Methacholine Airway Responsiveness Research Articles

Tuft cells are required for a rhinovirus-induced asthma phenotype in immature mice.

Infection of immature mice with rhinovirus (RV) induces an asthma-like phenotype consisting of type 2 inflammation, mucous metaplasia, eosinophilic inflammation, and airway hyperresponsiveness that is dependent on IL-25 and type 2 innate lymphoid cells (ILC2s). Doublecortin-like kinase 1-positive (DCLK1+) tuft cells are a major source of IL-25. We sought to determine the requirement of tuft cells for the RV-induced asthma phenotype in wild-type mice and mice deficient in Pou2f3, a transcription factor required for tuft cell development. C57BL/6J mice infected with RV-A1B on day 6 of life and RV-A2 on day 13 of life showed increased DCLK1+ tuft cells in the large airways. Compared with wild-type mice, RV-infected Pou2f3-/- mice showed reductions in IL-25 mRNA and protein expression, ILC2 expansion, type 2 cytokine expression, mucous metaplasia, lung eosinophils, and airway methacholine responsiveness. We conclude that airway tuft cells are required for the asthma phenotype observed in immature mice undergoing repeated RV infections. Furthermore, RV-induced tuft cell development provides a mechanism by which early-life viral infections could potentiate type 2 inflammatory responses to future infections.

Allergen-induced Increases in Sputum Levels of Group 2 Innate Lymphoid Cells in Subjects with Asthma.

Group 2 innate lymphoid cells (ILC2), a major source of type 2 cytokines, initiate eosinophilic inflammatory responses in murine models of asthma. To investigate the role of ILC2 in allergen-induced airway eosinophilic responses in subjects with atopy and asthma. Using a diluent-controlled allergen challenge crossover study, where all subjects (n = 10) developed allergen-induced early and late responses, airway eosinophilia, and increased methacholine airway responsiveness, bone marrow, blood, and sputum samples were collected before and after inhalation challenge. ILC2 (lin-FcεRI-CD45+CD127+ST2+) and CD4+T lymphocytes were enumerated by flow cytometry, as well as intracellular IL-5 and IL-13 expression. Steroid sensitivity of ILC2 and CD4+ T cells was investigated in vitro. A significant increase in total, IL-5+, IL-13+, and CRTH2+ ILC2 was found in sputum, 24 hours after allergen, coincident with a significant decrease in blood ILC2. Total, IL-5+, and IL-13+, but not CRTH2+, CD4+ T cells significantly increased at 24 and 48 hours after allergen in sputum. In blood and bone marrow, only CD4+ cells demonstrated increased activation after allergen. Airway eosinophilia correlated with IL-5+ ILC2 at all time points and allergen-induced changes in IL-5+ CD4+ cells at 48 hours after allergen. Dexamethasone significantly attenuated IL-2- and IL-33-stimulated IL-5 and IL-13 production by both cell types. Innate and adaptive immune cells are increased in the airways associated with allergic asthmatic responses. Total and type 2 cytokine-positive ILC2 are increased only within the airways, whereas CD4+ T lymphocytes demonstrated local and systemic increases. Steroid sensitivity of both cells may explain effectiveness of this therapy in those with mild asthma.

A nonsteroidal glucocorticoid receptor agonist inhibits allergen-induced late asthmatic responses.

Effective antiinflammatory therapies are needed for the treatment of asthma, but preferably without the systemic adverse effects of glucocorticosteroids. We evaluated the effect of an inhaled nonsteroidal glucocorticoid receptor agonist, AZD5423, on allergen-induced responses. Twenty subjects with mild allergic asthma were randomized to receive 7 days of treatment with nebulized AZD5423 (75 or 300 μg) once daily, budesonide 200 μg twice daily via Turbuhaler, or placebo in a double-blind, four-period, crossover design study. Allergen challenge was performed on Day 6. FEV1 was measured repeatedly for 7 hours after allergen challenge for early and late asthmatic responses. Sputum inflammatory cells was measured before and at 7 and 24 hours after allergen challenge, and methacholine airway responsiveness was measured before and 24 hours after allergen challenge. AZD5423 significantly attenuated the fall in FEV1 during the late asthmatic response (both doses led to an 8.7% fall) versus placebo (14% fall) (P < 0.05) with no effect of budesonide (12.5% fall) versus placebo (P > 0.05). There was no effect on the fall in FEV1 during early asthmatic response. AZD5423 300 and 75 μg significantly attenuated allergen-induced sputum eosinophilia by 63 and 61% at 7 hours, respectively, and by 46 and 34% at 24 hours after allergen challenge, respectively, versus placebo (all P < 0.05). Budesonide did not reduce allergen-induced sputum eosinophilia versus placebo. AZD5423 at 300 μg significantly attenuated allergen-induced airway hyperresponsiveness at 24 hours after allergen challenge versus placebo (P < 0.05). Both doses of AZD5423 were well tolerated. Seven-day treatment with inhalation of the nonsteroidal glucocorticoid receptor agonist AZD5423 effectively reduced allergen-induced responses in subjects with mild allergic asthma. Clinical trial registered with www.clinicaltrials.gov (NCT01225549).

Effects of ASM-024, a modulator of acetylcholine receptor function, on airway responsiveness and allergen-induced responses in patients with mild asthma.

To evaluate the safety, tolerability and clinical activity of ASM-024, a new cholinergic compound with dual nicotinic and muscarinic activity, in mild allergic asthma. The present study involved 24 stable, mild allergic asthmatic subjects. In a cross-over design, ASM-024 (50 mg or 200 mg) or placebo were administered once daily by nebulization over three periods of nine consecutive days separated by a three-week washout. The effect of each treatment on the forced expiratory volume in 1 s (FEV1), provocative concentration of methacholine causing a 20% decline in FEV1 (PC20), early and late asthmatic responses, and allergen-induced inflammation were measured. Seventeen subjects completed the study. During treatment with ASM-024 at 50 mg or 200 mg, the PC20 value increased respectively from a mean (± SD) 2.56±3.86 mg/mL to 4.11 mg/mL (P=0.007), and from 3.12±4.37 mg/mL to 5.23 mg/mL (P=0.005) (no change with placebo). On day 7 (day preceding allergen challenge), postdosing FEV1 increased by 2.0% with 50 mg (P=0.005) and 1.9% with 200 mg (P=0.008) (placebo -1.1%). ASM-24 had no inhibitory effect on early and late asthmatic responses, nor on sputum eosinophil or neutrophil levels. ASM-024 induced no serious adverse events, but caused cough in 22% and 48% of the subjects with 50 mg and 200 mg, respectively, compared with 10% who were on placebo. ASM-024 did not inhibit allergen-induced asthmatic response and related airway inflammation, but reduced methacholine airway responsiveness and slightly improved lung function. The mechanism by which ASM-024 improves these outcomes requires further study.

Lung-Homing of Endothelial Progenitor Cells and Airway Vascularization Is Only Partially Dependant on Eosinophils in a House Dust Mite-Exposed Mouse Model of Allergic Asthma

BackgroundAsthmatic responses involve a systemic component where activation of the bone marrow leads to mobilization and lung-homing of progenitor cells. This traffic may be driven by stromal cell derived factor-1 (SDF-1), a potent progenitor chemoattractant. We have previously shown that airway angiogenesis, an early remodeling event, can be inhibited by preventing the migration of endothelial progenitor cells (EPC) to the lungs. Given intranasally, AMD3100, a CXCR4 antagonist that inhibits SDF-1 mediated effects, attenuated allergen-induced lung-homing of EPC, vascularization of pulmonary tissue, airway eosinophilia and development of airway hyperresponsiveness. Since SDF-1 is also an eosinophil chemoattractant, we investigated, using a transgenic eosinophil deficient mouse strain (PHIL) whether EPC lung accumulation and lung vascularization in allergic airway responses is dependent on eosinophilic inflammation.MethodsWild-type (WT) BALB/c and eosinophil deficient (PHIL) mice were sensitized to house dust mite (HDM) using a chronic exposure protocol and treated with AMD3100 to modulate SDF-1 stimulated progenitor traffic. Following HDM challenge, lung-extracted EPCs were enumerated along with airway inflammation, microvessel density (MVD) and airway methacholine responsiveness (AHR).ResultsFollowing Ag sensitization, both WT and PHIL mice exhibited HDM-induced increase in airway inflammation, EPC lung-accumulation, lung angiogenesis and AHR. Treatment with AMD3100 significantly attenuated outcome measures in both groups of mice. Significantly lower levels of EPC and a trend for lower vascularization were detected in PHIL versus WT mice.ConclusionsThis study shows that while allergen-induced lung-homing of endothelial progenitor cells, increased tissue vascularization and development lung dysfunction can occur in the absence of eosinophils, the presence of these cells worsens the pathology of the allergic response.

Pathophysiological characteristics of asthma in the elderly: a comprehensive study

BackgroundComprehensive studies of the pathophysiologic characteristics of elderly asthma, including predominant site of disease, airway inflammation profiles, and airway hyperresponsiveness, are scarce despite their clinical importance. ObjectiveTo clarify the pathophysiologic characteristics of elderly patients with asthma. MethodsPatients older than 65 years (elderly; n = 45) vs those no older than 65 years (nonelderly; n = 67) were retrospectively analyzed by spirometry, computed tomographic indices of large airway wall thickness and small airway involvement (air trapping), impulse oscillation measurements, exhaled nitric oxide levels, blood and induced sputum cell differentials, methacholine airway responsiveness, and total and specific serum IgE levels. ResultsElderly patients with asthma had significantly lower values for forced expiration volume in 1 second, mid-forced expiratory flow (percentage predicted), and ratio of forced expiration volume in 1 second to forced vital capacity than nonelderly patients with asthma (median 81.2% vs 88.8%, P = .02; 50.9% vs 78.6%, P = .03; 0.72 vs 0.78, P = .001, respectively). In computed tomographic measurements, elderly patients with asthma had significantly greater airway wall thickening and air trapping than nonelderly patients. Impulse oscillation measurements indicated that elderly patients with asthma showed significantly greater resistance at 5 Hz (used as an index of total airway resistance), greater decrease in resistance from 5 to 20 Hz, a higher ratio of decrease in resistance from 5 to 20 Hz to resistance at 5 Hz, higher integrated area between 5 Hz and frequency of resonance, greater frequency of resonance, and lower reactance at a frequency of 5 Hz (potential markers of small airway disease) than nonelderly patients. There were no significant differences in blood or sputum cell differentials, exhaled nitric oxide, or methacholine airway responsiveness between the 2 groups. Total serum IgE levels and positive rates of specific IgE antibodies against several allergens were significantly lower in elderly than in nonelderly patients with asthma. ConclusionBased on spirometric, computed tomographic, and impulse oscillation analyses, elderly patients with asthma have greater involvement of small and large airways than nonelderly patients with asthma.

Comprehensive efficacy of omalizumab for severe refractory asthma: a time-series observational study

BackgroundOmalizumab, a humanized anti-IgE monoclonal antibody, is reportedly an effective treatment for severe allergic asthma. However, there have been few comprehensive analyses of its efficacy, including assessments of small airways or airway remodeling. ObjectiveTo comprehensively evaluate the efficacy of omalizumab, including its effects on small airways and airway remodeling, in adult patients with severe refractory asthma. MethodsIn this prospective, time-series, single-arm observational study, 31 adult patients with severe refractory asthma despite the use of multiple controller medications, including high-dose inhaled corticosteroids (1,432 ± 581 μg/d of fluticasone propionate equivalent), were enrolled. Clinical variables, including Asthma Quality of Life Questionnaire, asthma exacerbations, exhaled nitric oxide, pulmonary function, methacholine airway responsiveness, induced sputum, and chest computed tomogram, were assessed at baseline and after 16 and 48 weeks of treatment with omalizumab. ResultsTwenty-six of the 31 patients completed 48 weeks of treatment. For these patients, Asthma Quality of Life Questionnaire scores and peak expiratory flow values significantly and continuously improved throughout the 48 weeks (P < .001 for all comparisons). Unscheduled physician visits, asthma exacerbations requiring systemic corticosteroids, fractional exhaled nitric oxide at 50 mL/s and alveolar nitric oxide levels, sputum eosinophil proportions, and airway-wall thickness as assessed by computed tomography significantly decreased at 48 weeks (P < .05 for all comparisons). ConclusionOmalizumab was effective for adult patients with severe refractory asthma. Omalizumab may have anti-inflammatory effects on small airways and reverse airway remodeling. Trial registrationUMIN000002389.

Cough frequency in health and disease

To the Editor: Chronic cough is a difficult clinical problem, partly because there is an absence of well-validated means to assess cough [1, 2]. We have previously reported that the semi-automated computerised Leicester Cough Monitor detects cough accurately over 6 h and that cough frequency is increased in patients with chronic cough compared to controls [3, 4]. There remains uncertainty on the performance of the system over 24 h and across the range of expected cough frequency in larger populations. We set out to address these questions in healthy adult volunteers and adult volunteers with respiratory disease. 44 healthy volunteers were recruited from those responding to a poster advertisement. All reported no current respiratory symptoms, were nonsmokers with a <5 pack-yr past smoking history and had normal spirometric values, methacholine airway responsiveness and induced sputum inflammatory cell counts. 78 patients with respiratory disease were recruited from respiratory clinics. The diagnostic criteria for the conditions have been described previously [5]. Six current smokers and four males taking angiotensin converting enzyme inhibitors (ACEi) were also recruited. The study was approved by the Leicestershire, Northampton and Rutland Research Ethics Committee. All volunteers underwent spirometry and those with normal spirometry had a methacholine inhalation test using the tidal breathing method. The Leicester Cough Monitor (iRiver iFP-799 mp3 device; iRiver Europe GmbH, Eschborn, Germany and Sennheiser MKE 2–5 field microphone; Sennheiser electronic GmbH & Co. KG, Wedemark, Germany) was attached and recordings obtained and analysed as …

Clinical, Physiological and Anti-Inflammatory Effect of Montelukast in Patients with Cough Variant Asthma

Background: Cough variant asthma (CVA) is a phenotype of asthma presenting solely with coughing, characterized by airway hyperresponsiveness, eosinophilic inflammation and a cough response to bronchodilators. Leukotriene receptor antagonists (LTRAs) are antiasthma medications with anti-inflammatory and bronchodilatory properties. Although LTRAs exert antitussive effects in CVA, the mechanisms involved are unknown. Objectives: This study aimed to clarify the antitussive mechanisms of LTRAs in CVA patients. Methods: We prospectively observed the effect of montelukast (10 mg) daily for 4 weeks in 23 consecutive nonsmoking adults with anti-inflammatory treatment-naive CVA. We evaluated, before and after treatment, the cough visual analogue scale (VAS), pulmonary function (spirometry and impulse oscillation), methacholine airway responsiveness, cough receptor sensitivity, expressed by the concentration of capsaicin inducing 2 or more (C2) and 5 or more (C5) coughs, sputum eosinophil counts and levels of inflammatory mediators, including cysteinyl leukotrienes, leukotriene B₄, prostaglandin (PG) D₂, PGE₂, PGF₂_α and thromboxane B₂. We compared the baseline characteristics of the patients based on the symptomatic response to montelukast, defined as a decrease in the cough VAS of >25% (n = 15) or ≤25% (n = 8). Results: Montelukast significantly decreased the cough VAS (p = 0.0008), sputum eosinophil count (p = 0.013) and cough sensitivity (C2: p = 0.007; C5: p = 0.039), whereas pulmonary function, airway responsiveness and sputum mediator levels remained unchanged. Multivariate analysis showed that a better response to montelukast was associated solely with younger age (p = 0.032). Conclusion: The antitussive effect of montelukast in CVA may be attributed to the attenuation of eosinophilic inflammation rather than its bronchodilatory properties.

Validation study of asthma screening criteria based on subjective symptoms and fractional exhaled nitric oxide

In the latest Global Initiative for Asthma guideline, neither sputum eosinophilia nor fractional exhaled nitric oxide (FeNO) have been evaluated prospectively as an aid in asthma diagnosis, but these measurements are being evaluated for potential use in determining optimal treatment. To report criteria for screening asthma using subjective symptoms and FeNO levels and results of a prospective validation study using these criteria. Sixty-one outpatients with recurrent cough, wheezing, or dyspnea underwent measurements of FeNO levels, pulmonary function, methacholine airway responsiveness, and inflammatory cells in induced sputum. The sensitivity, specificity, and concordance achieved using the FeNO-based criteria (at least 1 of the following subjective symptoms: recurrent cough, wheezing, or dyspnea and/or FeNO level ≥ 40 ppb) were analyzed and compared with the values obtained using conventional asthma diagnostic criteria, which includes subjective symptoms with any 2 of the following conditions: airway hyperresponsiveness, reversible airflow limitation, and eosinophilia in induced sputum. Of the 61 patients, 41 were diagnosed as having asthma by the conventional criteria, and 33 were diagnosed as having asthma by the FeNO-based criteria, which showed a sensitivity of 78.6%, a specificity of 89.5%, and a concordance rate of 0.62. Nine of 42 patients were misdiagnosed as not having asthma by FeNO-based criteria (mean [SD] FeNO level, 23.9 [8.0] ppb). Seven of 9 patients were diagnosed as having nonatopic asthma according to IgE levels. Asthma may be accurately diagnosed in daily practice on the basis of subjective symptoms and FeNO levels, particularly in atopic patients.

Allergen inhalation challenge in smoking compared with non-smoking asthmatic subjects

Smoking asthmatics experience more severe symptoms, require more rescue medication and have more asthma-related hospitalizations than non-smoking asthmatics. However, studies in mice suggest that mainstream cigarette smoke may reduce airway inflammation and may attenuate airway hyperresponsiveness. A comparison of allergen-induced airway inflammatory responses of smoking and non-smoking atopic asthmatics has not been examined previously. To determine whether allergen-induced airway responses and inflammatory profiles are attenuated in smoking when compared with non-smoking mild allergic asthmatic subjects. Allergen inhalation challenges were performed in 13 smoking and 19 non-smoking mild allergic asthmatic subjects. The forced expired volume in 1 s (FEV(1) ) was measured up to 7 h after allergen inhalation. Methacholine airway responsiveness was measured before and at 24 h after allergen and sputum was induced before and at 7 and 24 h after allergen. Both the smoking and non-smoking groups developed similar allergen-induced falls in FEV(1) during the early and late asthmatic responses and similar increases in allergen-induced airway eosinophils. The mean maximum fall in FEV(1) during the late response was 16.3 ± 4.3% in non-smokers and 12.9 ± 7.2% in smokers. The smoking asthmatics, however, did not develop allergen-induced methacholine airway hyperresponsiveness, whereas the non-smoking controls developed a 1.18 doubling dose shift in methacholine PC(20) (P < 0.05). Mild allergic asthmatic subjects, who were current smokers with a mean 6-year pack history, develop allergen-induced eosinophilic airway inflammation and late responses, similar in magnitude to non-smoking asthmatics, but do not develop methacholine airway hyperresponsiveness associated with the allergen-induced airway eosinophilia.

Change in airway responsiveness over a workweek in organic waste loaders

Organic waste workers are exposed to high endotoxin levels that may result in respiratory health effects. This study describes changes in lung function and methacholine airway responsiveness over a workweek in household organic waste loaders. Assessment of lung function and methacholine airway responsiveness before and after a workweek in six organic waste loaders with and ten loaders without regular respiratory symptoms. Methacholine responsiveness was expressed as dose-response slope, i.e. % fall in FEV(1) per mg methacholine compared to either the post-saline value (DRS(sal)), or the highest FEV(1) (DRS(max)). Monday morning, FEV(1) was similar in cases and controls. Over the workweek, FEV(1) and MMEF decreased slightly in both cases and controls (P > 0.10). In contrast, DRS increased in cases and decreased in control subjects (P < 0.10). The difference in % change of DRS was statistically significant after adjustment for smoking and age. Our results suggest exaggeration of pre-existent airway inflammation during the workweek in organic waste loaders with regular respiratory symptoms. This needs confirmation in larger studies.

Structural and functional localization of airway effects from episodic exposure of infant monkeys to allergen and/or ozone

Both allergen and ozone exposure increase asthma symptoms and airway responsiveness in children. Little is known about how these inhalants may differentially modify airway responsiveness in large proximal as compared to small distal airways. We evaluated whether bronchi and respiratory bronchioles from infant monkeys exposed episodically to allergen and/or ozone differentially develop intrinsic hyperresponsiveness to methacholine and whether eosinophils and/or pulmonary neuroendocrine cells play a role. Infant monkeys were exposed episodically for 5 months to: (1) filtered air, (2) aerosolized house dust mite allergen, (3) ozone 0.5 ppm, or (4) house dust mite allergen + ozone. Studying the function/structure relationship of the same lung slices, we evaluated methacholine airway responsiveness and histology of bronchi and respiratory bronchioles. In bronchi, intrinsic responsiveness was increased by allergen exposure, an effect reduced by bombesin antagonist. In respiratory bronchioles, intrinsic airway responsiveness was increased by allergen + ozone exposure. Eosinophils were increased by allergen and allergen + ozone exposure in bronchi and by allergen exposure in respiratory bronchioles. In both airways, exposure to allergen + ozone resulted in fewer tissue eosinophils than did allergen exposure alone. In bronchi, but not in respiratory bronchioles, the number of eosinophils and neuroendocrine cells correlated with airway responsiveness. We conclude that episodically exposing infant monkeys to house dust mite allergen with or without ozone increased intrinsic airway responsiveness to methacholine in bronchi differently than in respiratory bronchioles. In bronchi, eosinophils and neuroendocrine cells may play a role in the development of airway hyperresponsiveness.

Comparison of asthma treatment given in addition to inhaled corticosteroids on airway inflammation and responsiveness

There is increasing evidence that the assessment of eosinophilic airway inflammation using induced sputum and measurement of airway hyperresponsiveness provides additional, clinically important information concerning asthma control. The aim of this study was to directly compare the effects of different treatments on these markers in patients with asthma and persistent symptoms, despite the use of low-dose inhaled corticosteroids. A double-blind four-way crossover study was performed, which compared a 1-month treatment with budesonide 400 mug b.i.d., additional formoterol, additional montelukast and placebo in 49 patients with uncontrolled asthma despite budesonide 100 mug b.i.d., with each treatment separated by a 4-week washout period. The change in sputum eosinophil count with formoterol (2.4 to 3.8% change, 0.6-fold reduction, 95% confidence interval (CI) 0.5-0.9) differed significantly from placebo (2.8 to 2.5% change, 1.1-fold reduction, 95% CI 0.7-1.6) and high-dose budesonide (2.7 to 1.6% change, 1.6-fold reduction, 95% CI 1.2-2.2). The effects of montelukast did not differ from placebo. The changes in methacholine airway responsiveness were small and did not differ between treatments. High-dose budesonide had the broadest range of beneficial effects on other outcomes, including symptom scores, morning peak expiratory flow and forced expiratory volume in one second. In conclusion, treatment given in addition to low-dose inhaled corticosteroids results in modest benefits. Formoterol and high-dose budesonide have contrasting effects on eosinophilic airway inflammation.

Diagnosing occupational asthma: insight from induced sputumThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigator's Forum.

The diagnosis of occupational asthma needs to be made objectively using as many criteria as possible. The latter include laboratory exposure tests with occupational agent(s), which are only available in specialized centers. Another approach is to monitor peak expiratory flow (PEF) and (or) methacholine airway responsiveness during periods at work and away from work. However, these measurements are open to misinterpretation when they are not optimally performed. Airway inflammation is one of the main characteristics of asthma. Induced sputum, a non-invasive method to assess airway inflammation, has been successfully used in the management of asthma. However, airway inflammation is seldom assessed during the investigation of occupational asthma. This article reviews the studies that have investigated and characterized the changes in sputum cell counts occurring in subjects with occupational asthma after exposure to occupational agents in the laboratory, or at the workplace to assess to place of induced sputum in the investigation of occupational asthma.

Mast cell mediator releasability correlates with AMP airway responsiveness in atopic subjects

RATIONALE: Mast cells are likely to play a major role in the bronchoconstrictor response to inhaled AMP. BHR to AMP appears to reflect airway allergic inflammation more accurately than BHR to methacholine. Aim of this study was to evaluate whether mast cell degranulation in the nasal lavage fluid (NLF) of atopic individuals undergoing nasal provocation with AMP is better related to AMP than methacholine airway responsiveness.

The use of sputum eosinophils in the evaluation of occupational asthma.

The diagnosis of occupational asthma needs to be made objectively using as many criteria as possible. These include laboratory exposure tests with occupational agent(s), which are only available in specialized centres. Another approach is to monitor peak expiratory flow or methacholine airway responsiveness during periods at work and away from work. However, these measurements are open to misinterpretation when they are not performed optimally. Airway inflammation is one of the main characteristics of occupational asthma, but is not often assessed during its investigation. The purpose of this work was to review recent studies that have investigated and characterized the changes in sputum cell counts occurring in patients with occupational asthma, in order to evaluate the role of the analysis of sputum cell counts. There is evidence that monitoring sputum eosinophils can help in the management of asthma. In the majority of cases of occupational asthma, the percentage of sputum eosinophils increases after exposure to occupational agents in the laboratory compared with baseline, but an increase in sputum neutrophils has also been observed. The changes in airway inflammation occurring at the workplace have been less investigated, but indicate that there are significant changes in airway inflammation and especially sputum eosinophils when workers are exposed to a sensitizer at their workplace compared with periods away from the workplace. Induced sputum has successfully been used to manage patients with mild to moderate asthma. Its use is promising in occupational asthma, and its role in the investigation of occupational asthma needs to be better defined.

Intranasal corticosteroids for asthma control in people with coexisting asthma and rhinitis.

Allergic rhinitis and asthma are mediated by similar allergic mechanisms. They may represent two manifestations of the same united airway disease and therefore intranasal corticosteroids (INCS) could improve asthma. Nevertheless none of the asthma guidelines have advocated intranasal corticosteroids for asthma. To assess the efficacy of intranasal corticosteroids on asthma outcomes in people with rhinitis and asthma. We searched the Cochrane Airways Group trials register, the Cochrane Central Register of Controlled Trials (Issue 1, 2003), MEDLINE and reference lists of articles. We also contacted researchers in the field. Last search updated in March 2003. Randomised controlled trials comparing intranasal corticosteroids to intranasal placebo or to other traditional asthma treatments were included. Intrabronchial corticosteroids were not allowed but a device combining intranasal and intrabronchial corticosteroid was considered as being a primary INCS technique and was therefore also compared to placebo. Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Quality assessment for the 14 eligible studies was performed using the Jadad score and by ranking allocation concealment. Statistical analysis for continuous data was done by weighted mean difference or standardised mean difference. Fourteen trials involving 477 people were included. Meta-analysis for asthma outcomes failed to show a statistically significant benefit of INCS in asthma. However, for symptom scores and forced expiratory volume in one second, the trend favoured a beneficial effect of INCS. For asthma symptom scores (two parallel studies), the standardised mean difference was 0.61 (95% confidence interval (CI) -0.04 to 1.26). Meta-analysis for forced expiratory volume in one second (five parallel studies) gave a standardised mean difference of 0.31 (95% CI -0.04 to 0.65). In the parallel studies, meta-analysis of peak expiratory flow gave a standardised mean difference of -0.10 Litres/min (95% CI -0.55 to 0.35) for mean peak flow (three studies). Meta-analysis for methacholine airway responsiveness (three parallel studies) showed a standardised mean difference of -0.20 (-95% CI 0.64 to 0.24). Intranasal corticosteroids were well tolerated. While INCS tended to improve asthma symptoms and forced expiratory volume in one second, the results did not reach significance. The combination of intranasal plus intrabronchial corticosteroids should remain the current clinical practice until more research is done.

Allergen-induced fluctuation in CC chemokine receptor 3 expression on bone marrow CD34+ cells from asthmatic subjects: significance for mobilization of haemopoietic progenitor cells in allergic inflammation.

There is increasing evidence that primitive progenitors migrate from the bone marrow (BM) via the peripheral circulation to tissue sites where they undergo in situ differentiation to provide a continued source of effector cells, such as eosinophils, during an allergic inflammatory response. To study mechanisms of progenitor cell mobilization in allergic reactions, we investigated fluctuations in the expression of the eotaxin receptor, CC chemokine receptor 3 (CCR3), on CD34+ cells from stable asthmatics following allergen (i.e. antigen) challenge. BM aspirates were taken from seven early responder (ER) and 10 dual responder (DR) asthmatics who, following antigen challenge developed only an early bronchoconstrictor response and an early and late- bronchoconstrictor response, respectively. Expression of CCR3 was detected on primitive (CD34+ cells) and eosinophil-lineage committed progenitors (CD34+ interleukin-5 receptor alpha-subunit+ cells) by flow cytometry and confirmed by co-localization of CCR3 messenger RNA to CD34 immunopositive cells using in situ hybridization. When preantigen levels were compared to 24-hr postantigen levels, significant increases in BM CD34+ CCR3+ cells were detected in DR, who also developed a significant sputum and blood eosinophilia and increased methacholine airway responsiveness. In contrast, a significant attenuation of BM CD34+ CCR3+ cells was observed in ER. In a dose-dependent manner eotaxin, but not interleukin (IL)-5, stimulated CD34+ progenitor cell migration in vitro. This migrational response to eotaxin was abrogated by anti-CCR3 monoclonal antibody and primed by preincubation with IL-5. We propose that fluctuations in CCR3 expression on human BM CD34+ cells may facilitate chemokine-mediated progenitor cell mobilization to the peripheral circulation and the resultant development of pulmonary eosinophilia, a cardinal feature of asthma.

Serum Cytokine Levels, Cigarette Smoking and Airway Responsiveness among Pregnant Women

Background: Five to twenty percent of healthy, nonasthmatic individuals exhibit airway hyperreactivity. Because cytokines are important intermediates in airway responses, we investigated the relationship between serum cytokines and airway responsiveness in a well-characterized population of pregnant women. Methods: We analyzed serum levels of interleukin-4 (IL-4), IL-5, IL-6, interferon-γ (IFN-γ), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in frozen sera from 240 pregnant nonasthmatic subjects from a previous study of airway responsiveness and preterm labor for their relationship to methacholine challenge test results. Results: Serum IFN-γ and GM-CSF levels were significantly related to levels of methacholine airway responsiveness among nonasthmatics in this population. Nonasthmatics with PD₂₀ <8 µmol (the highest level of airway responsiveness) had the highest mean serum levels of IFN-γ and GM-CSF, those with 8 ≤ PD₂₀ ≤ 50 µmol had intermediate levels, and those with PD₂₀ >50 µmol had the lowest levels. Both serum IFN-γ and GM-CSF levels were also significantly related to the log dose-response slope for methacholine responsiveness. These relationships were confirmed in a multiple linear regression analysis controlling for age, ethnic background, and cigarette smoking. Current smoking was uniformly associated with decreased cytokine levels. Conclusion: IFN-γ, GM-CSF, and other cytokines may be useful serum markers in population studies of airway responsiveness.