Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial.

Thorax. 2013 Jan 3;

Authors: Brusselle GG, Vanderstichele C, Jordens P, Deman R, Slabbynck H, Ringoet V, Verleden G, Demedts IK, Verhamme K, Delporte A, Demeyere B, Claeys G, Boelens J, Padalko E, Verschakelen J, Van Maele G, Deschepper E, Joos GF

Abstract
BACKGROUND: Patients with severe asthma are at increased risk of exacerbations and lower respiratory tract infections (LRTI). Severe asthma is heterogeneous, encompassing eosinophilic and non-eosinophilic (mainly neutrophilic) phenotypes. Patients with neutropilic airway diseases may benefit from macrolides. METHODS: We performed a randomised double-blind placebo-controlled trial in subjects with exacerbation-prone severe asthma. Subjects received low-dose azithromycin (n=55) or placebo (n=54) as add-on treatment to combination therapy of inhaled corticosteroids and long-acting β(2) agonists for 6 months. The primary outcome was the rate of severe exacerbations and LRTI requiring treatment with antibiotics during the 26-week treatment phase. Secondary efficacy outcomes included lung function and scores on the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ). RESULTS: The rate of primary endpoints (PEPs) during 6 months was not significantly different between the two treatment groups: 0.75 PEPs (95% CI 0.55 to 1.01) per subject in the azithromycin group versus 0.81 PEPs (95% CI 0.61 to 1.09) in the placebo group (p=0.682). In a predefined subgroup analysis according to the inflammatory phenotype, azithromycin was associated with a significantly lower PEP rate than placebo in subjects with non-eosinophilic severe asthma (blood eosinophilia ≤200/µl): 0.44 PEPs (95% CI 0.25 to 0.78) versus 1.03 PEPs (95% CI 0.72 to 1.48) (p=0.013). Azithromycin significantly improved the AQLQ score but there were no significant between-group differences in the ACQ score or lung function. Azithromycin was well tolerated, but was associated with increased oropharyngeal carriage of macrolide-resistant streptococci. CONCLUSIONS: Azithromycin did not reduce the rate of severe exacerbations and LRTI in patients with severe asthma. However, the significant reduction in the PEP rate in azithromycin-treated patients with non-eosinophilic severe asthma warrants further study. CLINICALTRIALS.GOV NUMBER: NCT00760838.

PMID: 23291349 [PubMed - as supplied by publisher]

The case of drug causation of childhood asthma: antibiotics and paracetamol.

Eur J Clin Pharmacol. 2013 Jan 5;

Authors: Heintze K, Petersen KU

Abstract
AIM: The rising prevalence of bronchial asthma has led to world-wide efforts to understand and stem this development. Cross-sectional studies appear to show that early childhood use of antibiotics may be an important contributory factor, with paracetamol as an additional suspected cause. However, mounting evidence, which is reviewed here, points to various confounding factors as the major reasons for these reported associations. METHODS: PubMed and EMBASE were systematically searched for studies on associations between antibiotics and/or paracetamol with asthma and/or wheezing, published up to November 2012. A total of 64 pertinent studies were identified, 35 focusing on antibiotics, 19 on paracetamol, and ten addressing both antibiotics and paracetamol, bringing the number of relevant datasets to 74. RESULTS: Numerous studies were cross-sectional and made no adjustment for the indication of antibiotics or paracetamol; consequently, they were unable to dismiss possible confounding by indication. Where such adjustments could be performed (mostly in longitudinal studies), they substantially weakened or entirely eliminated the association with asthma or asthma surrogates present in the unadjusted data. CONCLUSION: The weight of evidence of the collected studies in our review strongly suggests that the association of antibiotics with childhood asthma reflects various forms of bias, the most prominent of which is confounding by indication. Recent studies and meta-analyses support the same conclusion for paracetamol. Truly indicated antibiotics should not be withheld from infants or young children for fears they might develop asthma. Likewise, there is no sound reason to replace paracetamol as the preferred pain relief and fever medication in this age group.

PMID: 23292157 [PubMed - as supplied by publisher]

Bronchodilator responsiveness using spirometry in healthy and asthmatic preschool children.

Arch Dis Child. 2013 Jan 3;

Authors: Borrego LM, Stocks J, Almeida I, Stanojevic S, Antunes J, Leiria-Pinto P, Rosado-Pinto JE, Hoo AF

Abstract
OBJECTIVE: To assess repeatability and reproducibility of spirometry measurements, and bronchodilator responsiveness (BDR), in healthy 3-6-year-old preschool children and those with asthma. DESIGN: Spirometry was performed before and 20 minutes after administering either inhaled placebo (for repeatability) or 400 μg salbutamol (for BDR) on two separate occasions (reproducibility) 3-23 days apart in asthmatic preschoolers and healthy controls. SETTINGS: Lung Function Laboratory, Hospital de Dona Estefania, Lisbon. PARTICIPANTS: Healthy preschool children and those with physician-diagnosed asthma, recruited from local Health Clinics and Outpatient Clinic. MAIN OUTCOME MEASURES: Paired measurements of forced expired volume in 0.75 s (FEV(0.75)) and forced mid-expiratory flows (FEF(25-75)). RESULTS: Technically successful baseline results were obtained in 86% of children assessed. Paired data were obtained in 43 asthmatic and 22 controls (median (range) age: 5.1 (3.4-6.8) years). Baseline FEV(0.75) was significantly lower in asthmatic children (mean (SD): 90 (15)% predicted) than in controls (102 (13) % predicted; p<0.001). Within-occasion coefficient of repeatability following placebo was similar in both groups, being 10.4% in asthma and 13.2% in controls for FEV(0.75). Following bronchodilator, FEV(0.75) increased significantly more in asthmatic preschoolers (mean (SD): 15.0 (12) %) than in controls (4.5 (5) %; p<0.001), with no significant difference between groups post-bronchodilator. Between-occasion variability was similar to within-day repeatability in controls, but almost twice as high in asthmatic children. CONCLUSIONS: BDR can be assessed reliably using FEV(0.75) in wheezy preschoolers, provided within-subject variability and responsiveness in health are taken into consideration.

PMID: 23292523 [PubMed - as supplied by publisher]

A Randomized, Controlled Trial to Evaluate Inhibition of T Cell Costimulation in Allergen Induced Airway Inflammation.

Am J Respir Crit Care Med. 2013 Jan 4;

Authors: Parulekar AD, Boomer JS, Patterson BM, Yin-Declue H, Deppong CM, Wilson BS, Jarjour NN, Castro M, Green JM

Abstract
RATIONALE: T-lymphocytes are important in the pathogenesis of allergic asthma. Costimulation through CD28 is critical for optimal activation of T cells, and inhibition of this pathway with CTLA4Ig has been shown to be effective in preventing airway inflammation and hyperresponsiveness in animal models of asthma. Abatacept, a humanized version of CTLA4Ig, has been approved for treatment of rheumatoid arthritis, providing the opportunity to test whether inhibition of costimulation is an effective strategy to treat asthmatics. OBJECTIVE: To determine if 3 months of treatment with abatacept reduced allergen induced airway inflammation in mild atopic asthmatics. METHODS: Randomized, placebo controlled, double blinded study. Bronchoscopically directed segmental allergen challenge was performed on 24 subjects followed by bronchoalveolar lavage 48 hours later. Subjects were randomized 1:1 to receive abatacept or placebo, followed by a second allergen challenge protocol after 3 months of study drug. MEASUREMENTS AND MAIN RESULTS: There was no significant reduction in allergen induced eosinophilic inflammation in the abatacept treated group as compared to placebo (17.71% ± 17.25 vs 46.39% ± 29.21, p=0.26). In addition, we did not detect an effect of abatacept on FEV1, PC20 or asthma symptoms. Subjects treated with abatacept had an increased percentage of naïve and a corresponding decrease in memory CD4+ T cells in the blood as compared to placebo. CONCLUSIONS: Inhibition of CD28-mediated costimulation with abatacept does not appear to alter the inflammatory response to SAC or clinical measures of asthma symptoms in mild atopic asthmatics.

PMID: 23292882 [PubMed - as supplied by publisher]