Case of eosinophilic bronchitis and bronchiolitis associated with increased level of serum CEA in asthmatics]

A 50-year-old asthmatic woman showed peripheral blood eosinophilia, significantly increased level of CEA in serum (102.5ng/ml), and atelectasis of the right middle lobe on chest radiograph and CT. The level of CEA subsequently increased further, and then decreased with systemic corticosteroid therapy. Pathological findings of surgically biopsied lung showed eosinophilic broncho-bronchiolitis, without malignant cells. Two years later, chest CT demonstrated various findings such as mucoid impaction, peripheral bronchiectasis and centrilobular nodules, but allergic bronchopulmonary mycosis was not proved. These findings suggest that the eosinophilic bronchiolar inflammation in bronchial asthma caused an increase in serum CEA levels and various findings on chest CT.     

Small airways disease in asthma

A mounting body of physiologic and pathologic evidence indicates that asthma involves the central and the more distal airways. In patients with asthma, the peripheral lung accounts for a significant portion of airway resistance and, similar to the large airways, the small airways have been shown to be hyperresponsive to nonspecific stimuli, such as methacholine. Cellular inflammation, consisting of an infiltrate rich with lymphocytes and eosinophils, is present in the small airways of patients with asthma and may be more intense than that observed in the large airways. Clinical assessment of the peripheral airways continues to be a challenge, and new techniques, such as quantitative analysis of chest CT images, have proven to be useful research tools. The recognition of small airways involvement in asthma has clinical relevance, as new formulations of inhaled corticosteroids with smaller particle aerosols may be more effective in addressing this component of asthma.     

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.     

The role of small airway inflammation in asthma.

Although inflammation in the large central airways has been the subject of numerous asthma studies, inflammation in the small distal airways remained largely unexamined because of the relative inaccessibility of these structures. However, fiberoptic bronchoscopy, combining endobronchial and transbronchial biopsy, now allows specimens to be obtained from both proximal and distal areas of the lung. Newly refined morphometric and immunocytochemical techniques have been applied to both autopsy and lung biopsy specimens. Together, these technological changes have had a profound impact on the study of small airway inflammation. Now, it is understood that the asthma-associated inflammation evident in the large airways occurs in the distal airways as well. The inflammatory process in the two regions has related features: infiltrates contain activated T lymphocytes and eosinophils, increased mucus plugging, and smooth muscle hyperplasia can be observed. Although the similarities are pronounced, inflammation in the small airways differs in important ways from large airway inflammation. The eosinophilic infiltration that occurs throughout the asthmatic lung also is active in the small airways. The contribution of small airway inflammation to deficits in pulmonary function has been clarified by thoracic high-resolution computed tomography imaging. Results of such imaging suggest that the distal airways are a major site of airway obstruction in patients with asthma and may play a significant role in airway hyperresponsiveness; both disorders are cardinal features of asthma. In addition, functional bronchoscopic studies of the small airways in asthma patients have found high peripheral airflow resistance, even when lung function appears normal. Current formulations of inhaled anti-inflammatory medications, particularly corticosteroids administered by metered dose inhalers using chlorofluorocarbon propellants, treat the proximal airways more effectively than the distal airways. However, some new formulations of inhaled steroids that utilize hydrofluoroalkane propellants produce aerosols of smaller average particle size, with greater penetration into the peripheral airways. Their potential to treat inflammation at peripheral sites may account for the significant improvements in asthma outcomes that have been reported in clinical trials of these new formulations.     

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.     

A case of eosinophilic bronchiolitis complicated with eosinophilic sinusitis]

A 42-year-old man was admitted to our hospital, complaining of dyspnea and cough for six months. Chest CT demonstrated thickening of the bronchial walls and some centrilobular nodules. From the laboratory data and the clinical course, he was first suspected to have bronchial asthma. However, it was necessary to rule out bronchiolitis due to other causes, because he had no previous asthma history and also because of the CT findings. We performed surgical lung biopsy to make a definite diagnosis. The pathological findings revealed eosinophilic bronchiolitis. While dyspnea and the eosinophilic nasal polyp improved by treatment with oral steroid therapy, the eosionophilic sinusitis and bronchiolitis relapsed after steroid tapering. Improvement and relapse of nasal and lower airway symptoms were synchronously observed. Eosinophilic bronchiolitis and eosionophilic sinusitis in this case may be considered to be a category of airway eosinophilic inflammation.     

High-resolution CT findings in patients with near-fatal asthma: comparison of patients with mild-to-severe asthma and normal control subjects and changes in airway abnormalities following steroid treatment

STUDY OBJECTIVES: Extensive airway inflammation and excessive mucus production are implicated in deaths from asthma. High-resolution CT (HRCT) can be used to image both large and small airway abnormalities in asthmatics. The aims of this study were to clarify the distinction of HRCT features between near-fatal asthma (NFA) and non-NFA, and to evaluate serial follow-up HRCT scans of patients with NFA. PATIENTS AND DESIGN: Abnormalities of the large airway (bronchial wall thickness) and small airways (prominence of centrilobular structures and air trapping) were measured semiquantitatively on HRCT scans of 24 non-NFA, 16 NFA, and 16 control subjects. In addition, these abnormalities were reevaluated after intensive and relatively long-term (> 6 months) treatment with inhaled corticosteroids. RESULTS: Prominence of centrilobular structures was observed in 36% of mild asthma cases, in 70% of moderate-to-severe asthma cases, and in 100% of NFA cases. Prominence of centrilobular structures, but neither bronchial wall thickness nor the area of air trapping, was significantly increased in NFA, as compared with mild or moderate-to-severe asthma (p < 0.05). In the seven non-NFA and five NFA patients who underwent follow-up HRCT scans, only bronchial wall thickness was decreased significantly in the NFA cases (p < 0.05), while bronchial wall thickness and the prominence of centrilobular structures were significantly decreased in the non-NFA cases. These small airway abnormalities were partially reversible in the both groups. Residual prominence of centrilobular structures after long-term inhaled corticosteroid treatment was significantly higher in NFA than non-NFA patients. CONCLUSIONS: The results of our study indicate that extensive small airway abnormalities may be associated with NFA, and that these abnormalities are partially reversible after the successful control of asthma symptoms.     

A case of eosinophilic lung disease presenting asthma-like symptoms and centrilobular shadows in both lung fields]

This case, in a 23-year-old man presenting with cough, sputum, dyspnea on effort and wheezing, had been diagnosed as bronchial asthma at another hospital. Because inhaled steroid and theophylline were far from effective, he was admitted to our hospital for further evaluation. A blood test revealed marked eosinophilia. Chest radiography showed diffuse, small nodular shadows in both lung fields, and a chest CT scan demonstrated diffuse centrilobular nodules and thickening of the bronchi and bronchioles. A spirometric test showed obstructive and restrictive ventilatory impairment, but the depressed forced vital capacity failed to show improvement in response to bronchodilator inhalation, discouraging a diagnosis of asthma. Eosinophilic lung disease with prominent eosinophilic bronchiolitis was diagnosed on the basis of BAL eosinophilia and thoracoscopic lung biopsy findings. The symptoms and blood eosinophilia were responsive to administration of oral prednisolone (30 mg daily); radiographic and CT findings also showed improvement. This case showed a marked similarity to the recently reported "eosinophilic bronchiolitis", and was probably not a type of bronchial asthma.     

Cough in Asthma Is due to Eosinophilic Airway Inflammation: A Pro/Con Debate

Multiple prospective studies have demonstrated that asthma is among the most common etiologies of chronic cough, along with upper-airway cough syndrome (formerly known as postnasal drip syndrome) and gastroesophageal reflux disease. More recently, the entity of nonasthmatic eosinophilic bronchitis has been appreciated as a significant cause of chronic cough worldwide. Chronic cough associated with both of these conditions typically responds well to therapy with systemic or inhaled corticosteroids, thus leading to a general assumption that the suppression of eosinophilic airway inflammation explains the improvement in cough. However, some recent studies challenge a causal relationship between eosinophilic airway inflammation and cough in asthmatics. The 4th American Cough Conference, held in New York in June 2013, provided an ideal forum for discussion and debate of this issue between two internationally recognized experts in the field of asthma and chronic cough.     

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.     

Exhaled nitric oxide: A test for diagnosis and control of asthma?

The fractional concentration of nitric oxide (FE_NO) in exhaled breath is a noninvasive marker of airway inflammation in asthma. The precise role of FE_NO in the asthma management algorithm has not been defined. However, there are compelling data for use of FE_NO for diagnosing asthma, assessing control and severity, titrating inhaled corticosteroids, and detecting ongoing airway inflammation. This article reviews the biology of nitric oxide in airway pathology and its role in asthma.     

Effect of a leukotriene receptor antagonist pranlukast hydrate,on airway inflammation airway hyperresponsiveness in patients with moderate to severe asthma

Asthma is characterized by chronic airway inflammation and the recruitment of inflammatory cells, typically eosinophils and lymphocytes, into the airway. Although several chemical mediators are released during the inflammatory process of asthma, evidence strongly suggests that the cysteinyl leukotrienes (LT), LTC₄, LTD₄, and LTE₄, play key roles in asthma. The short-term clinical efficacy of an LT receptor antagonist, pranlukast hydrate, in symptomatic patients with asthma who had already been treated with moderate to high doses of inhaled corticosteroids was therefore investigated. Treatment with pranlukast hydrate for 4 weeks significantly improved respiratory function and decreased asthma symptoms, the rescue use of inhaled β2-agonists, the number of peripheral blood eosinophils and serum levels of eosinophil cationic protein. Furthermore, airway inflammation, as evaluated by the percentage of eosinophils in induced sputum and airway responsiveness to histamine, decreased significantly after treatment. There were no significant changes in these parameters in control patients with asthma whose treatment was not changed over 4 weeks. These preliminary results suggest that pranlukast hydrate, an LT receptor antagonist, is an effective agent in the management of asthma in combination with moderate to high doses of inhaled corticosteroids.     

Combination therapy of bronchial asthma.

For treatment of moderate and severe persistent asthma the National Heart Lung Blood Institute (NHLBI) Guidelines offer the alternative of moderately high doses of inhaled corticosteroids alone or a lower dose of inhaled corticosteroids combined with a long-acting bronchodilator. Three classes of drugs qualify for the combination with inhaled corticosteroids. They are long-acting beta-agonists, leukotriene receptor antagonists, and sustained-release theophylline. Each class of drug has been shown, when combined with inhaled corticosteroids, to provide equal or better asthma control than a higher dose of inhaled corticosteroids alone. Direct comparisons indicate that, of the three classes, the long-acting beta-agonists are the most effective. Furthermore, initial concerns regarding their masking airway inflammation appear to be unfounded, because when combined with inhaled corticosteroids, the long-acting beta-agonists further decrease both the frequency and the severity of asthma exacerbations and appear to have some modulating effect on airway inflammation.     

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.     

Differential role of mucus plugs in asthma: Effects of smoking and association with airway inflammation

BackgroundThe physiological importance of mucus plugs in computed tomography (CT) imaging is being increasingly recognized. However, whether airway inflammation and smoking affect the association between mucus plugs and clinical–physiological outcomes in asthma remains to be elucidated. The objective of this study is to examine how airway inflammation and/or smoking affect the correlation of CT-based mucus plug scores with exacerbation frequency and airflow limitation indices in asthma.MethodsA total of 168 patients with asthma who underwent chest CT and sputum evaluation were enrolled and classified in eosinophilic asthma (EA; n = 103) and non-eosinophilic asthma (NEA; n = 65) groups based on sputum eosinophil percentage (cut-off: 3%). The mucus plug score was defined as the number of lung segments with mucus plugs seen on CT.ResultsMore mucus plugs were detected on CT scans in the EA group than in the NEA group, regardless of smoking status. Mucus plug score and exacerbation frequency during one year after enrollment were significantly associated in the EA group but not in the NEA group after adjusting for demographics, blood eosinophil count, and fractional exhaled nitric oxide. Mucus plug score was associated with percentage of predicted forced expiratory volume in 1 s in non-smoking individuals in the EA and NEA group and in smoking individuals in the EA group but not in the NEA group after adjusting for demographics.ConclusionsThe association of mucus plug score with exacerbation frequency and reduced lung function may vary due to airway inflammatory profile and smoking status in asthma.     

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.     

Development of irreversible airflow obstruction in a patient with eosinophilic bronchitis without asthma.

Eosinophilic bronchitis is a recently described condition presenting with chronic cough and sputum eosinophilia without the abnormalities of airway function seen in asthma. The patient, a 48-yr-old male who had never smoked, presented with an isolated chronic cough. He had normal spirometric values, peak flow variability and airway responsiveness, but an induced sputum eosinophil count of 33% (normal <1%). Although his cough improved with inhaled corticosteroids the sputum eosinophilia persisted. Over 2 yrs he developed airflow obstruction, which did not improve following nebulized bronchodilators and a 2-week course of prednisolone 30 mg once daily sufficient to return the sputum eosinophilia to normal (0.5%). It is suggested that the progressive irreversible airflow obstruction was due to persistent structural change to the airway secondary to eosinophilic airway inflammation, and it is further speculated that eosinophilic bronchitis may be a prelude to chronic obstructive pulmonary disease in some patients.     

Induced sputum eosinophils in the assessment of asthma and chronic cough

OBJECTIVE: To evaluate induced sputum eosinophils in asthma and chronic cough. DESIGN: This was an analytical, cross-sectional study set in an ambulatory respiratory clinic. SUBJECTS: Subjects (n=75) referred for evaluation of symptomatic asthma or episodic respiratory symptoms had a clinical assessment, spirometry, hypertonic saline challenge and induced sputum. Two diagnostic groups were identified. The first group comprised subjects with symptomatic asthma and variable airway obstruction (VAO) (n=32). The second group included subjects with episodic respiratory symptoms and no VAO (n=43). RESULTS: The prevalence of eosinophilic bronchitis (eosinophils >2.75%) was greatest in asthma (n=14, 44%), compared to the episodic respiratory symptoms group (n=9, 21%, P = 0.02). Clinical variables did not predict increased eosinophils (P > 0.05). Sputum eosinophils were highest in asthmatics not using inhaled corticosteroids (6.5% vs 0.5%, P = 0.02). Sputum neutrophils were higher in subjects using inhaled corticosteroid (53% vs 25%, P = 0.04). CONCLUSION: Airway inflammation with eosinophilia was common among patients presenting to a respiratory clinic, especially those with asthma who were not using inhaled corticosteroids. Induced sputum also identified eosinophilic bronchitis in those without asthma. It was not possible to detect the presence or absence of airway eosinophilia by routine clinical assessment. The results in this study imply that the assessment of induced sputum eosinophils may be a useful guide to therapy, especially in the assessment of persistent symptoms in asthmatics on corticosteroids, and in the assessment of non-asthmatic subjects with symptoms.     

Inflammatory phenotypes in adult asthma: clinical applications

Background: The pattern of granulocyte infiltration can be used to identify different inflammatory phenotypes in asthma. Recognized granulocyte phenotypes using induced sputum are eosinophilic (EA), neutrophilic, mixed granulocytic and paucigranulocytic asthma. Methods: The recognition and importance of inflammatory phenotype analysis using induced sputum in adult asthma are reviewed using published literature. Results: Knowledge of inflammatory phenotype is useful because it relates to treatment response, mechanistic pathways involved in disease pathogenesis and future disease risk. The population attributable risk of asthma because of eosinophilic inflammation is about 50%, and conversely, this means that up to 50% of asthma cannot be attributed to eosinophilic inflammation, and represents asthma associated with non‐eosinophilic processes. In these patients, bronchial biopsy shows significantly fewer eosinophils in the bronchial mucosa than subjects with EA. This confirms that non‐eosinophilic asthma is a consistent pattern/phenotype in the airway lumen and the airway mucosa. A key aspect of asthma inflammatory phenotype analysis is that it can be applied to individual patients. The underlying principle relates to the association between a clinical response to corticosteroids and the presence of a selective sputum eosinophilia. Conclusions: Clinically useful applications of induced sputum analysis are the detection of non‐adherence to corticosteroid therapy, assessment of adequacy of inhaled corticosteroid therapy, long‐term therapy management in asthma, oral corticosteroid dose adjustment in refractory asthma and assessment of occupational asthma. Please cite this paper as: Gibson PG. Inflammatory phenotypes in adult asthma: clinical applications. The Clinical Respiratory Journal 2009; 3: 198–206.