Bronchial thermoplasty is a recent endoscopic technique for the treatment of severe asthma. It is an innovative treatment whose clinical efficacy and safety are beginning to be better understood. ...Since this is a device-based treatment, the evaluation procedure of risks and benefits is different that for pharmaceutical products; safety aspects, regulatory requirements, study design and the assessment of the magnitude of effects may all be different. The mechanism of action and optimal patient selection need to be assessed further in rigorous clinical and scientific studies. This technique is in harmony with the development of personalised medicine in the 21st century. It should be developed further in response to the numerous challenges and needs not yet met in the management of severe asthma.
L’anaphylaxie est une réaction d’hypersensibilité aiguë systémique dont le mécanisme classique fait intervenir des IgE spécifiques et la libération d’histamine par les mastocytes et les basophiles. ...Cependant, des données issues de modèles animaux suggèrent l’existence d’un mécanisme alternatif dépendant des IgG et de la libération de platelet-activating factor (PAF) par les monocytes/macrophages et les neutrophiles. Ce mécanisme n’a pu être montré chez l’homme que pour certains allergènes comme le dextran ou la protamine. Pour évaluer l’existence de ce mécanisme dans l’anaphylaxie médicamenteuse, nous avons réalisé une étude multicentrique sur des patients présentant une suspicion d’anaphylaxie aux curares.
Quarante-six patients et 86 témoins appariés ont été inclus prospectivement à partir de 10 départements d’anesthésie. Les IgE et IgG spécifiques anti-curares ont été mesurées par FEIA sur un ImmunoCAP 250. L’expression des récepteurs aux IgE et IgG sur les cellules circulantes et de marqueurs d’activation sur les neutrophiles ont été mesurés par cytométrie. Les neutrophil extracelllular traps (NET) et l’élastase circulants ont été mesurés par Elisa. L’activité de la PAF-acétylhydrolase (PAF-AH), un marqueur plasmatique inversement corrélé avec les concentrations de PAF, a été mesurée par méthode enzymatique.
Chez les patients, des IgG anti-curares sont détectables et leur titre corrèle avec la sévérité du choc. Les marqueurs d’activation du neutrophile ainsi que l’élastase et les NET sont mesurables dès 30min après le début des symptômes, et l’activité de la PAF-AH est significativement plus faible par rapport aux témoins. Les marqueurs d’activation du neutrophile et la libération de PAF sont associés avec la sévérité de l’anaphylaxie et peuvent être observés chez des patients sans signe d’un mécanisme IgE-dépendant. Enfin, des IgG anti-curares isolées à partir de sérum de patient sont capables de déclencher l’activation des neutrophiles ex vivo en présence de curare.
Cette étude est en faveur d’un axe pathogénique IgG-neutrophile-PAF dans l’anaphylaxie aux curares chez l’homme, qui pourrait contribuer à la sévérité et expliquer certaines réactions non IgE médiées.
To identify airway pathologic abnormalities selectively associated with severe asthma, we examined 10 control subjects, 10 patients with intermittent asthma, 15 patients with mild-to-moderate ...persistent asthma, 15 patients with severe persistent asthma, and 10 patients with chronic obstructive pulmonary disease. Bronchial biopsies were assessed for epithelial integrity; subepithelial basement membrane (SBM) thickness; collagen type III deposition; eosinophil, neutrophil, and fibroblast numbers; mucous gland and airway smooth muscle (ASM) areas; SBM-ASM distance; ASM hypertrophy (increased cell size); and the expression of the contractile proteins alpha-actin, smooth muscle myosin heavy-chain isoforms, myosin light-chain kinase, and the phosphorylated form of the regulatory light chain of myosin. Neither mucosal eosinophilia nor neutrophilia, epithelial damage, or SBM thickness reflected asthma severity. In contrast, higher numbers of fibroblasts (p < 0.001), an increase in collagen type III deposition (p < 0.020), larger mucous gland (p < 0.040) and ASM (p < 0.001) areas, augmented ASM cell size (p < 0.001), and myosin light-chain kinase expression (p < 0.005) distinguished patients with severe persistent asthma from patients with milder disease or with chronic obstructive pulmonary disease. Stepwise multivariate regression analysis established that fibroblast numbers and ASM cell size were negatively associated with prebronchodilator and postbronchodilator FEV1 values in patients with asthma. We conclude that fibroblast accumulation and ASM hypertrophy in proximal airways are selective determinants of severe persistent asthma.
Although H1 antihistamine compounds (H1) are highly effective in the treatment of allergic rhinitis (AR), their role in the treatment of asthma is still controversial. Because a strong association ...between AR and bronchial hyperresponsiveness (BHR) has been reported, this study was designed to assess the effect of a new H1 anti histamine, cetirizine (C), on nonspecific BHR in patients with AR. Twelve patients were included in a double‐blind, crossover, placebo‐controlled trial. All patients had positive skin tests for common allergens and showed BHR to inhaled methacholine after specific nasal allergenic challenge. After a washout period of 1 week to ensure the stability of the BHR, the patients received, by crossover randomization, C 10 mg daily or placebo (P) for 2 weeks. After each treatment period, BHR and nasal blocking index (NBI) were measured 1 and 6 h after nasal challenge. Bronchial responsiveness was expressed as methacholine PD20, the provocation dose of methacholine causing a 20% decrease in FEV1. Measurements were then performed after 2 weeks of C and after 2 weeks of P. Baseline values of PD20 (median) measured before challenge showed no difference after cetirizine or after placebo (1.36 mg). Results 1 h after allergen did not show significant differences between C (methacholine PD20=0.522 mg) and placebo (methacholine PD20=0.455 mg). By contrast, 6 h after challenge, methacholine PD20 was 0.918 mg for C and 0.483 mg for P (P=0.042). Similarly, NBI showed no change between C and P 1 h after challenge, whereas the difference was significant 6 h after challenge (P=0.011). These data demonstrate a protective nasal effect of C against BHR measured 6 h after nasal allergen challenge in patients with AR. They suggest that C may be useful in patients with asthma associated with AR.
BACKGROUND Inhaled corticosteroids are clearly beneficial for patients with asthma of moderate severity, but the risks and benefits of using them in patients with milder asthma are less clear. We ...have compared the change in bone mineral density over 2 years in adults with mild asthma randomised to receive an inhaled corticosteroid or non-corticosteroid treatment. METHODS Subjects with mild asthma (mean forced expiratory volume in one second (FEV1) 86% predicted, mean age 35 years, taking β agonists only) were randomised to receive inhaled budesonide, inhaled beclomethasone dipropionate, or non-corticosteroid treatment for 2 years in a prospective randomised open study in 19 centres in France, New Zealand, Spain, and the UK. The corticosteroid dose was adjusted according to a written self-management plan. The main outcome measure—change in bone mineral density after 6, 12, and 24 months—was measured “blind”. Secondary outcomes included lung function, the relation between change in bone density and inhaled steroid dose and change in biochemical markers of bone metabolism. RESULTS Of 374 subjects randomised, 239 (64%) completed the study and were included in the analysis. The median daily doses of inhaled budesonide (n=87) and beclomethasone (n=74) were 389 μg and 499 μg, respectively. Subjects treated with an inhaled corticosteroid had better asthma control than those in the reference group (n=78). Change in bone mineral density did not differ between the three groups over the 2 years, nor did it correlate with changes in markers of bone metabolism. The mean change in bone mineral density over 2 years in the budesonide, beclomethasone dipropionate, and reference groups was 0.1%, –0.4%, and 0.4% for the lumbar spine and –0.9%, –0.9%, and –0.4% for neck of the femur. Mean daily dose of inhaled steroid was related to reduction in bone mineral density at the lumbar spine but not at the femoral neck. CONCLUSION In subjects with mild asthma an inhaled corticosteroid provided better asthma control than alternative non-corticosteroid treatment with no difference in change in bone mineral density over 2 years. The relation between dose of inhaled corticosteroid and change in bone density at the lumbar spine may be due to a direct effect of inhaled corticosteroids on bone. Since inhaled steroid dose is also related inversely to lung function, an effect of asthma severity on bone density was also possible.
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