Eosinophilic bronchitis as a cause of chronic cough

Eosinophilic bronchitis is a recently described condition in patients with chronic cough, sputum eosinophilia, normal spirometry and no evidence of bronchial hyperreactivity. The aim of the study was to assess the causes of chronic cough and to identify the prevalence of eosinophilic bronchitis as a cause of chronic cough. Thirty-six patients [mean age 45.4 +/- 14.3 years (range 16-69 years), M/F: 4/32] with an isolated chronic cough lasting for more than 4 weeks were recruited from the outpatient clinic. In all patients, after a full history and physical examination, blood eosinophil count, eosinophilic cationic protein (ECP), serum total and specific IgE levels were measured. Spirometry, methacholine provocation test, skin prick tests, ear, nose and throat examination, induction of sputum and esophageal pH testing were performed. The mean duration of cough was 31.3 +/- 52.3 months. Sputum eosinophilia greater than 3% was present in 12 (33.3%) patients and they were diagnosed as eosinophilic bronchitis. Their induced sputum had a mean eosinophil count of 8.3% and a mean ECP level of 98.5 mg x l(-1), which were higher than the others (P=0.003, both). The diagnosis of the remaining patients were postnasal drip syndrome in eight, gastroesophageal reflux disease in eight, post-infectious cough in two and cough-variant asthma in one patient. In conclusion, eosinophilic bronchitis is an important cause of chronic cough and should be considered in the assessment of patients before regarding them as having idiopathic chronic cough.     

Bronchite à éosinophiles

Eosinophilic airway inflammation may be encountered in asthma and in non asthmatic eosinophilic bronchitis, which is a recently identified and common cause of chronic cough. Non asthmatic eosinophilic bronchitis may be differentiated from asthma by the absence of airflow limitation and of bronchial hyperreactiveness (potentially reflecting the different localization of mast cells within the airway wall). Diagnosis is based on the confirmation of eosinophilic airway inflammation, usually by induced sputum, in the absence of other causes of chronic cough or of radiological and lung function abnormality. The cough is generally improved by inhaled corticosteroids. The long-term outcome is still not known; non asthmatic eosinophilic bronchitis may lead to the onset of fixed airway obstruction or asthma.     

Bronchite à éosinophiles : (Rev Fr Allergol Immunol Clin 2008;48(3):196-200)

Eosinophilic airway inflammation may be encountered in asthma and in non asthmatic eosinophilic bronchitis, which is a recently identified and common cause of chronic cough. Non asthmatic eosinophilic bronchitis may be differentiated from asthma by the absence of airflow limitation and of bronchial hyperreactiveness (potentially reflecting the different localization of mast cells within the airway wall). Diagnosis is based on the confirmation of eosinophilic airway inflammation, usually by induced sputum, in the absence of other causes of chronic cough or of radiological and lung function abnormality. The cough is generally improved by inhaled corticosteroids. The long-term outcome is still not known; non asthmatic eosinophilic bronchitis may lead to the onset of fixed airflow obstruction or asthma.     

新疆地区不明原因慢性咳嗽的病因分布

目的观察新疆地区不明原因慢性咳嗽的病因分析。方法对于入选的慢性咳嗽患者,在询问病史和查体的基础上,进行诱导痰、肺通气功能、气道高反应性测定、X线胸片、鼻窦X线片或CT、24h食管PH值监测等检查。结果共收集慢性咳嗽患者148例,年龄17～72岁,平均咳嗽时间（64±76）个月（2～280个月）。慢性咳嗽病因依次为：嗜酸粒细胞性支气管炎33例次（22．5％）,鼻炎／鼻窦炎25例次（17．2％）,咳嗽变异性哮喘20例次（13．8％）,变异性咳嗽18例次（12．2％）,胃食管反流性咳嗽17例次（11．7％）,其他病因28例次（18．7％）,病因未明6例次（4．0％）。结论嗜酸粒细胞性支气管炎和变异性咳嗽是新疆地区慢性咳嗽的重要病因。     

Cough Due to Asthma and Nonasthmatic Eosinophilic Bronchitis

Asthma and nonasthmatic eosinophilic bronchitis are among the most common causes of chronic cough, accounting for about 25 and 10% of cases, respectively. Chronic cough due to asthma may present in isolation in which case it is known as cough-variant asthma. Nonasthmatic eosinophilic bronchitis is characterized by the presence of eosinophilic airway inflammation in the absence of variable airflow obstruction or airway hyperresponsiveness. Both conditions share many immunopathological features with the exceptions to date of mast cell infiltration into the airway smooth muscle, increased IL-13 expression, and narrowing and thickening of the airway wall, which are features reserved to asthma. In most cases the trigger that causes the cough is uncertain. However, removal of potential triggers is important to consider, in particular with respect to occupational exposure to known sensitisers. In both conditions there is subjective and objective improvement following treatment with inhaled corticosteroids, which is associated with the presence of an airway eosinophilia. Whether eosinophilic inflammation is the cause of cough or an epiphenomenon is uncertain, but the failure of anti-IL-5 to modify cough in asthma has questioned a causal association. In asthma, β-agonist theophylline, leukotriene receptor antagonist, and oral corticosteroid therapy improve cough. In noneosinophilic bronchitis, some patients require oral corticosteroids but the benefit of other additional therapies is unknown. In general, response to therapy in both conditions is very good and the limited long-term data available suggest that both usually have a benign course, although in some cases persistent airflow obstruction may occur.     

The Cough Hypersensitivity Syndrome: A Novel Paradigm for Understanding Cough

For many years patients with chronic cough have been investigated in an attempt to diagnose the cause of the cough. Here I suggest that the overwhelming majority of patients with chronic cough have a single diagnosis: cough hypersensitivity syndrome. This is demonstrated by the homogeneous nature of the clinical history and investigational results of patients attending cough clinics. The hypersensitivity facet of the syndrome is demonstrated by objective testing with capsaicin and other protussive agents. Within the cough hypersensitivity syndrome there are different phenotypes. Those patients with a predominantly Th2-type immune response will develop eosinophilic inflammation and either cough-variant asthma or eosinophilic bronchitis. Those with predominantly heartburn symptoms will have a phenotype that reflects GERD and cough. However, the similarities between the different phenotypes far outweigh differences in a unifying diagnosis of the cough hypersensitivity syndrome, providing a more rational understanding of chronic cough.     

Exhaled nitric oxide levels in patients with atopic cough and cough variant asthma

Background and objective:   Atopic cough (AC) is an established clinical entity in Japan, in which patients present with a chronic persistent non-productive cough. Exhaled nitric oxide (NO) is a biomarker of eosinophilic airway inflammation. The present study examined whether exhaled NO levels were increased in AC in comparison with cough variant asthma (CVA) and bronchial asthma (BA).
Methods:   Consecutive patients presenting with an isolated cough lasting at least 8 weeks were enrolled in the study. The aetiology of the chronic cough was determined according to the Japanese Respiratory Society guidelines for management of cough. Exhaled NO, capsaicin cough sensitivity (capsaicin concentration eliciting five or more coughs (C5)) and bronchial reversibility were measured at the patients' first visit. Bronchial responsiveness (PC20 to methacholine) was measured at their second visit following a 6-day course of bronchodilator therapy.
Results:   There were 58 patients recruited and fully investigated; of these 9 and 11 patients were diagnosed with AC and CVA, respectively, as single causes of chronic cough. Ten patients with BA who had not received corticosteroid therapy in the previous 4 weeks and who attended the same clinic in the same time period acted as controls. Exhaled NO levels in patients with AC were significantly lower than those in patients with CVA and BA. There was no significant difference in the exhaled NO levels between patients with CVA and BA.
Conclusions:   Exhaled NO may reflect eosinophilic inflammation of peripheral airways and its measurement may be useful in differentiating CVA from AC and other causes of chronic non-productive cough.     

支气管哮喘、咳嗽变异性哮喘及急性支气管炎气道反应性特点及意义

目的探讨支气管哮喘、咳嗽变异性哮喘及急性支气管炎气道反应性特点,以便为临床诊断提供依据。方法采用日本产ＡＳＴＯＧＡＰＨＴＣＫ６０００ＣＶ气道反应测定仪,以乙酰甲胆碱为气道激发剂,观察６０例支气管哮喘、５８例咳嗽变异性哮喘及３７例急性支气管炎患者气道反应性变化。结果支气管哮喘和咳嗽变异性哮喘病人气道激发试验均为阳性,哮喘病人的气道反应阈值（Ｄｍｉｎ）低于咳嗽变异性哮喘病人（Ｐ＜００５）。急性支气管炎病人中,气道激发试验３３例阴性,占８９％,４例阳性,占１１％。４例阳性急性支气管炎患者的气道反应性曲线与哮喘组及咳嗽变异性哮喘组明显不同,其Ｄｍｉｎ也显著高于哮喘组（Ｐ＜００１）及咳嗽变异性哮喘组（Ｐ＜００５）。结论气道反应性测定对于不同类型哮喘及急性支气管炎的鉴别和指导治疗具有很好的临床应用价值。     

Eosinophilic bronchitis is an important cause of chronic cough.

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 FEV(1) ([PC(20)] > 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 micrograms 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.     

Substance P-immunoreactive nerves in endobronchial biopsies in cough-variant asthma and classic asthma

BACKGROUND: Unlike classic asthma, cough-variant asthma does not show any evidence of airway obstruction. The main symptom is a dry cough with little known pathophysiology. Hypersensitivity of the cough receptors in cough-variant asthma and an increase in the sensory nerve density of the airway epithelium in persistent dry cough patients have been reported. Therefore, it is possible that there is a higher sensory nerve density in cough-variant asthma patients than in classic asthma patients. OBJECTIVES: This study was undertaken to compare the substance P (SP)-immunoreactive nerve density in mucosal biopsies of cough-variant asthma patients, classic asthma patients, and in control subjects. METHODS: Bronchoscopic biopsies were performed in 6 cough-variant asthma patients, 14 classic asthma patients, and 5 normal controls. The tissues obtained were stained immunohistochemically. The SP-immunoreactive nerve density was measured in the bronchial epithelium using a light microscope at 400 x magnification. RESULTS: SP- immunoreactive nerve density for the cough-variant asthma group was significantly higher than that of the classic asthma group (p = 0.001), and of the normal control group (p = 0.006). CONCLUSIONS: It is possible that a sensory nerve abnormality within the airway may be related to hypersensitivity of the cough receptor, and that this may be one of the pathophysiologies of cough-variant asthma.     

Eosinophils, bronchitis and asthma: pathogenesis of cough and airflow obstruction

Eosinophilic airway inflammation is commonly observed in chronic cough in patients with asthma and non-asthmatic eosinophilic bronchitis. Indeed asthma and non-asthmatic eosinophilic bronchitis are amongst the commonest causes of chronic cough accounting for about 25 and 10% of cases respectively. In most cases the trigger that causes the cough is uncertain; however removal of potential triggers is important to consider in particular with respect to occupational exposure to known sensitizers. In both conditions the cough improves subjectively and objectively following treatment with corticosteroids. This improvement is associated with the presence of an airway eosinophilia, but whether eosinophilic inflammation is the cause of cough or an epiphenomenon is uncertain. The success of anti-IL5 to reduce eosinophilic inflammation and asthma exacerbations contrasts with the lack of efficacy to modify cough in asthma and therefore challenges a causal association. Both asthma and non-asthmatic eosinophilic bronchitis can lead onto airway remodeling and result in persistent airflow obstruction. However, response to corticosteroid therapy in both conditions is generally very good and the limited long term data available suggests that both usually have a benign course. Interestingly, improvement in airway remodeling in response to anti-IL5 observed using CT imaging and analysis of sub-epithelial matrix deposition does suggest that the eosinophil may play a causal role in airway remodeling.     

Detection of Eosinophils in Hypertonic Saline-Induced Sputum in Patients with Chronic Nonproductive Cough

This study was conducted to examine (1) whether an appropriate sputum can be obtained by inducing with inhalation of hypertonic saline in patients with chronic nonproductive cough and (2) whether eosinophils can be detected in the induced sputum. Appropriate samples were obtained by the induction in 25 of 31 patients with bronchial asthma (BA), 12 of 17 patients with cough-variant asthma (CVA), 17 of 20 patients with bronchodilator-resistant cough associated with atopy (atopic cough, AC), and 23 of 25 healthy subjects. Eosinophils were detected in the successfully induced sputum in 100%, 66.6%, and 88.2% of the patients with BA, CVA, and AC, respectively. Detection of eosinophils in induced sputum may be the initial diagnostic procedure for nonproductive cough of allergic nature.     

Cough and asthma

PURPOSE OF REVIEW: The intention of this article is to discuss and place into perspective recent articles on cough and asthma. RECENT FINDINGS: Asthma continues to be a major diagnosis in most studies of cough. The first prospective study of sub-acute cough demonstrated an asthma incidence lower than that for chronic cough, a logical finding; upper airway cough syndrome often causes cough in the postinfectious state. The first prospective study of cough in infants suggested asthma to be a minor cause of cough in infants, but methodological flaws make the conclusions uncertain. Efforts to separate cough-variant asthma from classic asthma continue. One group has demonstrated that the maximal bronchoconstrictor response in cough-variant asthma is blunted when compared with classic asthma, a possible explanation for the absence of wheeze and dyspnea in cough-variant asthma. Another look at airway resistance showed a less rapid rate of rise in resistance in cough-variant asthma with increasing methacholine dosing than in classic asthma. On the biochemical front, a group has demonstrated differences in vascular endothelial growth factor, which may be the underpinnings of differences between cough-variant asthma and classic asthma. SUMMARY: Recent data suggest that cough-variant asthma is part of a continuum in the expression of asthma symptoms and in the asthmatic inflammatory response.     

不明原因慢性咳嗽的病因分布及诊断程序的建立

目的观察慢性咳嗽的病因分布,在此基础上建立慢性咳嗽的病因诊断程序。方法对于入选的慢性咳嗽患者,在询问病史和查体的基础上,进行诱导痰、肺通气功能+气道高反应性、X线胸片、鼻窦X线片或CT、24h食管pH值监测等检查,根据检查结果和治疗反应,最后确定病因诊断。结果共收集慢性咳嗽患者194例,平均年龄(41±12)岁(16～71岁),平均咳嗽时间(62±86)个月(2～487个月)。慢性咳嗽病因比例依次为:嗜酸粒细胞性支气管炎51例次(22.4%)、鼻炎/鼻窦炎39例次(17.1%)、咳嗽变异型哮喘31例次(13.6%)、变应性咳嗽28例次(12.3%)、胃食管反流性咳嗽27例次(11.8%)、其他病因43例次(18.8%),病因未明9例次(3.9%)。单一病因咳嗽者153例(82.7%),复合病因32例(17.3%)。结论慢性咳嗽的病因分布与国外相比有着较大的差别,嗜酸粒细胞性支气管炎和变应性咳嗽是慢性咳嗽的重要病因。根据上述慢性咳嗽病因分布和临床特征,提出了新的慢性咳嗽病因诊断程序。     

慢性咳嗽和白三烯受体拮抗剂

慢性咳嗽中两大重要病因为咳嗽变异性哮喘和嗜酸粒细胞性支气管炎,其病理变化为气道慢性炎症,白三烯受体拮抗剂有显著的抗炎作用,能明显改善咳嗽变异性哮喘等患者的咳嗽症状,有望成为治疗慢性咳嗽的重要药物。     

Development of chronic airway obstruction in patients with eosinophilic bronchitis: a prospective follow-up study

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, FEV(1), provocative concentration of methacholine causing a 20% fall in FEV(1), 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 FEV(1) 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 FEV(1) reduction > 20%. However, sputum eosinophilia recurred between 4 months and 24 months in 10 subjects. Mean values of FEV(1) 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.     

Eosinophilic Bronchitis

Eosinophilic bronchitis is a common and treatable cause of chronic cough. The major pathological feature is eosinophilic airway inflammation, similar to that seen in asthma. However, the associated airway dysfunction is quite different, with evidence of heightened cough reflex sensitivity, but no variable airflow obstruction or airway hyperresponsiveness. Recent evidence suggests that the differences in functional association are related to differences in localization of mast cells in airway wall, with airway smooth muscle infiltration occurring in asthma and epithelial infiltration in eosinophilic bronchitis.Diagnosis is usually made with induced sputum analysis after exclusion of other causes for chronic cough on clinical, radiological and lung function assessment. The cough responds well to inhaled corticosteroids but dose and duration of treatment remain unclear. Little is known about the natural history of this condition. However, some patients with COPD without a history of previous asthma have sputum eosinophilia, so one possibility is that some cases of eosinophilic bronchitis may develop fixed airflow obstruction. Further study of this interesting condition will increase our understanding of airway inflammation and airway responsiveness, leading to novel targets for therapeutics for both eosinophilic bronchitis and asthma.     

Eosinophilic bronchitis: clinical features, management and pathogenesis

Eosinophilic bronchitis is a common and treatable cause of chronic cough. The major pathological feature is eosinophilic airway inflammation, similar to that seen in asthma. However, the associated airway dysfunction is quite different, with evidence of heightened cough reflex sensitivity, but no variable airflow obstruction or airway hyperresponsiveness. Recent evidence suggests that the differences in functional association are related to differences in localization of mast cells in airway wall, with airway smooth muscle infiltration occurring in asthma and epithelial infiltration in eosinophilic bronchitis. Diagnosis is usually made with induced sputum analysis after exclusion of other causes for chronic cough on clinical, radiological and lung function assessment. The cough responds well to inhaled corticosteroids but dose and duration of treatment remain unclear. Little is known about the natural history of this condition. However, some patients with COPD without a history of previous asthma have sputum eosinophilia, so one possibility is that some cases of eosinophilic bronchitis may develop fixed airflow obstruction. Further study of this interesting condition will increase our understanding of airway inflammation and airway responsiveness, leading to novel targets for therapeutics for both eosinophilic bronchitis and asthma.     

嗜酸粒细胞性气道炎症和慢性咳嗽

嗜酸粒细胞性气道炎症是以气管和支气管壁存在明显嗜酸粒细胞浸润为特征的一种病理状态.哮喘、咳嗽变异性哮喘及非哮喘性嗜酸粒细胞性支气管炎是慢性咳嗽的常见病因,嗜酸粒细胞性气道炎症是其共同病理过程,提示嗜酸粒细胞性气道炎症与慢性咳嗽的发生可能有密切联系,并呈现不同的临床表型.     

Cough and asthma

Cough variant asthma and the closely related corticosteroid responsive cough syndromes eosinophilic bronchitis and atopic cough are common causes of chronic cough. The diagnosis is often not overt but detailed investigation of airway responsiveness and airway inflammation can be helpful. Cough variant asthma, eosinophilic bronchitis and atopic cough are all associated with eosinophilic airway inflammation, which is similar to that seen in non-cough predominant asthma. However, evidence of activated mast cells and increased concentrations of mast cell products appears to be confined to the conditions associated with cough, suggesting a role for mast cell degranulation in the superficial airway structures in the pathogenesis of cough. Cough variant asthma is typically corticosteroid responsive; leukotriene antagonists and antihistamines also help. Further study of this interesting asthma variant may increase our understanding of the relationship between airway inflammation and airway dysfunction.