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(Chest. 2004;125:1998-2004.)
© 2004 American College of Chest Physicians

Development of Chronic Airway Obstruction in Patients With Eosinophilic Bronchitis*

A Prospective Follow-up Study

Sung-Woo Park, MD; Young Mok Lee, MD; An Soo Jang, MD; June Hyuk Lee, MD; Young Hwangbo, MD; Do Jin Kim, MD and Choon-Sik Park, MD

* From the Asthma and Allergy Research Group, Soonchunhyang University Hospital, Bucheon, Korea.

Correspondence to: Choon-Sik Park, MD, Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, 1174, Jung Dong, Wonmi Ku, Bucheon, Gyeonggi Do, 420–021, Korea; e-mail: mdcspark{at}unitel.co.kr


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Eosinophilic bronchitis (EB) presents as a chronic cough and sputum eosinophilia without airflow limitation or bronchial hyperreactivity. Its long-term clinical course remains unknown. This study evaluated how frequently EB recurs and whether it develops chronic airway obstruction.

Design: This study was a prospective analysis.

Methods: Cough severity, FEV1, provocative concentration of methacholine causing a 20% fall in FEV1, and sputum eosinophil percentages were serially measured in 36 subjects for up to 48 months. All subjects inhaled corticosteroids until cough subsided.

Results: Five of the twenty four follow-up subjects (21%) had a recurrent episode of EB 4 to 6 months after disappearance of the first episode of EB (recurrent eosinophilic bronchitis). Progressive FEV1 reduction > 20% was observed in three of the subjects, including a subject with asthma developing at the ninth month. Nineteen subjects had no recurrence of cough (nonrecurrent eosinophilic bronchitis) and no progressive FEV1 reduction > 20%. However, sputum eosinophilia recurred between 4 months and 24 months in 10 subjects. Mean values of FEV1 at the ninth and 12th months of the study were significantly lower in the recurrent eosinophilic bronchitis group than in the nonrecurrent eosinophilic bronchitis group (p < 0.01).

Conclusion: These results suggest that repeated episode of EB is associated with the development of chronic airflow obstruction, including asthma.

Key Words: asthma • bronchitis • chronic airflow obstruction • eosinophil • sputum


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Asthma is a chronic eosinophilic airway inflammation that is associated with an increased number of mast cells and T-lymphocytes in the airways, which leads to reversible airflow limitation and bronchial hyperreactivity (BHR).1 However, there is a poorly defined group of patients with similar levels of eosinophilic airway inflammation, but a normal airflow and no evidence of BHR.2 Eosinophilic bronchitis (EB) is a common cause of chronic cough syndrome.3456 Moreover, because of a similarity in terms of the airway inflammation pattern and the response to inhaled steroids,247 EB could be regarded as a mild form of asthma, as EB shows BHR less frequently in response to adenosine monophosphate challenge than asthma.78 Different levels of prostaglandin D and histamine in the airways9 may be responsible for the difference in the airway responsiveness in the two conditions. The absence of BHR in EB may be due to the normal number of mast cells in airway smooth muscle as compared to asthma.10 However, the concept that EB is a mild form of asthma remains unproven, probably because its long-term natural course has not been evaluated. We previously observed relapse of EB-associated cough accompanied by a transient increase in the eosinophil percentages in the sputum of three subjects with EB during a 6-month follow-up.5 Hancox et al11 reviewed nine patients with EB at 5 to 10 years after diagnosis, and reported that one subject acquired clinical symptoms of mild asthma, but this was not proven objectively using lung function testing.

Sputum eosinophilia is not indicative of asthma or EB. Some patients with COPD, without a history of asthma, have sputum eosinophilia.12 In addition, it is possible that EB is an early manifestation of COPD, based on a patient with EB in whom irreversible airflow obstruction developed.13 These results suggest that EB can develop into COPD. To resolve these issues, prospective follow-up monitoring of the clinical and physiologic parameters in more subjects with EB is required. This prompted us to measure longitudinal changes in cough severity, prebronchodilator and postbronchodilator FEV1, provocative concentration of methacholine causing a 20% fall in FEV1 (PC20), and eosinophil percentages in sputum over a period of up to 48 months, to evaluate how many patients had a recurrent episode of EB, and to determine whether clinical or physiologic manifestations of chronic airway obstruction developed, including asthma.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients complaining of an isolated chronic cough of > 4 weeks in duration were referred to our tertiary university hospital. They were not treated with inhaled or systemic steroids. On the first day of the visit, a clinical history was obtained using a physician-administered questionnaire.14 Chest radiography and aeroallergen skin-prick tests were performed, and blood was sampled for differential cell counts and total IgE measurement. The study subjects were then asked to produce sputum by hypertonic saline solution aerosol induction.15 On the second visit, PC20 was measured. EB was diagnosed using the following criteria: (1) no abnormality in the lung parenchyma on simple chest posteroanterior radiograph; (2) FEV1 percentage and FVC > 75% of the predicted value with a negative response to a short-acting bronchodilator (< 15% of FEV1); (3) an absence of airway hyperreactivity (> 8 mg/mL PC20); and (4) sputum eosinophilia (> 3%). Patients with EB were prescribed one of two inhaled corticosteroids (budesonide, 800 µg/d, or the equivalent dose of fluticasone). If the cough then subsided completely for 2 weeks, the subjects were asked to stop the inhaled steroid. Physical and laboratory examinations were measured longitudinally during follow-up at 1, 2, 4, 6, 9, 12, 18, 24, 30, 36, and 48 months, and whenever the cough reappeared. PC20 was measured again during the second year of follow-up when the subject was cough free. The Ethics Committee of Soonchunhyang University Hospital approved the study, and informed written consent was obtained from each subject.

Procedures
Cough severity was rated by frequency and severity as follows: no cough (score 0); less than daily and not disturbing daytime activity (score 1); disturbing daytime activities (score 2); present daily and disturbing daytime activities (score 3); and present daily and causing sleep disturbance (score 4). Control of a cough was defined as when the cough score was lower than one. Spirometry was performed using a rolling-seal spirometer (SensorMedics max 22; SensorMedics; Yorba Linda, CA). A positive response to a bronchodilator was defined as when two salbutamol inhalations (100 µg/ inhalation) increased the FEV1 by > 15%. PC20 was conducted using the method of Juniper et al.16 Atopy was determined by skin-prick tests using 48 common inhalant allergens, including dust mites (Dermatophagoides farinae and Dermatophagoides pteronyssinus), cat fur, dog fur, fungus, cockroach, grass, tree, and ragweed pollen (Bencard; Brentford, UK). The test result was regarded as positive when the wheal size was equal to or larger than that of the histamine control. Total and differential cell counts of peripheral blood leukocytes were automatically analyzed using a Coulter GEN-S system (Beckman Coulter Corporation; Miami, FL). IgE was measured by radioimmunoassay. Sputum was induced by inhaling increasing concentrations (3%, 4%, and 5%) of hypertonic saline solution as an aerosol, as described by Pin et al.15 Freshly expectorated sputum was processed as described by Pizzichini et al.17 Briefly, the more opaque and gelatinous portions were treated by adding eight volumes of 0.05% dithiothreitol (Sputolysin; Calbiochem Corporation; San Diego, CA) in Dulbecco phosphate-buffered saline solution. The mixture was filtered through a nylon mesh with 48-µm pores (BNSH; Thompson; Scarborough, ON, Canada). The homogenized sample was then spun in a cytocentrifuge and stained using Diff-Quik solution (American Scientific Products; Chicago, IL). Cell viability was assessed using trypan blue exclusion. Two investigators each differentiated 500 cells. The sputum samples were examined to determine whether they contained < 10% squamous epithelial cells. The sputum samples were regarded as adequate for analysis when they contained < 10% squamous epithelial cells.

Data Analysis
The clinical characteristics and physiologic data are presented as means ± SD. Differences between groups were compared using the nonparametric Kruskal-Wallis H test for continuous data; if found significant, the Mann-Whitney U test was applied to compare any two groups. Logistic regression tests were used to identify which factor affected the recurrence of cough. Repeated-measures analysis of variance was used to compare the time-dependent change in FEV1 between the recurrent eosinophilic bronchitis group (RG) and the nonrecurrent eosinophilic bronchitis group (NRG). We excluded patients with missing data from this analysis. A Fisher exact test was used to evaluate associations between study groups and proportion of FEV1 reduction > 20%; p < 0.05 was considered statistically significant. Statistical analysis was completed using a statistical program (SPSS/PC+; SPSS; Chicago, IL).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Clinical Characteristics
Of the patients referred for a chronic cough, 36 subjects received a diagnosis of EB. The clinical characteristics of the study subjects are summarized in Table 1 . Their ages ranged from the second to the sixth decade. Cough scores at the initial visit were either 3 or 4. Cough duration ranged from 1 to 18 months. Thirteen subjects had atopy. Eleven subjects responded to D farinae or D pteronyssinus, one subject to Aspergillus species, and another subject to both mugwort and ragweed pollens. The cough of the subject atopic to mugwort and ragweed was not associated with the pollen season. Initial values of FEV1 and FVC were > 75% of the predicted value in all study subjects. Postbronchodilator increases in FEV1 percentage were < 15% in all study subjects. PC20 was > 25 mg/mL in all subjects except one, who had a PC20 of 12.9 mg/mL.


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  		Table 1. Demographic and Physiologic Profiles of the Study Subjects*

 
Clinical Course of Eosinophilic Bronchitis During the Follow-up Period
The cough disappeared in 75% (27 study subjects) within 2 months of receiving inhaled steroids, and in all subjects within 4 months (Fig 1 ). The numbers of subjects followed up with lung function tests and symptom scores were 24, 24, 8, 6, and 2 at 6, 12, 24, 36, and 48 months, respectively, and sputum eligible for analysis was obtained from 20, 12, 6, 4, and 2 subjects at the same times. A recurrent episode of EB with a cough score > 1 and sputum eosinophilia > 3% occurred in five patients in the fourth (n = 4) and sixth (n = 1) months (Fig 2 , arrowheads) [RG group]. Three of the subjects experienced a second episode of eosinophilic bronchitis in the ninth, 18th, or 24th months of the study, respectively (Fig 2, arrows). The second episode of EB that occurred in the ninth month was accompanied by asthma symptoms and a decreased FEV1 of up to 55% of the predicted value. The other two subjects experienced no further recurrence of EB during follow-up periods of 6 months and 24 months after the second episode of EB (Fig 2).



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  		Figure 1. Time-dependent changes of cough and EB recurrence. Cough disappeared in 75% of the study subjects within 2 months and in all subjects within 4 months. EB recurred at the fourth month and sixth month of follow-up. Total recurrence rate of EB during the follow-up period was 21%.

 


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  		Figure 2. Time-dependent changes of cough score, sputum eosinophil percentage, and FEV1 percentage of predicted (%pred) in the RG of EB. Recurrent cough with sputum eosinophilia > 3% occurred after withdrawal of the inhaled steroid (arrowheads). Three subjects experienced second episode of recurrent eosinophilic bronchitis (arrows). Wheezy dyspnea developed in one subject with a marked deterioration of FEV1 (open arrow). In two subjects, FEV1 was decreased up to 27% and 37% at maximum (double arrowheads), but wheeze did not develop.

 
Nineteen subjects did not experience a recurrent cough over follow-up periods ranging from 6 to 48 months (NRG group). However, sputum eosinophilia > 3% recurred in 10 of the patients in this group after the initial cough had been controlled (Table 1). The other 12 subjects dropped out of the study within the first 4 months. Their symptom scores were 0 on their last visits. Their demographic and physiologic parameters were comparable with those of the other groups, except for age (Table 1). The mean age of the RG group was higher than that of the dropped group (DG) [p < 0.05]. There was no significant predictive variable for the recurrence of eosinophilic bronchitis when sex, age, atopy, initial cough score, initial sputum eosinophil percentage, and smoking were analyzed using logistic regression (data not shown).

The initial sputum eosinophil percentage did not differ between the groups. The eosinophil percentages decreased markedly at the 1-month follow-up in the RG, NRG, and DG (Table 1). Concomitantly, cough severity also decreased markedly in the three groups (Table 1). Of the RG subjects, a 59-year-old nonsmoker acquired asthma symptoms during the ninth month with a marked decrease in FEV1 (Fig 2, open arrow). He had a cough of 2-months in duration before the study, was nonatopic, and well controlled by an inhaled steroid with a sputum eosinophil percentage reduction to < 3% at the 1-month follow-up. His cough recurred in the fourth month of the study in concert with an increase in the sputum eosinophil count to 16.5%. Once again, inhaled steroids controlled the recurrent cough. However, wheezy dyspnea developed in the ninth month with an FEV1 reduction to 55% of the predicted value and a positive bronchodilator response (18%). Readministration of the inhaled steroid relieved the asthma symptoms, improved FEV1, and decreased the sputum eosinophil percentage. Progressive FEV1 reduction > 20% was observed in three of five recurrent eosinophilic bronchitis subjects including the subject in whom asthma developed. However, there was no progressive FEV1 reduction > 20% in the 19 subjects with nonrecurrent eosinophilic bronchitis. There was a statistical difference between RG and NRG with respect to the occurrence of FEV1 reduction > 20% (Table 2 ) [p < 0.01].


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  		Table 2. Association of FEV1 Reduction by Recurrent and Nonrecurrent Eosinophilic Bronchitis*

 
Comparison of Time-Dependent Changes of FEV1 Between the RG and NRG
Longitudinal changes in the FEV1 were compared between the RG and NRG over the follow-up period. In the repeated-measures analysis of variance, there was a significant interaction between follow-up month and study groups (RG and NRG) in FEV1 (p = 0.029), and the means of FEV1 at the ninth and twelfth months of the study were significantly lower in the RG than in the NRG, while the means of initial FEV1 were similar between the two groups (p < 0.01). These results suggest that a recurrent episode of EB is associated with progressive deterioration of the airflow rate. The PC20 was remeasured during cough-free periods during the second year of the study and was > 25 mg/mL in 19 subjects, including 4 of the 5 RG subjects, excluding the subject in whom asthma developed.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, EB recurred in five study subjects (21%) within 4 months of stopping inhaled steroids. Moreover, two of these five subjects had multiple recurrent episodes of EB. This suggests that a small number of subjects with EB have a recurrence within 4 months of withdrawing inhaled steroids. Furthermore, repeated recurrence seems to be relatively frequent. In addition, one subject in the RG acquired the typical symptoms and physiologic changes associated with asthma 5 months after EB first recurred. Hancox et al11 retrospectively followed up 12 patients with EB for 5 to 10 years, and found that one subject acquired asthma symptoms, although this was not confirmed objectively using spirometry. They also observed four cases of recurrent cough, which were triggered by gastroesophageal reflux, postnasal drip, or bronchiectasis, but not by recurrent EB. Puolijoki and Lahdensuo18 reported that 16% of patients with chronic cough syndrome acquired asthma during a mean follow-up of 4.4 years; however, they did not analyze the cellular composition of the sputum. It is not known how many EB patients were included in their study. Although the dropout rate was high in our study, to our knowledge, our observation is the first prospective observation of EB recurrence and asthma development in EB to be documented with sputum and lung function analyses.

Eosinophilic airway inflammation is closely related to cough severity in EB.19 In our study, cough severity and eosinophil percentage at the initial visit were concomitantly decreased at the 1-month follow-up, when inhaled steroids were administered. This suggests that cough relief is closely related with the reduction in eosinophils in the sputum. However, our data in part contradict the association between sputum eosinophilia and cough development. Asymptomatic sputum eosinophilia (> 3%) reappeared between the fourth and 24th months of follow-up in 10 of the NRG subjects. They did not require inhaled steroids to control sputum eosinophilia. This indicates that eosinophilic inflammation is not always related to cough development in EB. The dissociation between lower respiratory symptoms and airway eosinophilia is supported by an observation in patients with nasal polyposis,20 who have airway hyperreactivity and eosinophilic bronchial inflammation levels that are similar to those of asthmatic patients, but do not have lower respiratory symptoms. Combined with our findings, these results suggest that cough development is a consequence of other contributory factors in addition to the presence of eosinophilia in the airways.

Given that sputum eosinophilia reflects eosinophilic airway inflammation well, which is a determinant of asthma severity1921 and airflow limitation in COPD,22 subjects with recurrent eosinophilic airway inflammation may have a reduced FEV1 during recurrence. We observed that the mean of initial FEV1 was similar in the RG and the NRG, and there was a significant interaction between follow-up month and study groups (RG and NRG) in FEV1 (p < 0.05), and the means of FEV1 were significantly lower in the RG than in the NRG at ninth and 12th months (Fig 3 ) [p < 0.01]. Progressive FEV1 reduction > 20% was observed in three of the five subjects with recurrent eosinophilic bronchitis. However, there was no progressive FEV1 reduction > 20% in the 19 nonrecurrent eosinophilic bronchitis subjects (Table 2) [p < 0.01]. This suggests that recurrent eosinophilic bronchitis is accompanied by deterioration in the airflow rate. Based on these findings, the possibility that some subjects with a recurrent episode of EB have a component of asthma or chronic asthmatic bronchitis should be considered. Since all of the subjects in the RG in our study were nonsmokers, smoking was not the cause of their FEV1 deterioration or the reappearance of sputum eosinophilia at follow-up. Given that sputum eosinophilia is observed in individuals with stable COPD who do not currently smoke,22 the possibility that the RG subjects in our study had a component of chronic bronchitis cannot be excluded.



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  		Figure 3. Time-dependent changes of FEV1 in the NRG ({blacksquare}) and RG (•). FEV1 values were significantly lower in the RG than the NRG at the ninth and 12th month of the study period. Data were mean ± SEM *p < 0.01 compared with the NRG.

 
The relationship between BHR and airway eosinophilia is well established in asthma.23 In this study, PC20 was measured during the second year of the study and was > 25 mg/mL in all of the subjects. It is not known why airway hyperreactivity is absent in EB. A morphometric and cellular analysis revealed that basement membrane thickness and the numbers of eosinophils, mast cells, and T-lymphocytes in the submucosa were comparable in EB and asthma.10 In addition, no differences in expression of eosinophil-active cytokines, chemokines, and activation markers on T-cells and exhaled nitric oxide have been found among individuals with these conditions.2425 The only difference found was that mast cell infiltration in smooth muscle was significantly higher in asthma than in EB and normal control subjects. Therefore, a lack of mast cells in smooth muscle is a major contributory factor that does not induce airway hyperreactivity in EB.10 The absence of eosinophil-mediated degranulation in EB, as in chronic bronchitis, may be another reason for the absence of BHR in EB. In chronic bronchitis, the number of eosinophils infiltrating the mucosa is similar to that found in asthma, but fewer cells in the airway are degranulated.26 Sputum cysteinyl leukotriene and eosinophilic cationic protein levels in EB are comparable with those in asthma,9 which indicates the same degree of degranulation in the airways in EB as in asthma.

In conclusion, many individuals with EB have a benign clinical course and no relapse. However, sputum eosinophilia and cough recur in a number of subjects with EB. Follow-up mean value of FEV1 over 12 months was significantly reduced in the subjects with recurrent EB, but not with nonrecurrent EB. Based on these findings, recurrent episodes of EB may be a risk factor for the development of chronic airway obstruction.


   Footnotes
 
Abbreviations: BHR = bronchial hyperreactivity; DG = dropped group; EB = eosinophilic bronchitis; NRG = non-recurrent eosinophilic bronchitis group; PC20 = provocative concentration of methacholine causing a 20% fall in FEV1; RG = recurrent eosinophilic bronchitis group

This study was supported by a grant of the Korea Health 21 R & D Project. Ministry of Health & Welfare, Rupublic of Korea (01-PJ3-PG6–01GN04–0003).

Received for publication October 7, 2003. Accepted for publication January 12, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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