Effects of azithromycin on asthma control, airway inflammation and bacterial colonisation in smokers with asthma: a randomised control trial

[摘要] Smokers with asthma represent an important sub-group of asthmatics displaying both reduced response to inhaled and oral corticosteroids as well as demonstrating accelerated decline in lung function and increased use of health care services.Clinical and laboratory studies have suggested that macrolide antibiotics may exhibit anti-inflammatory properties in a variety of airways disease including asthma. The anti-inflammatory properties of macrolides have been recognised for almost 50 years. Indirect evidence from both pre-clinical and clinical studies suggests that the mechanism of action may be of particular benefit in smokers with asthma.A proof of concept study was designed to test the hypothesis that the macrolide antibiotic azithromycin improves measures of asthma control, airway inflammation and bacterial colonisation in smokers with asthma.Azithromycin was chosen for its convenience of once daily dosing and its oral tolerability in addition to its more limited interactions.Seventy-seven adults with allergic asthma were recruited to a 12-week parallel group randomised controlled trial comparing the effects on asthma control, airway inflammation and bacterial colonisation of oral azithromycin 250 mg daily with matched placebo.The primary outcome measure was peak expiratory flow at the final study visit.Secondary outcome measures included spirometry, asthma control questionnaire [ACQ] score, asthma quality of life questionnaire [AQLQ], Leicester cough questionnaire [LCQ] score, provocation concentration to methacholine PC20, and inflammatory markers: exhaled nitric oxide, sputum differential cell counts, sputum supernatant and serum inflammatory markers such as interleukin-1β [IL-1β], IL-2, -4, -5, -6, -10, TNF-α, IFN-γ, GM-CSF, Leukotriene B4, and high sensitivity C-reactive protein.Microbiological culture and PCR of sputum was also performed to assess for any changes associated with treatment.At 12 weeks, the change in PEF at the final study visit, ascompared with baseline, did not differ significantly between the azithromycin and placebo treatment groups [mean difference azithromycin-placebo -10.3L/min, 95% CI -47.1 to 26.4, p=0.58].No statistically significant difference was observed between the azithromycin and placebo groups in each of the measures of spirometry, ACQ, AQLQ, LCQ, PC20, or evening PEF.The LCQ-psychological domain did reach statistical significance, [mean difference azithromycin-placebo -0.46, 95%CI -0.9 to 0.02 p=0.04], however this indicates a deterioration in the treatment group.No change was seen in exhaled nitric oxide.The total cell counts recovered from sputum were similar following treatment with azithromycin compared to placebo.In addition, differential cell counts remained unchanged and lymphocyte proliferation assays did not demonstrate any statistically significant changes following 12 weeks of treatment with azithromycin when compared to placebo.There was no substantial difference in any of the measured sputum supernatant or plasma cytokines.Peripheral blood monocyte stimulation was performed, with supernatant being measured against a panel of cytokines.There was again no substantial difference in any of the measured panel of cytokines collected from the monocyte stimulation assays when the azithromycin group was compared to placebo.There was no correlation between changes in ACQ, AQLQ, LCQ, PC20, sputum macrophage count, sputum neutrophil count, sputum eosinophil count, and PEF.Adverse event rates were similar in patients taking azithromycin compared with placebo.A total of 4 patients were lost to follow up [1 in the azithromycin group, 3 in the placebo group].One patient died of a cardiovascular cause.This occurred following completion of the study but within the pre-specified regulatory reporting period.In conclusion there were no clinically important improvements in a range of clinical indices of asthma control, airway inflammation or bacterial colonisation following 12 weeks treatment with azithromycin when compared with placebo in smokers with asthma.The lack of any evidence of clinical benefit of azithromycin in smokers with asthma is a new finding and extends the current knowledge base and evidence for the use of macrolides in asthma.There exists no firm evidence to suggest the widespread use of macrolides in asthma and the current study suggests that no benefit will be observed in the sub-group of asthmatics whom are current smokers.

[发布机构] University:University of Glasgow;Department:Institute of Infection Immunity and Inflammation

[关键词] AsthmaPEFMacrolideSmokerSteroid resistanceQuality of lifeAsthma control