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.     

Eosinophilic airway inflammation as an underlying mechanism of undiagnosed prolonged cough in primary healthcare patients

Prolonged cough is a common problem in patients seen in general practice. Using a simple method of sputum induction and processing of sputum samples, we determined whether eosinophilic airway inflammation could be a cause of undiagnosed prolonged cough. Eighty-two patients who had had cough for more than 1 month were enrolled into the study, in six primary healthcare centres. Patients with known pulmonary disease, including asthma or chronic obstructive pulmonary disease (COPD), or who were known to have another cause of cough, or to have recently suffered from a respiratory infection, were excluded. Fifty-three healthy individuals served as controls. Sputum was induced by inhalation of 3% saline. Inflammatory cells in smears were studied semi-quantitatively. Concentrations of eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), myeloperoxidase (MPO) and human neutrophilic lipocalin (HNL) were determined. Sputum induction proved safe and adequate samples were obtained from 91%. Sputum eosinophilia (eosinophils accounting for more than 5% of all cells in smears) was present in 14 patients with prolonged cough (19%) but in no healthy individual (P=0.001). Five of the 14 individuals (36%) who exhibited sputum eosinophilia appeared to have asthma, while nine of the 14 (64%) did not. Concentrations of ECP and EPO were higher in patients with prolonged cough than in healthy individuals (P=0.02 for ECP; 0.005 for EPO).We conclude that eosinophilic airway inflammation is a fairly common cause of prolonged cough, even in patients not suffering from asthma or COPD, or in whom no other cause of cough is known to be present. Induced sputum samples obtained in health centres can be studied in a central laboratory. Detection of eosinophilic airway inflammation could aid the decision regarding treatment.     

Eosinophilic airway disorders

Diseases of the airway are common and make up a significant proportion of the respiratory physician's workload. The major contributors to this situation, such as asthma, chronic obstructive pulmonary disease (COPD), and chronic cough, all result from airway inflammation and often have an overlapping clinical picture, which in some instances makes accurate clinical diagnosis difficult. Asthma is a condition characterized by variable airflow obstruction, airway hyper-responsiveness, and airway inflammation, which is usually eosinophilic. However, the relationship between eosinophilic inflammation and asthma is complex, with only a weak correlation between the severity of airway inflammation and the markers of the severity of asthma, such as Pc20 and FEV1. Eosinophilic bronchitis is characterized by a chronic cough and sputum eosinophilia without airway hyper-responsiveness or variable airflow obstruction. The asthma phenotype is characterized by microlocalization of mast cells in the airway smooth muscle, emphasizing the importance of airway smooth muscle dysfunction in asthma. COPD has generally been considered to be a neutrophilic disease, in contrast to asthma. However, there is increasing evidence that a significant subgroup exists consisting of patients with stable COPD who have chronic airway eosinophilia with a more steroid-responsive disease. This article covers the role of eosinophils in the airway disorders asthma, COPD, and eosinophilic bronchitis.     

Sputum eosinophils and the response of exercise-induced bronchoconstriction to corticosteroid in asthma

BACKGROUND: The relationship between eosinophilic airway inflammation and exercise-induced bronchoconstriction (EIB), and the response to inhaled corticosteroid (ICS) therapy was examined. METHODS: Twenty-six steroid-na?ve asthmatic patients with EIB were randomized to two parallel, double-blind, crossover study arms (13 subjects in each arm). Each arm compared two dose levels of inhaled ciclesonide that were administered for 3 weeks with a washout period of 3 to 8 weeks, as follows: (1) 40 vs 160 microg daily; and (2) 80 vs 320 microg daily. Baseline and weekly assessments with exercise challenge and sputum analysis were performed. RESULTS: Data were pooled and demonstrated that 10 subjects had baseline sputum eosinophilia >or= 5%. Only high-dose ICS therapy (ie, 160 and 320 microg) significantly attenuated the sputum eosinophil percentage. Sputum eosinophil percentage significantly correlated with EIB severity, and predicted the magnitude and temporal response of EIB to high-dose therapy, but not to low-dose therapy (ie, 40 and 80 microg). Low-dose ICS therapy provided a significant reduction in EIB at 1 week, with little additional improvement thereafter, irrespective of baseline sputum eosinophil counts. In contrast, high-dose ICS therapy provided a significantly greater improvement in EIB in subjects with sputum eosinophilia compared to those with an eosinophil count of < 5%. The difference between the eosinophilic groups in the magnitude of improvement in EIB was evident after the first week of high-dose ICS therapy and increased with time. CONCLUSIONS: These results suggest that eosinophilic airway inflammation may be important in modifying the severity of EIB and the response to ICS therapy. Measurements of sputum eosinophil percentage may, therefore, be useful in predicting the magnitude and temporal response of EIB to different dose levels of ICSs. Trial registration: clinicaltrial.gov; Identifier: NCT00525772.     

Clinical applications of induced sputum

The development of standardized methods for sputum induction has improved the quality and reproducibility of sputum samples. This technique has been used to optimize samples in the investigation of pulmonary tuberculosis and lung cancer, but its clinical application as a noninvasive measure of airway inflammation has highlighted the enormous potential of this technique. Sputum induction has allowed researchers to characterize the inflammatory profiles of a variety of airway diseases including asthma, COPD, and chronic cough. To date, the identification of sputum eosinophilia has the greatest clinical value as this predicts a favorable response to corticosteroids and can therefore guide treatment. In asthma and COPD management, protocols aimed at normalizing the sputum eosinophil count have markedly reduced exacerbations without an overall increase in therapy. Currently, no other noninvasive measure of airway inflammation has demonstrated a benefit in reducing exacerbations. The value of sputum induction and analysis is not restricted to the recognition of sputum eosinophilia but also may be used to direct novel antineutrophilic therapies. Thus, it is time for sputum induction to move from the research laboratory to the clinic.     

Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial.

Evidence suggests that eosinophilic airway inflammation is important in the pathogenesis of severe chronic obstructive pulmonary disease (COPD) exacerbations. The present authors tested the hypothesis that a management strategy that aims to reduce sputum eosinophil counts is associated with a reduction in exacerbations of COPD. A total of 82 patients with COPD were randomised into two groups. One group was treated according to traditional guidelines (British Thoracic Society (BTS) group) and the other (sputum group) was treated with the additional aim of minimising eosinophilic airway inflammation, assessed using the induced sputum eosinophil count. The primary outcome was exacerbations, which were categorised as mild, moderate or severe. The frequency of severe exacerbations per patient per year was 0.5 and 0.2 in the BTS and sputum groups, respectively (mean reduction 62%). The majority of this benefit was confined to patients with eosinophilic airway inflammation. There was no difference in the frequency of mild and moderate exacerbations. The average daily dose of inhaled or oral corticosteroids during the trial did not differ between the groups. Out of 42 patients in the sputum group, 17 required regular oral corticosteroids to minimise eosinophilic airway inflammation. A management strategy that aims to minimise eosinophilic airway inflammation, as well as symptoms, is associated with a reduction in severe exacerbations of chronic obstructive pulmonary disease.     

A perspective on point-of-care tests to detect eosinophilic bronchitis

Approximately 50% of asthma exacerbations and a third of COPD exacerbations are associated with an eosinophilic bronchitis. Quantitative cell counts reliably identify the number of eosinophils in sputum and treatment strategies that are guided by sputum eosinophil counts lead to significantly better outcomes than strategies guided by conventional assessments of symptoms and airflow. However, cell counts are not widely available and the results are not available in real time. Similarly, more sophisticated detection methods using immunoassays or genetic analysis via polymerase chain reaction are too costly and thus not amenable to rapid point-of-care diagnosis. Blood eosinophil counts and fraction of exhaled nitric oxide correlate poorly with airway eosinophilia, particularly in patients with severe airway diseases who are on corticosteroid therapy. Point of care assessments of eosinophil-specific activity may be provided by breathomics that employ metabolomics profiling of volatile compounds in breath. However, it is too early to decide if this would provide quantitative data to monitor therapy and disease activities longitudinally. Herein we provide a perspective on the potential for developing simple point-of-care tests with special emphasis on the potential for a bio-active paper diagnostic test to quantitatively assay the amount of eosinophil peroxidase in sputum samples by employing different types of detection systems.     

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.     

Evidence of mast-cell activation in a subset of patients with eosinophilic chronic obstructive pulmonary disease.

Although asthma has been viewed mainly as an eosinophilic disease, and chronic obstructive pulmonary disease (COPD) as a neutrophilic disease, recent studies have shown increased neutrophil counts in severe asthma and sputum eosinophilia in some COPD patients. In an attempt to further characterise these two syndromes according to pathology, the current authors have conducted a study of induced sputum in 15 subjects with COPD, 17 asthmatics, and 17 nonatopic healthy individuals. Sputum was analysed for cytology and levels of eosinophil cationic protein (ECP), albumin, tryptase and soluble intercellular adhesion molecule-1. The COPD subjects differed from the asthmatics as they had higher sputum neutrophil and lower columnar epithelial cell counts, but there were no differences in any soluble marker studied. When compared to control subjects, both the asthmatic and COPD subjects had raised eosinophil counts and ECP levels. In a subset of COPD subjects with sputum eosinophilia (>3% of total cells), significantly increased levels of tryptase were detected. In conclusion, although chronic obstructive pulmonary disease is a more neutrophilic disease than asthma, the two diseases are difficult to distinguish on the basis of sputum levels of the soluble markers traditionally associated with asthma. However, a subset of patients with chronic obstructive pulmonary disease with airway eosinophilia and mast-cell activation might represent a distinct pathological phenotype.     

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.     

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.     

Inhaled Fluticasone and Salmeterol Suppress Eosinophilic Airway Inflammation in Chronic Obstructive Pulmonary Disease: Relations with Lung Function and Bronchodilator Reversibility

The aim of this study was to determine whether combined inhaled corticosteroids and long-acting β₂ agonists can suppress eosinophilic inflammation in chronic dostructive plumonary disease (COPD) and to investigate the association between the level of eosinophilia and the degree of bronchodilator reversibility. Sixty-two patients with stable COPD (forced expiratory volume in 1 [FEV₁] of 30%–70% predicted before bronchodilation) were enrolled from our outpatient clinic. Patients received inhaled fluticasone (100 μg)/salmeterol (50 μg) twice daily for two months. Lung function measurements, bronchodilator tests, and sputum induction were performed. The number of inflammatory cells and mediators, including interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), and eosinophilic cationic protein (ECP), were measured. Treatment with inhaled fluticasone and salmeterol significantly suppressed eosinophilic inflammation in COPD patients with sputum eosinophilia (mean 8.9% ± 2.0% vs. 1.6% ± 0.5%, p = 0.003), but insignificant differences in FEV₁ and FVC between patients with and without eosinophilia suggested that suppression of eosinophilic inflammation had no effect on FEV₁ or FVC. Reduction in the percentage of eosinophils was significantly correlated with decreased levels of ECP (r = 0.48, p < 0.001). Levels of neutrophils, IL-8, and TNF-α were not affected. Sputum eosinophilia was not related to the degree of bronchodilator reversibility. The degree of bronchodilator reversibility did not predict the increase in FEV₁ and FVC after treatment with inhaled corticosteroids/long-acting β₂ agonists. Suppression of eosinophilic inflammation and bronchodilator responsiveness indices were not correlated with clinical outcomes in COPD patients treated with inhaled corticosteroids/long-acting β₂ agonists. Diahn-Warng Perng and Cheng-Che Wu contributed equally to this work.     

Sputum neutrophilia can mask eosinophilic bronchitis during exacerbations

BACKGROUND:

Exacerbations of airway disease are eosinophilic, neutrophilic, both or neither. The primary objective of the present study was to identify whether the treatment of a neutrophilic bronchitis can unmask an associated eosinophilia.

METHODS:

A retrospective survey of 2160 consecutive sputum cell counts from 1343 patients with airway disease was conducted to identify patients with an isolated neutrophilic bronchitis, which was defined as a sputum total cell count of greater than or equal to 12×10⁶ cells/g of sputum and a proportion of neutrophils of 80% or greater. The characteristics of the patients who subsequently demonstrated sputum eosinophilia (3% or greater) within eight weeks of resolving the neutrophilia were compared with the patients who subsequently did not have sputum eosinophilia.

RESULTS:

Two hundred thirty-seven patients had 273 neutrophilic exacerbations. The sputum was re-examined within eight weeks in 65 patients (27.4%), of whom 38 (58.5%) had resolution of the neutrophilic bronchitis after treatment with an antibiotic. Of these 38 patients, 13 (34%) showed eosinophilia.

CONCLUSIONS:

A neutrophilic exacerbation of airway disease was observed to mask sputum eosinophilia in one-third of patients who had sputum cell counts available before and after antibiotic therapy. Hence, the absence of sputum eosinophilia during an infective exacerbation should not be used as an indication to reduce the dose of corticosteroids. To optimize therapy, repeat sputum cell count measurements are recommended after antibiotic treatment before changing corticosteroid treatment.     

Exhaled Nitric Oxide Predicts Eosinophilic Airway Inflammation in COPD

Purpose

Chronic obstructive pulmonary disease (COPD) with eosinophilic airway inflammation may represent a unique phenotype, possibly with shared features of COPD and asthma. The role of exhaled nitric oxide (eNO) in identifying COPD patients with sputum eosinophilia was examined in this study.

Methods

Ninety COPD patients without past medical history of asthma or allergic diseases were prospectively enrolled, and their eNO, lung function, and cellular profile of induced sputum were measured. Eosinophil cationic protein and IgE in sputum and venous blood also were determined. Subjects with and without sputum eosinophilia (>3 %) were compared. The role of eNO in the prediction of sputum eosinophilia was assessed in a logistic regression model.

Results

Patients with sputum eosinophilia had significantly higher levels of eNO (29 vs. 18 ppb, p = 0.01) than those without. The difference in serum total IgE (168 vs. 84.9 IU/ml, p = 0.057) and percentages of positive allergen test results (48.3 vs. 29.5 %, p = 0.082) showed a trend toward significance. The sputum eosinophil level was significantly correlated to the eNO level (r = 0.485, p < 0.001). The eNO level at the cutoff of 23.5 ppb had the maximum sum of sensitivity (62.1 %) and specificity (70.5 %). The unadjusted and adjusted odds ratios of a higher eNO level (>23.5 ppb) in the prediction of sputum eosinophilia were 3.909 (confidence interval (CI) 1.542–9.91, p = 0.004) and 4.329 (CI 1.306–14.356, p = 0.017), respectively.

Conclusions

eNO is a good marker to identify COPD patients with eosinophilic airway inflammation.     

Induced sputum in the investigation of airway inflammation of COPD

During the last decade, the method of sputum induction (SI) has offered the opportunity to study inflammation in patients with chronic obstructive pulmonary disease (COPD). This paper reviews methodological aspects of SI and summarizes its uses in the research of inflammation in COPD, including sputum cellularity and soluble markers. SI is a relatively safe, reliable, and reproducible technique, used to investigate different aspects of airway inflammation. Although various methods of induction and processing have been proved safe and highly reproducible, a generally accepted method is needed. Sputum analysis has given evidence for increased numbers of macrophages and neutrophils in COPD patients compared to normal subjects. In some studies, increased numbers of eosinophils have been also reported. Changes in various mediators have been found in sputum supernatant of COPD patients (IL-8, LTB-4 and TNF-a). The clinical usefulness of the method in the follow-up of the disease has not been explored extensively. A number of observations in patients with different clinical characteristics could be proven useful in identifying patterns of inflammation associated with different prognosis. Finally, SI could also guide treatment; such as, sputum eosinophilia in COPD could predict response to inhaled corticosteroids.     

Practical Guide to the Identification and Diagnosis of Asthma-COPD Overlap (ACO)

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortality around the world. COPD is characterised by a heterogeneous clinical presentation and prognosis which may vary according to the clinical phenotype. One of the phenotypes of COPD most frequently studied is the asthma-COPD overlap (ACO), however, there are no universally accepted diagnostic criteria for ACO. It is recognised that the term ACO includes patients with clinical features of both asthma and COPD, such as more intense eosinophilic bronchial inflammation, more severe respiratory symptoms and more frequent exacerbations, but in contrast, it is associated with a better prognosis compared to COPD. More importantly, ACO patients show better response to inhaled corticosteroid treatment than other COPD phenotypes. The diagnosis of ACO can be difficult in clinical practice, and the identification of these patients can be a challenge for non-specialized physicians. We describe how to recognise and diagnose ACO based on a recently proposed Spanish algorithm and by the analysis of three clinical cases of patients with COPD. The diagnosis of ACO is based on the diagnosis of COPD (chronic airflow obstruction in an adult with significant smoking exposure), in addition to a current diagnosis of asthma and/or signficant eosinophilia.     

Airway inflammation and cellular stress in noneosinophilic atopic asthma

STUDY OBJECTIVES: It has been suggested that patients with noneosinophilic asthma (NEA) show increased numbers of sputum neutrophils and a lack of response to therapy with corticosteroids, which are features that are commonly related to COPD. The aim of our study was to test the hypothesis that airway inflammation in NEA patients is different from that seen in patients with eosinophilic asthma (EA) and is similar to COPD. DESIGN: Sputum cellular stress markers and neutrophilic and eosinophilic fluid-phase mediators were analyzed in asthma and COPD patients. NEA patients were identified based on a sputum eosinophil count of < or = 2.2% of the total nonsquamous cell count, and were compared to EA and COPD patients. SETTING: University Hospital of Heraklion, Department of Thoracic Medicine. PATIENTS: A total of 37 atopic asthmatic patients and 25 patients with COPD. MEASUREMENTS: Sputum cell counts, cellular expression of heme oxygenase-1, inducible nitric oxide synthase, and nitrotyrosine, and sputum levels of eosinophilic cationic protein (ECP), myeloperoxidase (MPO), interleukin-8, and granulocyte macrophage colony-stimulating factor. RESULTS: A total of 17 asthmatic patients (46%) belonged to the NEA group and 20 patients (54%) to the EA group. Patients with NEA showed no difference in neutrophil counts, fluid-phase mediators, or cellular stress markers compared to patients with EA. Compared to COPD patients, NEA patients showed the following significant differences: lower total cell counts (p < 0.03); lower neutrophil counts (p < 0.01); lower nitrotyrosine positive cell counts (p < 0.003); lower ECP levels (p < 0.005); lower MPO levels (p < 0.000); higher lymphocyte counts (p < 0.01); and higher macrophage counts (p < 0.03). CONCLUSIONS: Despite low eosinophil counts, airway inflammation in NEA patients may share common features with that in EA patients but is distinct from COPD. Larger studies are needed to investigate further the clinical and inflammatory characteristics of NEA before we are able to categorize asthma patients into those with or without eosinophilic inflammation.     

Exhaled nitric oxide: A biomarker for chronic obstructive pulmonary disease

The fractional concentration of exhaled nitric oxide (FeNO) is recognized as a biomarker of type 2 inflammation in asthma, which is related to airway eosinophilia. We conducted a prospective observational study in a cohort of Japanese patients with chronic obstructive pulmonary disease (COPD) to evaluate the relationship between FeNO and clinical features and patient outcomes over a 3-year period. Participants were categorized into two groups based on FeNO levels (high and low), and the clinical features and outcomes were compared between the groups. Patients with high FeNO levels showed features of asthma and eosinophilic inflammation compared to those with low levels. However, high FeNO levels were not associated with worse outcomes (exacerbations, hospital admissions, all-cause and disease-specific mortality) compared to low levels. These results provide evidence that baseline FeNO is related to eosinophilic inflammation; however, is not a predictor of future exacerbations or prognosis in patients with stable COPD.     

Airway inflammation, airway responsiveness and cough before and after inhaled budesonide in patients with eosinophilic bronchitis.

Eosinophilic bronchitis is a common cause of chronic cough, characterized by sputum eosinophilia similar to that seen in asthma, but unlike asthma the patients have no objective evidence of variable airflow obstruction or airway hyperresponsiveness. The reason for the different functional associations is unclear. The authors have tested the hypothesis that in eosinophilic bronchitis the inflammation is mainly localized in the upper airway. In an open study the authors measured the lower (provocative concentration causing a 20% fall in forced expiratory volume in one second (PC20)) and upper (PC25 MIF50) airway responsiveness to histamine, lower and upper airway inflammation using induced sputum and nasal lavage, in II patients with eosinophilic bronchitis. The authors assessed changes in these measures and in cough reflex sensitivity to capsaicin and cough severity after 400 microg of inhaled budesonide for 4 weeks. A nasal eosinophilia was present in only three patients with one having upper airway hyperresponsiveness. Following treatment with inhaled corticosteroids the geometric mean sputum eosinophil count decreased from 12.8% to 2.9% (mean difference 4.4-fold, 95% confidence interval (CI) 2.14-10.02), the mean +/- sem cough visual analogue score on a 100 mm scale decreased from 27.2 +/- 6.6 mm to 12.6 +/- 5.7 mm (mean difference 14.6, 95% CI 9.1-20.1) and the cough sensitivity assessed as the capsaicin concentration required to cause two coughs (C2) and five coughs (C5) improved (C2 mean difference 0.75 doubling concentrations, 95% CI 0.36-1.1; C5 mean difference 1.3 doubling concentration, 95% CI 0.6-2.1). There was a significant positive correlation between the fold change in sputum eosinophil count and doubling dose change in C5 after inhaled budesonide (r=0.61). It is concluded that upper airway inflammation is not prominent in eosinophilic bronchitis and that inhaled budesonide improves the sputum eosinophilia, cough severity and sensitivity suggesting a causal link between the inflammation and cough.     

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.