Effect of low-dose ciclesonide on allergen-induced responses in subjects with mild allergic asthma

BACKGROUND: Inhalation of allergens by sensitized patients with asthma induces reversible airway obstruction, airway hyperresponsiveness, and eosinophilic airway inflammation. Attenuation of allergen-induced bronchoconstriction and inflammation has been used to examine the efficacy of therapeutic agents such as inhaled corticosteroids in asthma. Ciclesonide, a nonhalogenated inhaled corticosteroid being developed for the treatment of persistent asthma, remains inactive until cleaved by esterases in the lung. OBJECTIVE: This study examined the effect of low doses of inhaled ciclesonide, 40 microg and 80 microg, on allergen-induced bronchoconstriction, serum eosinophil cationic protein, and eosinophilic airway inflammation. METHODS: Twenty-one nonsmokers with mild atopic asthma completed a multicenter, randomized, 3-way crossover study comparing the effects of 7-day treatment of ciclesonide or placebo. Allergen-induced responses, including the early and late fall in FEV1, peripheral blood eosinophils, serum eosinophil cationic protein levels, and eosinophils in induced sputum were measured. RESULTS: Ciclesonide 80 microg attenuated the early and late asthmatic responses, including the change in FEV1, serum eosinophil cationic protein, and sputum eosinophils measured at 24 hours postchallenge (P < .025). Ciclesonide 40 microg attenuated the late asthmatic responses and sputum eosinophils measured at 24 hours postchallenge (P < .025), with no effect on the early allergen-induced bronchoconstriction, 24-hour FEV1, or serum eosinophil cationic protein levels (P < .025). CONCLUSION: With the exception of 24-hour postchallenge peripheral blood eosinophils, a low dose of ciclesonide, 80 microg, was effective in blocking all allergen-induced responses measured.     

激素治疗对运动诱发性哮喘患者痰嗜酸性粒细胞计数的影响

目的探讨气道嗜酸性粒细胞性炎症和运动诱发的支气管痉挛（EIB）之间的关系,及其对吸入糖皮质激素（ICS）治疗的反应。方法本研究为随机、双盲、二阶段交叉试验,将26例有运动诱发性支气管痉挛发作史且从未接受过激素治疗的哮喘患者随机分为两组,每组分别给予两个剂量水平的布地奈德吸入：①100μg/d与400μg/d对比;②200μg/d与800μg/d对比。每一阶段为3周,洗脱期3～8周。治疗前及开始治疗后每隔1周进行1次运动激发试验并留取痰液标本行嗜酸性粒细胞计数。结果高剂量ICS治疗（400μg/d和800μg/d）可显著减少痰嗜酸性粒细胞比例。痰嗜酸性粒细胞百分比与运动诱发性支气管痉挛严重程度相关,且对EIB的严重程度有预测作用;高剂量ICS治疗时,尚可预测EIB对激素治疗有效,而对低剂量ICS组（100μg/d和200μg/d）则无预测作用。低剂量ICS治疗,不管基线痰嗜酸性粒细胞计数是否增多,EIB在第1周末发作显著减轻,尔后几无改善。而高剂量ICS治疗对EIB的改善作用在痰嗜酸性粒细胞增多的患者中显著优于嗜酸性粒细胞计数小于5%者,这种明显的差异在开始治疗1周后即显现,且随时间的推移而继续加大。结论气道嗜酸性粒细胞性炎症可能在EIB的发生及其对ICS治疗有效的调节机制中起重要的作用。测定痰嗜酸性粒细胞计数在预测EIB的严重程度及其对不同剂量ICS治疗的反应具有一定的临床应用价值。     

Observational study of the natural history of eosinophilic bronchitis

BACKGROUND: Eosinophilic bronchitis is an important cause of chronic cough. Treatment with inhaled corticosteroids is associated with a short-term improvement in cough and reduced sputum eosinophil count but the long-term outcome is uncertain. OBJECTIVE: To determine the long-term outcome in patients diagnosed with and treated for eosinophilic bronchitis. METHODS: We have performed a longitudinal study of symptoms, eosinophilic airway inflammation, spirometry and airway hyper-responsiveness in all patients diagnosed with eosinophilic bronchitis over 7 years. RESULTS: We identified 52 patients with eosinophilic bronchitis and longitudinal data of greater than 1 year (mean 3.1 years) was available in 32 patients, all of whom were treated with inhaled steroids. Three (9%) patients developed symptoms consistent with asthma and a methacholine PC20<8 mg/mL on one or more occasion. Five (16%) patients developed fixed airflow obstruction defined by a persistent post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity<70%. One (3%) patient had complete resolution of symptoms and eosinophilic airway inflammation off treatment. The remaining patients had ongoing eosinophilic airway inflammation and/or continuing symptoms. Multiple linear regression identified smoking, female gender and area under the curve of sputum eosinophil count over time as the most important predictors of decline in FEV1. CONCLUSIONS: The most common outcome in eosinophilic bronchitis is continuing disease and complete resolution is rare. Asthma and fixed airflow obstruction developed in relatively few patients. The most important factors associated with a more rapid decline in FEV1 were female gender, smoking and prolonged eosinophilic airway inflammation.     

Increased prostaglandin E2 levels in the airway of patients with eosinophilic bronchitis

Background: Eosinophilic bronchitis is a common cause of chronic cough, which like asthma is characterized by sputum eosinophilia, but unlike asthma there is no variable airflow obstruction or airway hyperresponsiveness. We tested the hypothesis that the different airway function in patients with eosinophilic bronchitis and asthma could be caused by an imbalance in the production of bronchoconstrictor (LTC₄) and bronchoprotective (prostaglandin E₂; PGE₂) lipid mediators. Methods: We measured cytokines levels, proinflammatory mediators and eicosanoids concentration in sputum from 13 subjects with nonasthmatic eosinophilic bronchitis, 13 subjects with asthma, and 11 healthy control subjects. Cytokines mRNA levels were measured by real time PCR, proinflammatory mediators, PGE₂, and LTC₄ were measured by enzyme immunoassays. Results: The median sputum eosinophil count was not statistically different in patients with asthma (7.95%) and eosinophilic bronchitis (15.29%). The levels of mRNA specific to interleukin‐5 (IL‐5), IL‐4, IL‐10, IL‐13, interferon γ (IFN‐γ), IL‐2, vascular endothelial growth factor and transforming growth factor β were similar in both conditions. In addition, no differences were found between asthma and eosinophilic bronchitis in proinflammatory cytokines, such as IL‐8, IFN‐γ and tumor necrosis factor α (TNF‐α) levels. Sputum cysteinyl‐leukotrienes concentration was raised both in eosinophilic bronchitis and asthma patients. We found that induced sputum PGE₂ concentrations were significantly increased in subjects with eosinophilic bronchitis (838.3 ± 612 pg/ml) when compared with asthmatic (7.54 ± 2.14 pg/ml) and healthy subjects (4 ± 1.3 pg/ml). Conclusion: This data suggest that the difference in airway function observed in subjects with eosinophilic bronchitis and asthma could be due to differences in PGE₂ production in the airways.     

House dust mite-specific IgE antibodies in induced sputum are associated with sputum eosinophilia in mite-sensitive asthmatics.

BACKGROUND: Although allergen-specific IgE antibodies have been considered to play an important role in the pathogenesis of atopic asthma, the role of IgE antibodies in the development of airway inflammation is not well defined. OBJECTIVE: To evaluate the association between allergen-specific IgE antibodies and inflammation of the asthmatic airway. METHODS: We measured house dust mite (HDM; Dermatophagoides farinae)-specific IgE antibodies in both serum and induced sputum from 16 HDM-sensitive asthmatic patients, and evaluated their association with sputum eosinophilia and eosinophil cationic protein (ECP) levels in induced sputum. RESULTS: Levels of HDM-specific IgE antibodies in induced sputum were significantly higher in asthmatic patients than in controls (P < .01). In asthmatic patients, levels of HDM-specific IgE antibodies were significantly higher in induced sputum samples with eosinophilia (sputum eosinophil count > or = 5% of 200 counted non-squamous cells) than in those without eosinophilia (P < .05). There were no significant differences in serum levels of HDM-specific IgE antibodies between asthmatic patients with sputum eosinophilia and asthmatic patients without sputum eosinophilia. In asthmatic patients, sputum ECP levels were significantly correlated with levels of HDM-specific IgE antibodies (r = 0.60, P = .01) in induced sputum but not with those in serum. CONCLUSION: We conclude that allergen-specific IgE antibodies in induced sputum from atopic asthmatics are associated with sputum eosinophilia. This result suggests that IgE-dependent mechanisms are involved in eosinophilic inflammation of the airway in atopic asthmatics.     

The small airway inflammation of asthmatic patients who have used dry powder type inhaled steroid for moderate-long term evaluated by induced sputum and the efficacy of HFA-BDP (QVAR) inhalation]

Although the dry powder type inhaled steroids, such as Fluticasone Propionate Diskhaler (FP-DH), FP Diskus (FP-DK), Budesonide Turbuhaler (BUD-TH), are widely distributed in daily clinical fields, we clinicians are required to evaluate whether it is effectively inhibiting inflammation of distal airway or not. We also investigated the effect of Hydrofluoroalukan-beclomethasone dipropionate (HFA-BDP), a new type of inhaled steroid which forms super micro aerosol particles, in the distal small airway. METHOD: 85 patients with moderate asthma, who daily used dry powder type inhaled steroid for at least more than 6 months with stable asthmatic condition, were the subject of this study. All subjects underwent sputum induction with the inhalation of 10% of hypertonic saline solution for 15 min and eosinophil counts and eosinophil cationic protein (ECP) in individual induced sputum were measured. Then, patients who had eosinophils detected in their induced sputum changed their previously inhaled steroid to HFA-BDP inhalation (400 i.g./day). Their eosinophil counts and the values of eosinophil cationic protein (ECP), Eotaxin, RANTES and neutrophil elastase (PMN-E) in their induced sputum were also examined before and 4weeks after changing HFA-BDP inhalation. RESULT: Increased eosinophils were found in the induced sputum of 40.5% patients of the FP-DK group, 36.3% of the FP-DH group and 32.4% of the BUD-TH group, respectively. Compared with group of patients in which no sputum eosinophil were detected, the sputum ECP values, in which sputum eosinophils were detected, were significantly high. 4 weeks after changing to HFA-BDP inhalation, eosinophil counts, ECP, Eotaxin, RANTES and PMN-E in their induced sputum were decreased in every group. CONCLUSION: Compared with the ordinary dry powder type inhaled steroids, HFA-BDP can effectively diminish distal airway inflammation, suggesting the possibility that HFA-BDP can effectively reach to the distal small airway by forming super micro aerosol particles.     

Airway inflammation assessed by invasive and noninvasive means in severe asthma: eosinophilic and noneosinophilic phenotypes

BACKGROUND: Airway inflammation assessed by bronchial biopsies demonstrates distinct eosinophilic and noneosinophilic phenotypes in severe asthma, but their relationship to other biomarkers of disease (induced sputum and nitric oxide [NO]) is not clear. OBJECTIVES: We sought to compare airway inflammation using noninvasive (induced sputum, exhaled NO), and invasive (bronchial biopsies) methods in moderate and severe asthma and to assess whether induced sputum and exhaled NO would allow the identification of eosinophilic and noneosinophilic phenotypes in severe asthma. METHODS: We performed a cross-sectional study of 32 subjects with severe asthma and 35 subjects with moderate asthma, from whom we obtained bronchial biopsies, induced sputum, and exhaled NO measurements. RESULTS: Among subjects with severe asthma, we identified eosinophilic and noneosinophilic phenotypes using both bronchial biopsies and sputum cell counts. However, the vast majority of subjects with high sputum eosinophil counts did not have high mucosal eosinophil counts. Exhaled NO was increased in the eosinophilic phenotype as judged from bronchial biopsy findings, but not on the basis of induced sputum. Subjects with high sputum eosinophil counts experienced more asthma exacerbations than the subjects with low sputum eosinophil counts. In contrast, we did not find any differences in the clinical characteristics between eosinophilic and noneosinophilic phenotypes that were identified by bronchial biopsies. CONCLUSION: The use of sputum cell counts allowed the identification of a subgroup of subjects with severe asthma who were at risk of more frequent asthma exacerbations. CLINICAL IMPLICATIONS: Monitoring sputum eosinophil counts in subjects with severe asthma may allow identifying the subjects with the greatest disease activity.     

Correlation between airway hyperresponsiveness and airway inflammation in a young adult population: eosinophil, ECP, and cytokine levels in induced sputum.

BACKGROUND: Eosinophil counts and eosinophil cationic protein (ECP) levels in the airway are elevated in asthmatic patients. However, few studies have examined the correlation between various cytokines in the sputum and airway hyperresponsiveness (AHR) in young adults with or without asthma. OBJECTIVE: We examined the correlation between AHR and eosinophil counts or ECP, and levels of several cytokines in the sputum. METHODS: We studied 120 nonsmoker students (group 1: intermittent mild asthmatic patients; group 2: subjects with history of childhood asthma; group 3: subjects sensitized by Dermatophagoides farinae with atopic disease; group 4: normal subjects sensitized by D. farinae; group 5: subjects with cedar pollinosis; and group 6: normal subjects). In each subject, AHR and lung function tests were measured, together with eosinophil count, ECP, granulocyte-macrophage colony-stimulating factor, TNF-alpha, IL-5, and interleukin-1beta in induced sputum. RESULTS: AHR in groups 1 and group 2 were high, in groups 5 and 6 low, and in groups 3 and 4 lower than in groups 1 and 2 but higher than groups 5 and 6. Percentages of eosinophils, ECP, and TNF-alpha in induced sputum in groups 1 and 2 were high, those in groups 5 and 6 were below detection limits, and those in groups 3 and 4 were lower than the percentages in groups 1 and 2. Granulocyte-macrophage colony-stimulating factor in the sputum was elevated only in group 1. The correlations between AHR and sputum eosinophil count, ECP, and TNF-alpha were significant, with the strongest correlation with TNF-alpha. CONCLUSIONS: Our results suggest that TNF-alpha levels in the sputum play an important role in determining the severity of AHR in young individuals. Further once AHR develops, it does not disappear, and the severity of airway inflammation influences the extent of AHR.     

Airway inflammation in asthma and perennial allergic rhinitis. Relationship with nonspecific bronchial responsiveness and maximal airway narrowing

BACKGROUND: Eosinophilic airway inflammation is the hallmark of asthma, but it has also been reported in other conditions such as allergic rhinitis. We have tested whether the analysis of cells and chemicals in sputum can distinguish between patients with mild allergic asthma, those with allergic rhinitis, and healthy controls. The relationship between inflammation markers in sputum and nonspecific bronchial hyperresponsiveness to methacholine (BHR) (PD20 and maximal response plateau [MRP] values) was also evaluated. METHODS: We selected 31 mild asthmatics and 15 rhinitis patients sensitized to house-dust mite. As a control group, we studied 10 healthy subjects. Every subject underwent the methacholine bronchial provocation test (M-BPT) and sputum induction. Blood eosinophils and serum ECP levels were measured. Sputum cell differentials were assessed, and eosinophil cationic protein (ECP), tryptase, albumin, and interleukin (IL)-5 levels were measured in the entire sputum supernatant. RESULTS: Blood eosinophils and serum ECP levels were higher in asthma patients and rhinitis than in healthy controls, but no difference between asthma patients and rhinitis patients was found. Asthmatics had higher eosinophil counts and higher ECP and tryptase levels in sputum than rhinitis patients or control subjects. Sputum albumin levels were higher in asthmatics than in controls. Rhinitis patients exhibited higher sputum eosinophils than healthy controls. An association between sputum eosinophil numbers and MPR values (r= -0.57) was detected, and a trend toward correlation between sputum ECP levels and PD20 values (r= -0.47) was found in the rhinitis group, but not in asthmatics. No correlation between blood eosinophilic inflammation and lung functional indices was found. CONCLUSIONS: Induced sputum is an accurate method to study bronchial inflammation, allowing one to distinguish between rhinitis patients and mildly asthmatic patients. The fact that no relationship was detected between sputum inflammation and BHR suggests that other factors, such as airway remodeling, may be at least partly responsible for BHR in asthma.     

Effect of obesity on airway inflammation: a cross-sectional analysis of body mass index and sputum cell counts

BACKGROUND: Several observational studies have demonstrated an association between obesity and asthma. Studies evaluating exhaled nitric oxide levels and obesity have revealed that a higher body mass index (BMI) is associated with elevated exhaled nitric oxide levels. Airway inflammation using sputum cell counts has not been assessed in obese patients with airway diseases. OBJECTIVE: The primary aim of this study was to determine whether obesity (based on BMI) is associated with eosinophilic or neutrophilic bronchitis. METHODS: The results from a database of induced sputum cell counts were compared with BMI and analysed using correlation statistics, regression and parametric and non-parametric analysis. RESULTS: Seven-hundred and twenty-seven adult participants with an equal number of sputum samples were included in the analysis. BMI varied from 14.5 to 55 kg/m(2). Sputum total cell count (mean+/-SD: 12.9 x 10(6) cell/g+/-21.5), eosinophil percent (median; min to max: 0.3%; 0-89.0), and neutrophil percent (mean+/-SD: 63.5+/-26.6%) were within normal limits. Participants with asthma had a higher percentage of sputum eosinophils than those without asthma (P=0.01). However, there was no difference in the total or differential cell counts among the obese and non-obese participants, when the data were analysed according to BMI category, gender, dose of inhaled corticosteroid, and presence or absence of asthma. CONCLUSION: In this large sample of adult asthmatic and non-asthmatic participants, there was no association between BMI and airway inflammation measured by sputum cell counts. Other mechanisms to explain the relationship between obesity and asthma will need to be explored if this association is to be better understood.     

Effects of inhaled corticosteroids on exhaled leukotrienes and prostanoids in asthmatic children

BACKGROUND: Lipid mediators play an important pathophysiologic role in atopic asthmatic children, but their role in the airways of atopic nonasthmatic children is unknown. OBJECTIVE: We sought (1) to measure leukotriene (LT) E 4 , LTB 4 , 8-isoprostane, prostaglandin E 2 , and thromboxane B 2 concentrations in exhaled breath condensate in atopic asthmatic and atopic nonasthmatic children; (2) to measure exhaled nitric oxide (NO) as an independent marker of airway inflammation; and (3) to study the effect of inhaled corticosteroids on exhaled eicosanoids. METHODS: Twenty healthy children, 20 atopic nonasthmatic children, 30 steroid-naive atopic asthmatic children, and 25 atopic asthmatic children receiving inhaled corticosteroids were included in a cross-sectional study. An open-label study with inhaled fluticasone (100 microg twice a day for 4 weeks) was undertaken in 14 steroid-naive atopic asthmatic children. RESULTS: Compared with control subjects, exhaled LTE 4 ( P <.001), LTB 4 ( P <.001), and 8-isoprostane ( P <.001) levels were increased in both steroid-naive and steroid-treated atopic asthmatic children but not in atopic nonasthmatic children (LTE 4 , P=.14; LTB 4 , P=.23; and 8-isoprostane, P=.52). Exhaled NO levels were increased in steroid-naive atopic asthmatic children ( P <.001) and, to a lesser extent, in atopic nonasthmatic children ( P <.01). Inhaled fluticasone reduced exhaled NO (53%, P <.0001) and, to a lesser extent, LTE 4 (18%, P <.01) levels but not LTB 4 , prostaglandin E 2 , or 8-isoprostane levels in steroid-naive asthmatic children. Conclusions Exhaled LTE 4 , LTB 4 , and 8-isoprostane levels are increased in atopic asthmatic children but not in atopic nonasthmatic children. In contrast to exhaled NO, these markers seem to be relatively resistant to inhaled corticosteroids.     

Exhaled nitric oxide of childhood asthma]

Chronic airway inflammation is a central feature of pathology of bronchial asthma. In order to evaluate inflammatory status in asthma, examinations such as bronchoscope or induced sputum test can be done. Because of difficulty of those examinations we need non-invasive and simple measures for childhood asthma. Here we investigated eNO in childhood asthma. Twenty-six of atopic asthma, 13 non-asthmatic atopic children and 12 normal children were enrolled in this study. eNO was measured by chemiluminescence analyzer. eNO was significantly collerated with % FEV 1.0 and blood eosinophil counts (R = -0.494, R = 0.416, respectively). Geometrical mean of eNO in normal, non-asthmatic atopic, asthma without inhaled corticosteroid (ICS) and asthma with ICS was 16.3, 23.7, 71.6, 43.6 ppb, respectively. eNO was significantly higher in asthma than in normals. eNO in patients without ICS were significantly higher than in non-asthmatic atopic. We concluded that eNO might be useful marker for evaluation of airway inflammation in asthmatic children.     

Induced sputum: comparison of postinfectious cough with allergic asthma in children

BACKGROUND: Cough persisting after a respiratory infection is common in children and is often managed as asthma. However, little is known about the pathophysiologic mechanisms of such cough and how it compares with asthma. OBJECTIVE: We used the technique of induced sputum to examine the inflammatory index values associated with persistent cough or allergic asthma in children. We hypothesized that the sputum from children with persistent postinfectious cough would differ from that of children with allergic asthma in that the former would lack eosinophils compared with the latter.Study design: Sputum production was induced with hypertonic saline solution in 34 children: 12 with cough persisting for 1 month or more after an apparent respiratory tract infection, not treated with corticosteroid; 11 with untreated atopic asthma, not using inhaled corticosteroid; and 11 with treated atopic asthma using inhaled corticosteroid. RESULTS: The percentage of eosinophils in the sputum of children with cough was significantly lower than in the sputum of children with untreated allergic asthma (median 0.5% vs 14.5%, P <.0001). Similarly, the percentage of eosinophils in the sputum of children with asthma treated with inhaled steroids was significantly lower compared with untreated asthmatic children (1.5% vs 14.5%, P <.0001). The peripheral blood eosinophils, serum eosinophil cationic protein, and nasal percent eosinophils of the patients with cough were also significantly lower than those from patients with untreated asthma. Methacholine challenge in 6 of the 11 cough patients tested showed mild-to-moderate hyperresponsiveness, whereas the other 5 had a negative methacholine challenge. CONCLUSIONS: Children with persistent postinfectious cough do not have airway eosinophilia typical of untreated asthma. Despite the absence of eosinophilic inflammation, some of the patients with chronic cough had reactive airways. These results suggest that postinfectious cough in children has different pathophysiologic features than allergic asthma and probably represents a different disease.     

Serum eosinophil cationic protein levels measured during exacerbation of asthma: characteristics of patients with low titres

BACKGROUND: Serum eosinophil cationic protein (ECP) levels reflect ongoing eosinophilic airway inflammation and are used as a marker for asthma activity. ECP levels, however, may not be elevated in some asthmatic patients, even when they are symptomatic. OBJECTIVE: To clarify the characteristics of patients with 'low' ECP titres despite asthma exacerbation. METHODS: Serum ECP levels were measured in 113 asthmatic patients during exacerbation. Patients were divided into two groups according to ECP titre: a high ECP group (H; ECP > or = 16.0 microg/L) and a low ECP group (L; ECP <16.0 microg/L). Twenty-two patients who had recently received systemic steroids were excluded and the clinical features of the remaining patients in H (n = 54) and L (n = 37 were compared. RESULTS: Gender, atopic or smoking status, disease severity, inhaled steroid or theophylline usage, peak expiratory flow (% personal best) and forced expiratory volume in 1 s (FEV1) (% predicted) did not significantly differ between the two groups. Patients in L were significantly older and had longer disease duration and lower serum IgE levels than those in H. Multivariate analysis combining age, disease duration and IgE levels showed that age and disease duration were independently associated with ECP level. Airway wall thickness, assessed in a subset of patients using computed tomography, was significantly larger in L. CONCLUSION: Serum ECP levels in asthmatic patients may not be elevated during exacerbation and thus may not be a useful marker in patients who are older, have longer disease duration or possibly have thicker airway walls. Mechanisms other than eosinophilic inflammation, such as airway remodelling, may be involved in asthma exacerbation in these patients.     

CD14-dependent airway neutrophil response to inhaled LPS: role of atopy

BACKGROUND: Inhaled endotoxin (LPS) is associated with airway neutrophilic (PMN) inflammation in both asthmatic and control subjects, with asthmatic subjects demonstrating possibly higher sensitivity. CD14 is the principal receptor mediating LPS responses in vivo. It is unknown whether constitutive CD14 can predict the magnitude of the PMN response after LPS inhalation and whether atopy plays a role in this response. OBJECTIVE: We sought to examine associations between constitutive airway CD14 expression and LPS-induced PMNs after 5 microg of LPS inhalation and to examine associations between markers of atopy (eosinophils and eosinophil cationic protein) and CD14 expression and LPS-induced PMNs. METHODS: Ten atopic asthmatic subjects and 8 healthy control subjects inhaled 0.9% saline and LPS (Escherichia coli 026:B6, 5 microg) separated by 3 weeks. Induced sputum was collected at 24 hours before and 6 hours after inhalation. Induced sputum was analyzed for total and differential cell counts and soluble markers (soluble [s]CD14, eosinophil cationic protein, IL8, and total protein). Flow cytometry was used to analyze membrane-bound CD14 expression. RESULTS: Significant associations were found between the LPS-induced PMN response (PMNs per milligram of sputum) and both constitutive sCD14 (R = 0.7, P =.005) and membrane-bound CD14 (R = 0.9, P =.01). Asthmatic subjects demonstrated significantly higher levels of constitutive sCD14 compared with control subjects, and baseline eosinophils were significantly associated with baseline sCD14 (R = 0.7, P =.01) and LPS-induced PMNs (R = 0.6, P =.03). CONCLUSION: Constitutive airway CD14 expression can predict the magnitude of the PMN response after inhaled LPS. Atopy appears to play a role in the level of CD14 expression and may contribute to LPS sensitivity in asthmatic subjects.     

Chronic cough with eosinophilic bronchitis: examination for variable airflow obstruction and response to corticosteroid

The purpose of this study was to examine airway responsiveness, sputum cells and the effects of inhaled corticosteroid in the chronic cough syndrome associated with eosinophilic bronchitis. We studied nine consecutive referrals with chronic cough, sputum with >10% eosinophils, normal spirometry, and normal methacholine airway responsiveness. Clinical assessment, sputum analysis, allergy skin tests and a methacholine inhalation test were performed at the first visit. Peak expiratory flow (PEF) was measured twice daily for 1 week followed by an adenosine monophosphate (AMP) inhalation test. Subjects were then treated with inhaled beclomethasone 0.4 mg twice daily for 7 days. Sputum analysis and measurement of methacholine responsiveness were then repeated. Excessive airway narrowing to methacholine was not present in any of the subjects. A methacholine plateau response was present in five subjects. Hyperresponsiveness to AMP was absent in six of the nine subjects, and PEF variability was not increased for eight subjects. Corticosteroid therapy led to a reduction in sputum eosinophil counts from 40.1 (so 21.4)% to 4.0 (4.5)% but there was no significant change in metachromatic cell counts (0.8 so 0.5% vs 0.6 sd 0.6%) or total cell counts. Methacholine responsiveness improved within the normal range in the three subjects in whom it could be determined. Chronic cough associated with eosinophilic airway inflammation can occur in the absence of variable airflow obstruction (asthma) and can improve after treatment with inhaled corticosteroid. This treatment can reduce the level of methacholine responsiveness within the normal range and reduces sputum eosinophils but not mast cells. These results suggest that the occurrence of variable airflow obstruction depends on the baseline level of methacholine responsiveness, the degree of eosinophilic infiltration and the degree to which methacholine responsiveness becomes heightened.     

Eotaxin in induced sputum of asthmatics: relationship with eosinophils and eosinophil cationic protein in sputum

BACKGROUND: Eosinophilic inflammation is a crucial aspect of allergic diseases such as bronchial asthma. An eosinophil-active chemokine, eotaxin, may play a role in the pathogenesis of the tissue eosinophilia accompanying asthma. METHODS: Induced sputa were obtained from 53 patients with atopic asthma and six healthy subjects, and the concentration of eotaxin in the sputum was measured by ELISA. We investigated whether the sputum content of eotaxin is related to 1) asthma status or corticosteroid therapy, and 2) other sputum indices, including percentage of eosinophils and concentration of eosinophil cationic protein (ECP). RESULTS: The patients with stable or unstable asthma showed significantly higher concentrations of sputum eotaxin than the normal controls. The level of sputum eotaxin demonstrated a positive correlation with the percentage of eosinophils in stable asthmatics not receiving corticosteroid therapy, but not in stable patients treated with corticosteroids, or in unstable patients. Sputum eotaxin demonstrated a positive correlation with ECP in asthmatic patients who were either in a stable state or not receiving steroid therapy. CONCLUSIONS: The elevated level of eotaxin detected in association with increased eosinophils and ECP in the sputum of asthmatics suggests that eotaxin is involved in the pathogenesis of eosinophilic airway inflammation. The relationship of eotaxin to airway eosinophilia may be modified by the stability status of asthma and corticosteroid therapy.     

Changes in sputum cell counts after exposure to occupational agents: what do they mean?

BACKGROUND: Exposure to occupational agents can induce eosinophilic inflammation in subjects with occupational asthma (OA). It might also induce nonspecific changes in airway inflammation in subjects without OA. OBJECTIVES: We sought to investigate the changes in airway inflammation induced by exposure to occupational agents in subjects with and without OA and to determine which changes in sputum eosinophil numbers and bronchial responsiveness to methacholine should be regarded as clinically significant for predicting a 20% fall in FEV(1). METHODS: We performed specific inhalation challenges (SICs) in 3 groups of subjects: subjects reporting a history consistent with OA with a positive SIC response (n = 17); subjects reporting a history consistent with OA with a negative SIC response (n = 14); and asthmatic subjects without any history of OA (n = 10). Induced sputum and methacholine challenges were performed at the end of the control day and again at the end of the last day of exposure; the last day of exposure was always performed in the laboratory. RESULTS: There was an increase in median sputum eosinophil and neutrophil numbers in subjects with positive SIC responses. Cell counts remained unchanged after exposure in asthmatic subjects without OA. A combination of a greater than 0.26 10(6)/mL increase in sputum eosinophil numbers and a decrease in the concentration of methacholine inducing a 20% fall in FEV(1) of at least 1.8-fold compared with baseline values predicted a 20% fall in FEV(1) in 96% (95% CI, 70%-99%) of patients. CONCLUSION: Exposure to occupational agents per se does not induce airway inflammation. Changes in both sputum eosinophil counts and methacholine responsiveness are satisfactory predictors of a significant bronchial responsiveness to occupational agents.     

Clinical significance of measurement of urinary leukotriene E4 in asthmatic patients without attack]

To evaluate clinical significance of measurement of urinary leukotriene E4 (LTE4) in asthmatic patients without attack, we measured urinary LTE4 in 68 asthmatic patients without attack and investigated its correlation with severity of asthma, % FEV1, bronchial hyperresponsiveness and peripheral eosinophil counts. Values of urinary LTE4 were significantly higher in the asthmatic patients (113.6 +/- 9.7 pg/mg.cr) than in healthy control subjects (67.8 +/- 4.7, n = 31), and the level of urinary LTE4 was in proportion to the severity of disease. Urinary LTE4 showed significant negative correlation with % FEV1 in atopic patients (Rs = -0.43, p = 0.025, n = 28), which was not recognized in non-atopic patients. Urinary LTE4 showed no significant correlation with bronchial hyperresponsiveness and peripheral eosinophil counts. Our findings suggested that basal LTE4 in urine reflected chronic airway inflammation of asthma.     

Sputum eosinophil count in a large population of patients with mild to moderate steroid-naive asthma: distribution and relationship with methacholine bronchial hyperresponsiveness

BACKGROUND: Although airway eosinophilia is seen as a cardinal feature of asthma, data eosinophilia are still lacking on the proportion of the asthma group exhibiting raised airway eosinophilia. This study aimed to assess the distribution of sputum eosinophil count and its relationship with methacholine bronchial hyperresponsiveness in mild to moderate steroid-naive asthmatic people. METHODS: Sputum was induced by inhalation of hypertonic saline (NaCl 4.5%) in 118 mild to moderate steroid-naive asthmatic people consecutively recruited from our outpatient clinic, and in 44 healthy people. The asthma group was selected on the basis of an forced expiratory volume in 1 s (FEV(1)) of > or = 70% predicted, and a provocative methacholine concentration causing a fall of 20% in FEV(1) (PC20 methacholine; PC(20)M) < or = 16 mg/ml. RESULTS: In the asthma group, the median (range) of the percentage and the absolute values of sputum eosinophils were 4.8% (0-75) and 38 10(3)/g (0-14,191), respectively, vs 0% (0-2.3) (P < 0.001) and 0 10(3)/g (0-53) (P < 0.001) in healthy participants. Based on the 95% percentile for normal values calculated from our healthy group, 69% of the asthma group had significantly raised sputum eosinophil count (that is > 2%). In the asthma group, multiple regression analysis followed by a stepwise procedure revealed that sputum eosinophil count was significantly and inversely associated with PC(20)M accounting for 16% of its total variance (P < 0.001) while neutrophil counts positively related to PC(20)M accounting for 4% of total variance (P < 0.05). By contrast, no significant relationship was found between either eosinophil or neutrophil counts and the slope of forced vital capacity (FVC) vs FEV(1) from the methacholine challenge. CONCLUSIONS: We conclude that two-thirds of people in the mild to moderate asthma group had increased sputum eosinophilia, which plays a limited role in determining the degree of methacholine airway hyperresponsiveness.