unexplained | 6 (6.6%) | |
| COPD | 6 (6.6%) | |
| Bronchiectasis | 5 (5.5%) | |
| ACE inhibitor-induced cough | 4 (4.4%) | |
| Lung cancer | 2 (2.2%) | |
| Cryptogenic fibrosing alveolitis | 1 (1.1%) |
| No. of subjects | 12 | |
| Age* | 52 (28–76) | |
| Male | 2 | |
| FEV1, % predicted* | 107 (95–133) | |
| FEV1/FVC, %* | 80 (72–94) | |
| Methacholine PC20 < 16, mg/ml | 0 | |
| Atopy | 5 | |
| Sputum eosinophils, %*,† | 10.5 (4.7–38) | |
| Peripheral blood eosinophil count (cells × 109/l)* | 0.18 (0.09–1.1) | |
| Symptoms of rhinitis | 4 | |
| Cough duration, months* | 26.3 (2–120) | |
| Current smokers | 0 | |
| Pack-yr > 5 | 1 |
We successfully identified a cause or causes for chronic cough in most patients, confirming the diagnostic value of the anatomic-diagnostic approach suggested by Irwin and colleagues (4). Our treatment success rate of 93% was very similar to those reported by Irwin and colleagues (4, 5) and others (11) in a similar patient population, and was slightly higher than that reported by O'Connell and coworkers (8) and McGarvey and associates (12) in patients referred to a tertiary referral center. We have confirmed that rhinitis and gastroesophageal reflux are common causes of chronic cough in this clinical setting. Our modified protocol allowed us to recognize eosinophilic bronchitis in 13% of patients. This estimate of the incidence of eosinophilic bronchitis is similar to that reported by Carney and associates (10), who used diagnostic criteria identical to ours and found three cases in 30 patients with chronic cough.
Our data and those of Carney and associates suggest that assessment of airway inflammation is an important addition to the algorithm for investigating chronic cough. We chose to assess airway inflammation with induced sputum, since this method is noninvasive and has been shown to be successful in the majority of patients with asthma (13). Sputum differential cell counts have been shown to be valid and repeatable in patients with asthma (7). We have shown that sputum induction is also successful in most patients with chronic cough, and that sputum eosinophilia is the only significant finding in 13% of cases of such cough. Although we chose to analyze induced sputum, spontaneous sputum could be used if patients have a productive cough. Differential cell counts are similar with the two methods, but the cell viability is greater and squamous cell contamination less with induced sputum, resulting in better quality cytospin preparations (14).
The patients with eosinophilic bronchitis in our study presented with a cough without wheezing, dyspnea, or objective evidence of variable airflow obstruction, and thus did not meet conventional criteria for the diagnosis of asthma (13). They had a subjective improvement in their cough and a significant decrease in their sputum eosinophil count after treatment with inhaled corticosteroids, which resembled the findings of Gibson and coworkers (3). We did not formally assess the time course of the response to corticosteroids, although anecdotally, improvement began 2 to 3 wk after inhaled corticosteroids were begun.
Most previous studies have not identified patients with eosinophilic bronchitis as a distinct subgroup among patients with chronic cough. Although one cannot discount the possibility that eosinophilic bronchitis is a new condition, we feel that the failure to recognize it in previous studies is more likely to reflect differences in referral pattern, or less stringent criteria for the diagnosis of asthma. Many patients, particularly tertiary referrals, are likely to have received a trial of corticosteroids before referral, and those patients who responded to corticosteroids may have been diagnosed as having asthma before further tests were done or irrespective of the results of objective tests of variable airflow obstruction or airway responsiveness. We diagnosed asthma in patients with consistent symptoms and objective evidence of variable airflow obstruction and/or AHR. Our criteria for an objective demonstration of variable airflow obstruction and AHR are widely accepted (6, 9, 15), and particularly in the case of methacholine inhalation testing are sensitive markers of currently symptomatic asthma. In common with previous reports, our diagnosis of asthma was subjectively supported by successful response to treatment (12, 16). It has been proposed that a negative histamine or methacholine challenge rules out asthma and therefore obviates the need for a trial of inhaled steroids (12). We agree that normal airway responsiveness makes a diagnosis of asthma very unlikely, but disagree that this precludes the need for a trial of inhaled corticosteroids, since this approach would deny effective treatment to a significant number of patients.
Typically, the patients with eosinophilic bronchitis in our study presented in middle age with a dry cough or a cough productive of small amounts of viscid sputum in the morning. Few were smokers, perhaps reflecting a selection bias, since primary-care physicians are likely to attribute a chronic cough in smokers to chronic bronchitis, and would therefore not refer these patients for a specialist's opinion. Four of our patients with eosinophilic bronchitis had symptoms of rhinitis, although the absence of other clinical or radiographic features and lack of improvement in cough following treatment of rhinitis by their primary-care physicians lead us to perform further investigations and to conclude that eosinophilic bronchitis was the primary cause of cough in these patients. We have not studied the natural history of this condition, but the long duration of symptoms before referral suggests that it is a chronic problem.
The recognition of patients with sputum eosinophilia without variable airflow obstruction (eosinophilic bronchitis) has important implications for understanding the role of airway inflammation in asthma, and suggests that in some cases, the conventional view of a direct relationship between eosinophilic airway inflammation and AHR (17) is overly simplistic. Possible explanations for the relative absence of a functional effect of eosinophilic airway inflammation in our patients include differences in the site or state of activation of the inflammatory response. An alternative possibility is that AHR is increased by the airway inflammation in eosinophilic bronchitis, but stays within the normal range because baseline airway responsiveness is far to the right of the normal range. We have recently observed such a phenomenon in a patient with eosinophilic bronchitis studied during an exacerbation of eosinophilic airway inflammation (18). Further research is required into the cause of and relationship between airway inflammation, AHR, and cough in patients with eosinophilic bronchitis.
We conclude that eosinophilic bronchitis is a common cause of chronic cough in patients referred for a specialist's opinion. Recognition of patients with a cough caused by eosinophilic bronchitis is important, since effective treatment is possible. We suggest that assessment of airway inflammation be added as an important component of the investigation of cough.
The authors thank the staff of the Respiratory Physiology Department, Glenfield Hospital, for help with the sputum inductions, and the Department of Histopathology for help with sputum processing.
Supported by a grant from Glenfield Hospital Local Research Committee and Astra Charnwood, Loughborough, UK.
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