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Notes: Background Granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin-4 (IL-4) and IL-5 are important in tissue eosinophil accumulation and high IgE production in allergic inflammatory reaction.Objective We examine lung GM-CSF, IL-4 and IL-5 expression in a murine model of allergic bronchopulmonary aspergillosis (ABPA) characterized by eosinophil and lymphocyte lung infiltration and elevated serum IgE level.Methods C57BL/6 mice were intranasally treated three times a week for 1, 2 or 3 week(s) with Aspergillus fumigatus (Af) antigen or saline and were sacrificed on days 7, 14 and 21. Immunohistochemical analyses for GM-CSF, IL-4 and IL-5 were performed on lung sections.Results Af treatment induced a remarkable pulmonary eosinophil influx. Increased numbers of lung T lymphocytes and GM-CSF positive cells were observed on days 14 and 21. IL-4 and IL-5 positive cells were increased significantly only on day 14. Immunostained serial sections showed that most (≥98%) cytokine positive cells were CD3 positive. Few eosinophils (〈2% of cytokine positive cells) were immunoreactive for GM-CSF and IL-5. Significant correlations were found between the number of GM-CSF and IL-5 positive cells, and the number of eosinophils in Af-treated lung (r = 0.62, P 〈 0.05 and r = 0.52, P 〈 0.05, respectively), and between the number of IL-4 positive cells and the serum total IgE level (r = 0.64, P〈0.01).Conclusions Our data suggest a role for T lymphocyte GM-CSF, IL-4 and IL-5 in Af-induced mouse pulmonary eosinophilia and increased serum IgE production and further support the importance of T helper (TH) cells in the pathogenesis of ABPA.

Notes: Background Pathophysiology of corticosteroid (CS)-resistant asthma remains incompletely understood.Objective To determine if failure of asthma to clinically improve with CS is due to a defective response of airway bronchial inflammation to these drugs.Methods Twenty-one asthmatics having a decreased baseline FEV1 that improved ≥ 30% with inhaled β2 agonist got bronchial biopsies before and at the end of an oral CS treatment (methylprednisolone 40 mg daily for 14 days). They were arbitrarily divided into two groups according to baseline FEV1 improvement following this treatment: ≥ 23% designated as CS-sensitive (CSS) (n = 10) and 〈 15% as CS-resistant (CSR) (n = 11).Results Before oral CS, counts of bronchial mucosa inflammatory cells identified by immunohistochemistry (CD3, MBP, tryptase, CD68, neutrophil elastase and CD25 for lymphocytes, eosinophils, mast cells, macrophages, neutrophils and IL-2 receptors, respectively) were similar in CSS and CSR subjects. Oral CS decreased CD3+ cell counts (medians: 60–20 cells/mm2; P = 0.014) and MBP+ cell counts (medians: 19–4 cells/mm2; P = 0.03) in CSS asthmatics, but only tryptase+ cell counts in CSR asthmatics (medians: 30–18 cells/mm2; P = 0.05). Few bronchial neutrophil elastase+ cells were observed and their counts were similar in the two groups of asthmatics before and when on oral CS (all medians: = 2 cells/mm2).Conclusions These data show that, in these subjects with moderate to severe asthma, lymphocytes and eosinophils constitute most of the inflammatory cells infiltrating the bronchial mucosa. They also demonstrated that clinical impaired response to CS is associated with a persistent bronchial mucosa cellular infiltrate despite oral CS treatment. Additional studies are required to determine the role of this CS-resistant bronchial inflammation in the impaired asthma clinical response to these drugs.

Notes: Background Low-dose allergen challenge (LDAC) may be a useful tool for studying the capacity of allergens to induce airway inflammation in atopic subjects.Objective To evaluate lower airway inflammatory changes following repeated inhalation of very low doses of allergen (VLDAC) in non-asthmatic subjects with allergic rhinitis (NAAR) compared with mild allergic asthmatic subjects (AA).Methods Fourteen NAAR and 11 AA were seen out of the pollen season and had skin prick tests with common aeroallergens. Baseline spirometry (S) and methacholine challenge (MC) were done and blood and induced sputum (IS) differential cell counts were obtained. Each subject underwent VLDAC on four consecutive mornings with a relevant allergen. S, MC, and blood and IS samplings were repeated 6 h after the second and fourth VLDAC and one week later.Results Although there were, as expected, no changes in FEV1 or PC20 in either group, mean percentage eosinophils on IS were significantly increased in NAAR on day 2 of VLDAC and decreased in all but one subject on day 4, with a tendency to return to baseline levels one week later. In AA, there was a non-significant trend for sputum eosinophils to increase on day 2; four subjects showed a decrease of eosinophils on day 4 of VLDAC. There was a correlation between eosinophil cationic protein (ECP) levels and eosinophil counts in NAAR throughout the study. There were no variations in other sputum cells or blood inflammatory cells.Conclusion VLDAC can increase the percentage of eosinophils in IS of NAAR subjects without associated respiratory symptoms nor physiological modifications. A reduction in eosinophilic response despite repeated exposure, more common in NAAR subjects, suggests an adaptation process that needs to be further evaluated.

Notes: Background and objectives The determinants of variability in the clinical expression of atopy are still to be documented. The goals of this study were to determine, in subjects with a clinical diagnosis of symptomatic asthma or rhinitis, what is the possible contribution of different types of indoor and outdoor allergens to the development of their disease, by looking at the prevalence and degree of sensitization to these allergens according to age and gender.Subjects and methods We analysed allergy skin prick tests to common airborne indoor and outdoor allergens in 3371 consecutive patients, grouped according to diagnosis of allergic asthma, rhinitis, or both. For each of these three groups, we calculated the prevalence of sensitization to indoor/outdoor allergens, the atopic index (Al), the number of positive responses to allergy skin prick test and the mean wheal diameter (MWD) of these responses.Results The prevalence of atopy and the values of Al and MWD peaked in subjects aged 16 to 25 years, declining afterwards; in subjects ± 18 years old, atopic indices were slightly higher in men than in women. In atopic subjects, the prevalence of sensitization was, in decreasing order: housedust (84.2%), cat hair-epithelium (76.5%), dog hair-dander (63.0%), house dust mite (54.2%), grasses (51.9%), trees (47.2%) and ragweed pollens (44.9%) and finally, moulds (25.4%). Among subjects sensitized only to outdoor allergens (n= 195), 73.8% had a rhinitis, 11.8% had asthma and 14.4% had both diagnoses; for those sensitized only to indoor allergens (n= 710), these values were respeetively 48.6, 24.5 and 26.9%, and for those sensitized to both indoor and outdoor allergens (n= 1793), the comparable values were 55.5, 14.6 and 29.9%.Conclusion These data show that in our population of subjects with respiratory allergic symptoms, indoor allergen sensitization is strongly associated with asthma, while exclusive sensitization to pollens is associated primarily with rhinitis. Sensitization was more prevalent for indoor allergens than for outdoor allergens in all groups determined according to diagnosis or age. Indices of atopy were higher in men in the group ± 18 years old. Prevalence and degree of sensitization were shown to peak in young adults, regardless of the allergen, and to diminish with age. This study stresses the role of indoor allergens in the development of asthma and shows the variability of allergic manifestations according to the type of sensitization.

Notes: Relationships between cutaneous and bronchial responses to allergen were examined in nineteen atopic asthmatics. Allergen inhalation tests elicited an isolated early asthmatic response (EAR) in ten subjects and a dual asthmatic response (DAR) in nine subjects. Ragweed IgE RAST, performed with the sera of those patients tested with ragweed antigen, yielded higher values in all but one patient who experienced DAR than any of the patients with EAR. In one patient with annual symptoms in the ragweed season, positive skin tests with ragweed antigen and DAR to inhaled ragweed extracts, the IgE RAST was entirely negative and the serum IgE concentration was low. Dilutions of the allergen used in each individual for inhalation were also used in skin-prick tests. Early cutaneous allergic response (ECAR) mean wheal diameters were obtained at 10 min and late cutaneous allergic response (LCAR) mean diameters at 6-8 hr. Early asthmatic response (EAR) subjects differed modestly from DAR subjects in the relationships between ECAR and LCAR; in the EAR group, a significantly larger wheal diameter (P 〈 0.01) was required before an LCAR ensued, however there was some overlap. Once LCAR developed, there was no difference between EAR and DAR groups in the magnitude of the LCAR. There was a trend (not significant) towards a requirement for a higher antigen concentration in the EAR group to elicit an LCAR.In conclusion, correlates of an isolated EAR from inhaled antigen include: (i) a low positive IgE RAST result with the antigen, (ii) ECAR 6 mm or greater with the antigen which does not proceed to a LCAR, and (iii) a high concentration of antigen is needed in skin tests to elicit an LCAR. Correlates of a DAR include:(i) a high IgE RAST result with the antigen, (ii) an ECAR wheal diameter less than 5 mm with the antigen proceeds to a LCAR, and (iii) a low antigen concentration in skin tests elicits an LCAR.The observed correspondence between the tendency to late skin and late airway responses is evidence of a common immunologic basis.

Notes: A previous study suggested that the long-acting β2-adrenergic agonist salmeterol (SM) had inhibitory effects on bronchial mucosal inflammation 6 hours after allergen exposure.To further evaluate the influence of SM on allergen-induced airway inflammation.We studied, in a randomized, double-blind, cross-over trial, 16 mild asthmatic patients who had a dual asthmatic response to allergen inhalation. Subjects received 50 µg of SM or placebo (P), twice daily for 1 week each, separated by a 2-week wash-out period. At the end of each treatment period, after withholding SM for 24 h, they had a methacholine inhalation test (medication was resumed after the test), followed 24 h later by an AC with the concentration of allergen that had induced a LAR at baseline. Airway inflammation was assessed 24 h after the AC by bronchoalveolar lavage (BAL) (n = 16) and bronchial biopsies (n = 13).As expected, SM improved baseline FEV1 and PC20 (P ≤ 0.009) and decreased the allergen-induced early bronchoconstrictive response. There were no significant differences in BAL cell counts after the two treatments. On bronchial biopsies, numbers (median, mm2) of submucosal CD45 (P: 43 ± 23; SM: 161 ± 43, P = 0.031), CD45Ro (P: 37 ± 19; SM: 126 ± 41, P = 0.047) and AA1 positive cells (P: 38 ± 6, SM: 65 ± 17, P = 0.006) were significantly higher after SM than P treatment. The numbers of CD4 (P: 11 ± 10; SM: 32 ± 7, P = 0.085), HLA-DR (P: 65 ± 30; SM: 116 ± 36, P = 0.079) and EG2 positive cells (P: 25 ± 15; SM: 38 ± 26, P = 0.09) tended to increase with SM treatment.In summary, compared to placebo, 1 week of regular use of SM is associated with an increase in bronchial inflammatory cells 24 h after AC. This is in keeping with the recommendation that salmeterol should only be used with an anti-inflammatory agent, particularly in the context of significant allergen exposure.

Notes: Background:  Inhaled corticosteroids (ICS) are recommended therapy for persistent asthma, although side effects can limit appropriate use. Ciclesonide, a novel ICS, is activated in the lung, thereby reducing systemic activity and side effects. This 12-week, double-blind, randomized, parallel-group, placebo-controlled study evaluated the efficacy and safety of ciclesonide in adults with persistent asthma.Methods:  After a 2-week baseline period in which current ICS treatment was continued, 329 patients were randomized to receive ciclesonide 160 μg (n = 107) or 640 μg (n = 112) (ex-actuator doses, equivalent to 200 and 800 μg ex-valve, respectively), or placebo (n = 110) once daily in the morning. Efficacy was monitored by asthma symptom scores, rescue medication use, morning and evening peak expiratory flow (PEF) measurements, spirometry, and probability of study completion without experiencing lack of efficacy.Results:  Morning PEF remained stable with either ciclesonide dose but decreased with placebo; the differences were significant (P 〈 0.0001) for both ciclesonide doses vs placebo. The forced expiratory volume in 1 s and forced vital capacity decreased significantly with placebo (P 〈 0.005), but were unchanged with ciclesonide. Lack of efficacy was significantly greater for patients switched to placebo (63%) than it was for those treated with ciclesonide 160 μg (30%) (P 〈 0.0001 vs placebo) or ciclesonide 640 μg (31%) (P 〈 0.0001 vs placebo). There were no significant differences between the two tested doses of ciclesonide with respect to efficacy and safety. Serum and 24-h urine cortisol were unaffected by ciclesonide treatment. Both doses of ciclesonide were well tolerated with no cases of oral candidiasis.Conclusion:  Ciclesonide (160 or 640 μg) once daily in the morning effectively maintains asthma control, does not affect cortisol levels, and has an adverse event profile comparable with placebo in adults with primarily mild to moderate asthma.

Notes: Background:  The allergen-induced early asthmatic response [provocation concentration (PC)20, the concentration causing a 20% forced expiratory volume in 1 s (FEV)1 fall] depends on the level of IgE sensitivity and the degree of nonallergic airway hyperresponsiveness (AHR) and can be predicted from histamine PC20 and allergen skin test endpoint.Objectives:  We examined the relationships between allergen PC20, methacholine PC20, and allergen skin test endpoint and assessed the accuracy of both the histamine PC20-based prediction of allergen PC20 (using methacholine) and a new methacholine PC20-based prediction equation.Methods:  From 158 allergen challenges, the allergen PC20, the methacholine PC20, and the skin test endpoint were recorded and relationships between these three were sought. We compared the measured allergen PC20 to that predicted from the previous histamine PC20-based and the new methacholine-based formulae.Results:  In single regressions, allergen PC20 correlated with both methacholine PC20 (r = 0.25, P = 0.0015) and skin test endpoint (r = 0.52, P 〈 0.00005). The relationship was improved by multiple regression of log-allergen PC20vs. log-methacholine PC20 and log-endpoint (r = 0.61, P 〈 0.00005). The histamine-based formula predicted allergen PC20 to within 2 doubling concentrations in 80% and within 3 in 92%. The new methacholine-based formula to within 2 and 3 concentrations in 81% and 94%, respectively; only nine of 158 subjects were outside the 3 concentrations.Conclusions:  We have confirmed the dependence of the allergen-induced early asthmatic response upon the level of allergic sensitivity and the degree of AHR, the latter as assessed by methacholine challenge. The allergen PC20 can be predicted to within 3 doubling concentrations in 94% of cases.

Notes: Background:  Anti-IgE therapy could be particularly beneficial for patients with concomitant disease as it targets a common factor in both diseases. The aim of this study was to evaluate the efficacy and safety of omalizumab in patients with concomitant moderate-to-severe asthma and persistent allergic rhinitis.Methods:  This multicentre, randomized, double-blind, parallel-group, placebo-controlled trial evaluated the safety and efficacy of omalizumab. A total of 405 patients (12–74 years) with a stable treatment (≥ 400 μg budesonide Turbuhaler®) and ≥ 2 unscheduled medical visits for asthma during the past year or ≥ 3 during the past 2 years were enrolled. Patients received omalizumab (≥ 0.016 mg/kg/IgE [IU/ml] per 4 weeks) or placebo for 28 weeks.Results:  Fewer patients treated with omalizumab experienced asthma exacerbations (20.6%) than placebo-treated patients (30.1%), P = 0.02. A clinically significant (≥ 1.0 point) improvement in both Asthma Quality of Life Questionnaire and Rhinitis Quality of Life Questionnaire occurred in 57.7% of omalizumab patients compared with 40.6% of placebo patients (P 〈 0.001). Omalizumab reduced Wasserfallen symptom scores for asthma (P = 0.023), rhinitis (P 〈 0.001) and the composite asthma/rhinitis scores (P 〈 0.001) compared with placebo. Serious adverse events were observed in 1.4% of omalizumab-treated patients and 1.5% of placebo-treated patients.Conclusion:  Omalizumab is well tolerated and effective in preventing asthma exacerbations and improving quality of life in patients with concomitant asthma and persistent allergic rhinitis.