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Given the high proportion of patients with asthma who remain uncontrolled despite controller treatment, there remains a need for the development of more effective treatment options with a proven safety and tolerability profile. Recently, asthma guidelines have evolved to incorporate new therapies, including long-acting muscarinic antagonists (LAMAs) and biologics. Here we focus on the safety profile of tiotropium, a LAMA, using data from the large-scale UniTinA-asthma ® clinical trial program, which investigated the use of tiotropium in over 6000 patients with asthma who remained symptomatic despite receiving inhaled corticosteroids (ICS) maintenance therapy, with or without other adjunct therapies. The large number of patients included allows robust analysis of safety and tolerability. Overall, a similar incidence of patients reporting any adverse event (AE) was observed in the tiotropium (5 µg and 2.5 µg) and placebo groups. Asthma worsening, decreased peak expiratory flow, and upper respiratory tract infections were the most frequently reported AEs. Serious AEs (SAEs) and investigator-defined drug-related AEs were infrequently reported across all treatment groups, including the placebo group, and there were no deaths in any study. Reports of side effects typically associated with anticholinergic drugs, such as dry mouth and urinary retention, were either infrequent or not reported in children, adolescents or adults. The similar proportions of tiotropium- versus placebo-treated patients reporting AEs and SAEs in African-American and Japanese populations, as well as in elderly patients, contribute to the accumulating evidence of the safety and tolerability of tiotropium across broad ethnic and age populations.

Background: Tiotropium, a long-acting anticholinergic bronchodilator, has demonstrated efficacy and safety as add-on therapy to inhaled corticosteroids (ICS), with or without other maintenance therapies, in patients with symptomatic asthma., Objective: To evaluate safety and tolerability of tiotropium delivered via the Respimat(®) device, compared with placebo, each as add-on to at least ICS therapy, in a pooled sample of adults with symptomatic asthma at different treatment steps., Methods: Data were pooled from seven Phase II and III, randomised, double-blind, parallel-group trials of 12-52 weeks' treatment duration, which investigated once-daily tiotropium Respimat(®) (5 μg, 2.5 μg) versus placebo as add-on to different background maintenance therapy including at least ICS. Adverse events (AEs) including serious AEs were assessed throughout treatment + 30 days after the last dose of trial medication., Results: Of 3474 patients analysed, 2157 received tiotropium. The percentage of patients with AEs was comparable between treatment groups: tiotropium 5 μg, 60.8%; placebo 5 μg pool, 62.5%; tiotropium 2.5 μg, 57.1%; placebo 2.5 μg pool, 55.1%. Consistent with the disease profile, the most frequent AEs overall were asthma, decreased peak expiratory flow rate (both less frequent with tiotropium) and nasopharyngitis. Overall incidence of dry mouth, commonly associated with use of anticholinergics, was low: tiotropium 5 μg, 1.0%; placebo 5 μg pool, 0.5%; tiotropium 2.5 μg, 0.4%; placebo 2.5 μg pool, 0.5%. The percentage of cardiac disorder AEs was comparable between tiotropium and placebo: tiotropium 5 μg, 1.4%; placebo 5 μg pool, 1.4%; tiotropium 2.5 μg, 1.4%; placebo 2.5 μg pool, 1.1%. The proportions of patients with serious AEs were balanced across groups: tiotropium 5 μg, 4.0%; placebo 5 μg pool, 4.9%; tiotropium 2.5 μg, 2.0%; placebo 2.5 μg pool, 3.3%., Conclusion: Tiotropium Respimat(®) demonstrated safety and tolerability comparable with those of placebo, as add-on to at least ICS therapy, at different treatment steps in adults with symptomatic asthma., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: In asthma, inflammation affects both the proximal and distal airways and may induce significant hyperinflation (HI). This study sought to evaluate the prevalence of HI in asthmatic patients with poorly controlled disease and/or dyspnea., Methods: Poor asthma control was defined by an Asthma Control Test (ACT) score <20 (n = 287), and dyspnea was defined as a modified Medical Research Council score ≥1 (n = 18). HI was defined as either a residual volume/total lung capacity (RV/TLC) above the upper limit of normal (RV-HI) or a functional residual capacity (FRC) >120% predicted (FRC-HI). HI reversibility after administration of salbutamol (400 μg) was defined as a decrease in RV >20% or a reduction in FRC >10%. Changes in dyspnea and chest tightness were evaluated on a visual analogue scale., Results: Both RV-HI and FRC-HI were observed in 48% of the 305 patients (mean ± SD age: 49 ± 17; FEV1 : 75 ± 18% predicted) included in the study. The prevalence of HI was higher in patients with a FEV1 <60% predicted (93% for RV-HI and 71% for FRC-HI, vs 21% and 41% in patients with a FEV1 > 80%). In patients with HI, the ACT score was lower and chest tightness higher. HI reversibility was obtained in 38% of the asthmatics with FRC-HI and 29% of the asthmatics with RV-HI, whereas FEV1 reversibility was obtained in half of these patients., Conclusions: HI is highly prevalent in poorly controlled asthmatics suggesting small airway dysfunction and may represent an additional criteria for evaluating responsiveness to bronchodilators., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Asthma is a disease characterized by inflammation which affects both proximal and distal airways. We evaluated the prevalence of small airway obstruction (SAO) in a group of clinically stable asthmatics with both normal forced expiratory volume in the first second (FEV1) and normal FEV1/forced vital capacity (FVC) and treated with an association of inhaled corticosteroids (ICSs) and long acting β2-agonists (LABAs). Clinical evaluation included the measurement of dyspnea, asthma control test and drug compliance. The prevalence of SAO was estimated by spirometry and plethysmography and defined by the presence of one or more of the following criteria: functional residual capacity (FRC) > 120% predicted (pred), residual volume (RV) > pred + 1.64 residual standard deviation (RSD), RV/total lung capacity (TLC) > pred + 1.64 RSD, forced expiratory flow (FEF)25-75% < pred - 1.64 RSD, FEF50% < pred - 1.64 RSD, slow vital capacity (SVC) - FVC > 10%. Among the 441 patients who were included, 222 had normal FEV1 and FEV1/FVC. At least one criteria of SAO was found in 115 (52%) mainly lung hyperinflation (39% based on high FRC, RV or RV/TLC) and more rarely distal airflow limitation (15% based on FEF25-75% or FEF50%) or expiratory trapping (10% based on increased SVC - FVC). In the patients with only SAO (no PAO), there was no relationship between SAO, asthma history and the scores of dyspnea, asthma control or drug compliance. These results suggest that in asthmatics with normal FEV1 and FEV1/FVC, treated with ICSs and LABAs, SAO is found in more than half of the patients indicating that the routinely used lung function tests can underestimate dysfunctions occurring in the small airways., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Asthma treatment should be conducted in three successive steps: identify and reduce exposure to risk factors, determine whether the patient requires a permanent controller medication which should be adapted to its asthma severity and education of the patient who should acquire a minimum knowledge on his disease. Controller medications mostly involve inhaled medications because they are delivered in the airways where they are needed and they reduce their systemic effects. Controller medications are dominated by inhaled corticosteroids either alone or in association with inhaled beta-2 sympathomimetics. The main objective is to achieve and to maintain asthma control. Asthma control is assessed using six items which determine whether asthma is controlled, partially controlled or uncontrolled. Guidelines allow to adapt the intensity of anti-inflammatory controller medication (mostly inhaled corticosteroids) given alone or in association with inhaled beta-2 sympathomimetics to asthma control and taking into account the treatment steps of the patient at the time of evaluation. Severe asthma could justify exceptional treatments (such as omalizumab) which indications are the domain of specialists.

Two strategies are possible for targeting distal airways in asthma. The first one is systemic, with the delivery of medications either orally or intravenously. Montelukast is the only oral drug that has demonstrated its efficacy on distal airways by reducing lung hyperinflation. The second possible strategy is to deliver inhaled medications using ultrafine particles. Studies performed with formoterol-HFA solution (Formoair Modulite), the only available long-acting beta2 agonist with ultrafine particles have shown a non-inferior bronchodilator effect and a good tolerance as compared to inhaled long acting beta2 agonists with non-ultrafine particles. Studies performed with BDP-HFA alone (QVAR) or combined BDP-HFA/formoterol (Fostair) with ultrafine particles have mostly demonstrated their clinical non- inferiority on bronchodilation, quality of life, and symptoms in asthmatic subjects as compared to non-ultrafine inhaled medications. With the exception of a few studies, most publications have been performed in a limited number of patients and for only short durations. The available studies have not yet demonstrated a long-term benefit in terms of additional clinical efficacy of these ultrafine inhaled medications on symptoms, control and exacerbations of asthma.

The present review is the summary of an expert workshop that took place in Vence (France) in 2007 on the role of distal airways in asthma. The evidence showing inflammation and remodelling in distal airways, and their possible involvement in asthma control and natural history, was reviewed. The usefulness and limitations of various techniques used for assessing distal airways were also evaluated, including pulmonary function tests and imaging. Finally, the available data studying the benefit of treatment better targeting distal airways in asthma was examined. It was concluded that both proximal and distal airways were involved in asthma and that distal airways were the major determinant of airflow obstruction. Inflammation in distal airways appeared more intense in severe and uncontrolled asthma. Distal airways were poorly attained by conventional aerosol of asthma medications owing to their granulometry, being composed of 3-5&emsp14;μm particles. Both proximal and distal airways might be targeted either by delivering medications systemically or by aerosol of extra-fine particles. Extra-fine aerosols of long-acting β-agonists, inhaled corticosteroids or inhaled corticosteroid/long-acting β-agonist combinations have been shown in short-term studies to be not inferior to non-extra-fine aerosols of comparators. However, available studies have not yet demonstrated that extra-fine inhaled medications offer increased benefit compared with usual aerosols in asthmatic patients.

Objectives: To identify variables patients use to determine the severity of their asthma, the perceived severity (PS), using a fuzzy decision-making analysis (FDMA). To compare these variables with those involved in the assessment of asthma severity according to the global initiative for asthma (GINA) guidelines, the objective severity (OS)., Patients: Outpatients (51 men, 62 women), aged (m+/-SD) 42.9+/-16.3 years with (% patients) mild intermittent (6.2), mild persistent (15.9), moderate (65.5) and severe (12.4) asthma., Design: Cross sectional, observational study., Methods: Both OS (rated by doctors) and PS (rated by patients) were rated as mild intermittent, mild persistent, moderate, or severe. Variables involved in OS assessment, variables self-assessed by patients (dyspnea, perceived treatment efficacy, asthma-related quality of life questionnaire [AQLQ]), patients' sociodemographic characteristics, and asthma characteristics, were evaluated with questionnaires. These variables were pooled, and considered as potential variables patients might use to determine their PS. They were tested against the PS measurement using FDMA. This identified variables patients actually used to determine PS., Results: On the day of consultation, 68.1% of patients classed their asthma as mild intermittent or mild persistent, 23.9% as moderate persistent, and 8.0% as severe persistent. There was a significant discrepancy (p<0.01) between PS and OS with a clear patient tendency to underestimate asthma severity as compared to OS. Patients determined PS level according to variables assessing their asthma perception, i.e., AQLQ measures and dyspnea, but not variables involved in OS assessment, such as symptom frequency or knowledge of their peak flow rates. Duration of asthma and treatment characteristics were also involved., Conclusion: FDMA identified variables patients used to determine PS. It highlighted a discrepancy between patients' and doctors' perceptions of asthma severity, suggesting that assessment of asthma severity should consider both patients' and doctors' perceptions of the disease and includes an AQLQ measure.

This review is the synthesis of a working group on mild asthma. Mild asthma includes intermittent and persistent mild asthma according to the Global Initiative for Asthma (GINA) classification, and affects between 50% and 75% of asthmatic patients. Mild asthma is more frequent, more symptomatic, and less well controlled in children than in adults. Cohort studies from childhood to adulthood show that asthma severity usually remains stable over time. Nevertheless, mild asthma can lead to severe exacerbations, with a frequency ranging from 0.12 to 0.77 per patient-year. Severe exacerbations in mild asthma represent 30-40% of asthma exacerbations requiring emergency consultation. In mild asthma, inflammation and structural remodelling are constant, of varying intensity, but nonspecific. Therapy with inhaled corticosteroids (ICS) decreases bronchial inflammation, but has only a slight effect on structural remodelling, and, when stopped, inflammation immediately recurs. Permanent low-dose ICS therapy is the reference treatment for persistent mild asthma. Effectiveness is to be reassessed at 3 months, and if it is insufficient the patient is no longer considered mildly asthmatic, and treatment has to be stepped up. As mild asthma is the most frequent form of the disease, diagnosis and management require physicians' particular attention.

Objective: To update on the state of knowledge in mild asthma (intermittent and persistent mild asthma, according to the GINA classification) review the literature, and the position statement of the French Mild Asthma Working Group., Methods: The French Mild Asthma Working Group (11 lung specialists, 4 paediatricians, 1 pharmacologist, and 1 general practitioner) selected, analysed, and summarised the literature on the descriptive epidemiology, physiopathology, clinical signs, and management of mild asthma. The position of the working group on the descriptive epidemiology (causal factors excluded) and the nature of the bronchial inflammation has been presented in a previous article. The present article focuses on the clinical features of mild asthma and the use of medication for it., Results: Mild asthma was more frequent, more symptomatic, and less well controlled in children than in adults. Its generally benign evolution may in some (<10%) cases be complicated by severe episodes. Patients with mild persistent asthma require controller medication every day: permanent low-dose inhaled corticosteroid monotherapy is the reference foundation treatment for persistent mild asthma., Conclusions: The present findings should help clinicians and guide them in their approach to managing this condition.

Introduction: Update on the state of knowledge in the mild asthma (intermittent and persistent mild asthma, according to the GINA classification) literature, and position of a French Mild Asthma Working Group., State of the Art: The French Mild Asthma Working Group (11 lung specialists, 4 paediatricians, 1 pharmacologist, and 1 general practitioner) selected, analysed, and summarised the literature on the epidemiology, physiopathology, clinical signs, and management of mild asthma. The present article shows the position of the working group on mild asthma descriptive epidemiology (causal factors excluded) and the nature of the bronchial inflammation. Clinical signs and medicinal treatments will be presented in a second article., Perspectives: Between 50% and 75% of asthma patients, depending on the study, present mild asthma. Childhood-to-adulthood cohort monitoring found severity to be unchanged over developmental time. Its generally benign evolution may in some (<10%) cases be complicated by severe episodes. Inflammation and airway-wall remodelling were always found, although of variable intensity, and non-specific (except for absence of infiltration by polymorphonuclear neutrophils). Corticosteroid therapy by inhalation reduces bronchial inflammation, but with little impact on airway-wall remodelling., Conclusion: The present findings should help clinicians in identifying and understanding mild asthma.

Background: There is an increasing trend for the use of combination therapy of inhaled corticosteroids (ICS) and long-acting beta(2)-agonists as initial treatment for asthma., Objective: To assess the efficacy of initial monotherapy with ICS for achieving asthma control in steroid-naive mild to moderate asthmatics., Method: During an observational survey, steroid-naive patients received ICS in a dosage of 400-2,000 mug/day. After 4-8 weeks' treatment, achievement of asthma control, defined according to the Global Initiative for Asthma (GINA) guidelines, was assessed and the Asthma Control Questionnaire (ACQ) was completed., Results: Among 537 selected patients, 21 were excluded because of severe asthma and 96 because of inadequate ICS daily dosage. Four hundred and twenty patients were analyzed, 396 (94%) of whom completed the survey. Mean ICS dosage, in equivalent beclomethasone, was 479 +/- 62 mug/day for mild asthma (group A) and 1,115 +/- 306 mug/day for moderate asthma (group B). Asthma control was achieved for 71 and 65% of the patients, mean ACQ score improved from 1.1 +/- 0.6 to 0.5 +/- 0.5 (p < 0.001) and from 2.0 +/- 0.8 to 0.8 +/- 0.7 (p < 0,001), and FEV(1) (% predicted) improved from 93 +/- 9 to 96 +/- 13 (p < 0.05) and from 85 +/- 15 to 91 +/- 15 (p < 0.001) for groups A and B, respectively., Conclusion: Asthma control can be achieved by ICS monotherapy for two thirds of steroid-naive patients with mild to moderate asthma. For these patients, we suggest that ICS alone could be started as initial therapy and that additional therapy should be considered after 4-8 weeks for patients who do not achieve control.

Background: Pressurized metered-dose inhalers (pMDIs) have traditionally used CFCs as propellants. However, the worldwide phase-out of CFCs has necessitated the development of new pMDIs that use alternative propellants. One such replacement is the hydrofluoroalkane HFA-134a., Objectives: This study sought to establish the clinical non-inferiority of a new HFA-134a-containing pMDI to a conventional dry powder inhaler (DPI) in the administration of formoterol to adult patients with moderate-to-severe, stable persistent asthma. The secondary aim was to collect safety data in a multiple-dose long-term study., Methods: During this multicenter, double-blind, parallel study, 500 patients were randomized to receive 12 microg of formoterol twice daily for 12 weeks via either an HFA pMDI or a DPI. If necessary, the dose could be increased to 24 microg twice daily. At baseline, all patients (aged 18-70 years) had an FEV1 40-80% of predicted and a documented positive response to the reversibility test., Results: After 12 weeks' therapy, the adjusted mean morning PEFR was 343.69 l/min in the formoterol HFA pMDI group and 344.56 l/min in the formoterol DPI group. Because the lower limit of the 95% CI for the between-group difference (-11.64 l/min) was well within the non-inferiority margin (-20 l/min), the HFA device was deemed clinically non-inferior to the DPI device. This finding was confirmed when evening PEFR and FEV1 were assessed. Both formulations of formoterol were well tolerated during prolonged multiple dosing., Conclusions: This study provides evidence that the new HFA-formulated formoterol pMDI has a similar efficacy and safety profile to the conventional formoterol DPI in the treatment of patients with moderate-to-severe asthma.

A cross sectional survey was conducted in 2000 in coordination with the CHIESI medical representatives among 1758 French physicians caring for patients with persistent asthma (80% general practitioners, 20% specialists). This "Compli'Asthme" survey was based on a self-administered questionnaire designed to learn more about the physicians' experience with good use of inhaled drugs and to collect information on therapeutic observance, corticophobia, and use of prescribed inhalers. Poor observance was noted as an important problem by 58-85% of the participants. Most of the problems were related to inability to use the inhaler properly (children, elderly subjects) or to patients forgetting to take their medications (adults, parents). For 58% of the participating physicians, corticophobia is frequent. The patients are worried about the anabolizing effect, secondary effects, and dependence. When there is a potential problem with corticophobia, physicians generally question the patients and provide explanations to achieve good observance. Patient preference is taken into consideration by 86% of the physicians prescribing inhalation devices; 90% demonstrate use of the device at the first prescription and 68% make repeated demonstrations at subsequent consultations. For 56-87% of the physicians, poor therapeutic observance, corticophobia, and poor use of the inhaler can be detected and corrected. Patient education is an important element for 77% of the physicians for improving observance and achieving good use of the inhaler. When poor observance and poor use of the inhaler occur, the physicians responding to this questionnaire applied the currently recommended guidelines.

The first medical visit is an essential moment of asthma management because it is a chronic disease needing a long term follow-up. This initial assessment which takes time, can be done gradually, on several days or even weeks. Once the differential diagnosis is excluded, the diagnosis of asthma is confirmed and its severity assessed. The identification of precipitant factors of asthma exacerbations goes through a detailed interview. Planning a therapeutic and supervision strategy with the patient has for goal the control of the disease and improvement of quality of life. Including the patient in the management of his asthma is only possible if he has been educated, patient education must be controlled and reinforced all the long of further medical visits.

Eosinophils are the most characteristic inflammatory cells in the airway mucosa in asthma. Eosinophils release highly toxic products and cytokines which may influence the immune system, amplify the inflammatory response and participate in damaging and remodeling processes that occur in the airway mucosa. Eosinophilic inflammation in asthma is related to the blunted perception of bronchoconstriction. The magnitude of eosinophil influx and the degree of activation of these cells in the airway mucosa are related to the severity of asthma and appear to play a key role in some cases of asthma death. The number and activation of eosinophils in the airway mucosa are related to the magnitude of airway hyperresponsiveness to bradykinin but not to an agonist acting directly on smooth muscle such as methacholine. Inhaled corticosteroids reduce eosinophil inflammation in asthma whereas beta 2-agonists appear to increase the magnitude of eosinophilic inflammation induced by allergen exposure. The eosinophilic inflammation can be assessed by non-invasive methods using sputum analysis and, indirecly, by measuring the airway reactivity to bradykinin.

Background: Angiotensin-converting enzyme (ACE) is a peptidase involved in the metabolism of several bioactive peptides. It may be involved in the airway inflammation and hyperresponsiveness that occur in asthma., Objective: We studied the expression of ACE in the airway mucosa of normal and asthmatic subjects and assessed the relationship between ACE expression and airway inflammation and bronchial hyperresponsiveness in asthma., Methods: We used immunohistochemistry to study the ACE expression and airway inflammation in bronchial biopsy samples obtained by fiberoptic bronchoscopy from 20 asthmatic subjects randomly assigned to groups treated with (n = 10) or without inhaled corticosteroids (n = 10) and from normal subjects (n = 10). Airway response to methacholine and bradykinin was also determined for all subjects., Results: In normal subjects ACE was present in the surface epithelium, the endothelial cells of the lamina propria, and the submucosal glands, in which ACE was found in seromucous cells and in secreted mucus. ACE was not detected in smooth muscle cells and in most of the endothelial cells of the vascular network surrounding the glands. ACE was absent or present at lower levels in the surface epithelium of asthmatic subjects not treated with corticosteroids compared with those treated with corticosteroids and the control group. In asthmatic subjects low levels of ACE in the epithelium were associated with larger numbers of eosinophils in the epithelium and lamina propria. There was no relationship between ACE levels in the airway mucosa and airway responsiveness to methacholine and bradykinin., Conclusion: ACE expression is decreased in the epithelium of asthmatic patients and is associated with increased eosinophil inflammation.

Background: Allergic asthma is a multifactorial and probably multigenic inflammatory disease of the upper airways, and has been associated with the HLA class II alleles DR4 and DR7. Here we investigated possible associations with other polymorphic susceptibility/resistance genes located within the major histocompatibility complex, i.e., the genes coding the major 70-kDa heat-shock proteins (HSP; Hsp70) hsp70-1, hsp70-2, and hsp70-HOM, whose products are overexpressed in the bronchi of asthmatic patients., Methods: Genomic DNA was extracted from peripheral blood lymphocytes or buccal epithelial cells of 48 patients with allergic asthma and 31 selected nonatopic control subjects, in whom we previously reported a strong association of atopy with DR4/DR7 alleles., Results: No evidence was found for an independent role of hsp70 gene polymorphism in susceptibility to allergic asthma. However, hsp70 alleles might be involved in extended haplotypes of HLA markers., Conclusions: Our data suggest that Hsp70 overexpression in asthma results from complex interactions between environmental exposures and genetic background rather than from specific genetic variations in hsp70 genes.

Nebulization is a basic treatment for the management of severe acute asthma. Three mechanisms are involved in bronchial obstruction: bronchospasms, inflammation and an increase in bronchial secretions. Combination therapy including beta 2-sympatheticomimetic and synthetic atropinic drugs is strongly synergistic. In a French multicenter trial including 45 adult patients presenting with asthma, combination of nebulized Berotec and Atrovent was studied. It proved to be efficacious in two thirds of the patients. Results were even better for younger patients whose initial peak flow rate was high. Tolerance to this combination therapy was as good as that to beta 2-sympatheticomimetic monotherapy.

Heat shock proteins (HSPs), which are important targets for gammadelta T-lymphocytes, are thought to play a role in inflammatory and immune diseases. The purpose of this study was to characterize, in asthma, the presence and distribution of alphabeta and gammadelta T-lymphocytes and of hsp60, hsp70 and hsp90 in bronchial biopsies, and to seek for a co-localization of gammadelta T-cells and HSPs. Ten subjects with mild atopic asthma and nine control subjects underwent fibreoptic bronchoscopy and bronchial biopsies, to which specific monoclonal antibodies and immunohistochemical techniques were applied. T-lymphocytes present in bronchi both of asthmatic and control subjects were predominantly of the alphabeta T-cell receptor phenotype (median 642 cells x mm(-2) (range 85-1,510 cells x mm(-2)), and 855 cells x mm(-2) (286-2,424 cells x mm(-2)), respectively), whereas, gammadelta T-lymphocytes were always rare (median 26 cells x mm(-2) (range 0-114 cells x mm(-2)), and 0 cells x mm(-2 (0-57 cells x mm(-2), respectively). Both in asthmatic and control subjects, bronchial epithelium was positive for hsp60, hsp70 and hsp90. There was no significant difference in the percentages of positive epithelial cells between asthmatic and control subjects. No co-localization of HSPs and gammadelta T-cells was observed. Our findings do not support the hypothesis that heat shock proteins and gammadelta T-cells play an important role in inflammatory and immune responses in mild asthma.

We investigated the relationship between airway inflammation and airway responsiveness, as assessed by PD15, to methacholine and to bradykinin in asthmatic patients. Bronchoalveolar lavage (BAL), bronchial biopsies, and methacholine and bradykinin challenges were performed in 18 nonsmoking subjects with mild or moderate perennial asthma. Bradykinin PD15 correlated negatively with eosinophil count in BAL (p < 0.05), in the epithelium (p < 0.05), in the lamina propria (p = 0.02) and in the total submucosa (p < 0.01). Conversely, no significant correlation existed between airway responsiveness to methacholine and eosinophil count in BAL or in airway mucosa. Airway responsiveness to either agonist did not correlate with the thickness of the basement membrane, the shedding of the airway epithelium, the count of lymphocytes in the airway mucosa, or the percentage of neutrophils, lymphocytes, and macrophage in BAL. The presence of degranulated eosinophils was associated with an increased number of eosinophils in the airway epithelium (p = 0.04), in the lamina propria (p = 0.03), in the total submucosa (p = 0.02), and with increased airway responsiveness to bradykinin (p < 0.02). We conclude that in asthmatic patients, airway responsiveness to bradykinin but not to methacholine is related to the magnitude of eosinophilic inflammation in the airway mucosa.

We studied the perception of bronchoconstriction in asthmatic subjects who were randomly treated with inhaled beta 2 agonist given either alone (n = 9) or associated with inhaled corticosteroids (n = 9). Methacholine and bradykinin challenges, bronchoalveolar lavage, and bronchial biopsies were performed in all subjects. After each dose of agonist, breathlessness was assessed using a visual analog scale (VAS) and the forced expiratory volume in 1 s (FEV1) was measured. The relationship between VAS scores and FEV1 and the slope of the regression line of VAS scores on the corresponding FEV1 (VAS/FEV1 slope) were analyzed for each agonist. Subjects without corticosteroids had good perception of methacholine but poor perception of bradykinin-induced bronchoconstriction. In subjects with corticosteroids, bronchoconstriction was well perceived whatever the agonist. VAS/FEV1 slopes for bradykinin but not for methacholine correlated negatively with the magnitude of eosinophilic inflammation in airway mucosa. VAS/FEV1 slopes for each agonist correlated positively with the percentage of basement membrane covered by airway epithelium. We conclude that in asthmatic patients perception of bronchoconstriction is related to eosinophilic inflammation and to epithelial damage in airways and that corticosteroid treatment is associated with improved perception of bronchoconstriction induced by bradykinin, a mediator endogenously produced in asthma.

Asthmaexpert, an expert system (ES), was produced at the special request of several clinicians in order to better understand the medical decisions made clinical experts in managing an asthmatic patient. We describe and evaluate this knowledge base, focusing mainly on assessment of the severity of asthma. After compiling data from a patient, Asthmaexpert assesses the severity of the disease and identifies the trigger factors involved, suggests any further investigations that may be required, and offers a treatment strategy. Implemented with Nexpert and Hypercard, it runs on a MacIntosh personal computer. The validation stage involved eight clinical experts who provided 20 case report forms (CRF) with their conclusions about management of asthma. The CRF were then programmed into the ES, which provided its own conclusions about the same subjects. Afterward, all the experts evaluated the conclusions given by ES or by their colleagues in a double-blind manner. One hundred twenty-seven CRF were available. The reliability of the experts' opinions was good, with a substantial consensus between them when assessing severity scores (kappa = 0.27 to 0.54). There was no difference in concordance of opinions on severity scores either between the experts who designed the system and ES or between the other experts and ES (weighted kappa = 0.72 and 0.69, respectively). Experts judged that the severity scores given by ES were as good as those proposed by their colleagues, and that the overall conclusions given by ES were as good as or better than those given by their colleagues. The conclusions drawn by ES were given a good rating.(ABSTRACT TRUNCATED AT 250 WORDS)

As asthma is nearly always associated with non-specific bronchial hyperreactivity, this factor has been considered to be an essential requirement for the development of symptomatic asthma. Some factors appear to be inducers of bronchial hyperreactivity and others promotors of asthmatic symptoms. In clinical practice, it is very difficult to classify aetiological factors as inducers or promotors: there is evidence to support the fact that the same factors may cause both bronchial hyperreactivity and asthmatic symptoms; conversely, the evidence for hereditary non-specific bronchial hyperreactivity is hardly convincing. These observations suggest that non- specific bronchial hyperreactivity is more a marker of bronchial asthma than a true aetiological factor.

Background: Pressurized metered-dose inhalers (pMDIs) have traditionally used CFCs as propellants. However, the worldwide phase-out of CFCs has necessitated the development of new pMDIs that use alternative propellants. One such replacement is the hydrofluoroalkane HFA-134a. Objectives: This study sought to establish the clinical non-inferiority of a new HFA-134a-containing pMDI to a conventional dry powder inhaler (DPI) in the administration of formoterol to adult patients with moderate-to-severe, stable persistent asthma. The secondary aim was to collect safety data in a multiple-dose long-term study. Methods: During this multicenter, double-blind, parallel study, 500 patients were randomized to receive 12 μg of formoterol twice daily for 12 weeks via either an HFA pMDI or a DPI. If necessary, the dose could be increased to 24 μg twice daily. At baseline, all patients (aged 18–70 years) had an FEV1 40–80% of predicted and a documented positive response to the reversibility test. Results: After 12 weeks’ therapy, the adjusted mean morning PEFR was 343.69 l/min in the formoterol HFA pMDI group and 344.56 l/min in the formoterol DPI group. Because the lower limit of the 95% CI for the between-group difference (–11.64 l/min) was well within the non-inferiority margin (–20 l/min), the HFA device was deemed clinically non-inferior to the DPI device. This finding was confirmed when evening PEFR and FEV1 were assessed. Both formulations of formoterol were well tolerated during prolonged multiple dosing. Conclusions: This study provides evidence that the new HFA-formulated formoterol pMDI has a similar efficacy and safety profile to the conventional formoterol DPI in the treatment of patients with moderate-to-severe asthma. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background Atopy, with or without associated asthma, provides a useful model for evaluating the genetic factors that control human immune responsiveness. HLA class II gene products are involved in the control of immune responses. Objectives We investigated whether susceptibility or resistance to the disease was associated with HLA class II genes. Methods Blood samples were obtained from two groups of unrelated European-born white adults: 56 atopic patients (52 of them with asthma) and 39 healthy controls with no personal or familial history of asthma or atopy. Genomic DNA was extracted from peripheral blood lymphocytes. The exons of DQA1, DQB1, DRB and DPB1 genes were selectively amplified by the polymerase chain reaction (PCR) method. Geno-typing was carried out by digestion of the amplified DNA products with allele-specific endonucleases (PCR-RFLP), which can recognize allelic variations in the polymorphic exon. Results We found no significant differences in the frequency of DPB 1 alleles between patients and controls. HLA class II DR4 and DR7 alleles were present in 39.2% of the patients and in 2.5% of the healthy subjects (Pc*2&les; 3.9 10-3). Conversely, DQA 1*0103 and DQB 1*0502 alleles were more frequent in the control subjects. These results confirm a previous study of an extended pedigree, which showed that DR4 and DR7 alleles were absent in all healthy members of the family and were frequently observed in atopic and/or in asthmatic subjects. Conclusion We observed that HLA-DR 4 and DR7 alleles are significantly implicated in their susceptibility to the disease and suggest that this susceptibility is more related to atopy than to specific responses to allergens. According to previous studies, we could also submit that in atopic patients with asthma, DR4 alleles at the least, could be more closely associated with atopy than with asthma per se. Conversely, we suggest that some allelic DQA 1 and DQB 1 sequences might confer protection against the disease. [ABSTRACT FROM AUTHOR]

The article offers information on the study regarding the use of omalizumab for patients with allergic bronchopulmonary aspergillosis (ABPA) to diminish the use of systemic steroid therapy and the number of exacerbations. It says that ABPA is mostly seen in patients suffering from allergic asthma. Moreover, the study shows a reduction of the number of exacerbations and of the therapeutic load in ABPA patients treated by omalizumab without cystic fibrosis.