HE PATHOPHYSIOLOGY OF NONcystic fibrosis (CF) bronchiectasis is generally considered to be characterized by an airway inflammatory response to bacterial pathogens, and recent data provide further evidence to support this "vicious cycle" hypothesis. 1 However, studies of maintenance therapies designed to interrupt this cycle at differing points have failed to demonstrate convincing evidence of clinical efficacy, including prolonged oral antibiotics, 2 inhaled tobramycin, 3 inhaled corticosteroids, 4 and mucolytics. 5 Until recently, 6 there have arguably been no therapies with proven clinical benefit in non-CF bronchiectasis.Maintenance azithromycin was shown to reduce exacerbations in non-CF bronchiectasis 6 ; however, limitations of that study 7 included a treatment period of only 6 months and a lack of systematic evaluation for macrolide See also pp 1251 and 1295.

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Evidence before this study: Data sources and searches © 2019. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ Two investigators searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials andWeb of Science using the search strategy described in the online supplement. Searches were conducted from 2000 to 30 th September 2018. No language restrictions were applied. Searches were supplemented with review of reference lists and by reviewing previous meta-analyses and guidelines. Clearly ineligible studies were excluded based on abstract review alone.We identified 266 references and after exclusion of non-relevant studies we identified 3 randomized controlled trials comparing long term treatment with macrolide antibiotics (>3 months duration) compared with placebo where the primary outcome was the reduction of exacerbations. We identified several existing aggregate meta-analyses that suggested that macrolides reduce the frequency of exacerbations of bronchiectasis. Neither the individual trials nor the existing meta-analyses reported on the effectiveness of macrolides in different subpopulations. Identifying which patients benefit from macrolides was identified as a key research priority in bronchiectasis. The current European Respiratory Society guidelines suggest consideration of macrolides for patients without Pseudomonas aeruginosa infection with a history of at least 3 exacerbations in the previous year. Added value of this study:We report the first individual patient data meta-analysis of long term macrolide therapy in bronchiectasis. Our data from 341 patients enrolled in randomized clinical trials in the Netherlands, NewZealand and Australia suggests that macrolide treatment compared to placebo for 6-12 months results in a 50% reduction in the frequency of exacerbations. Additional benefits included prolongation of the time to first exacerbation and statistically significant improvements in quality of life measured by the St Georges Respiratory Questionnaire. Lung function was not significantly improved. Analyses in prespecified subgroups including age, sex, disease severity and baseline microbiology suggested that macrolides effectively reduced exacerbations across all subgroups of patients. Importantly, macrolides had a significant and clinically meaningful impact in patients where macrolide are not currently considered as first line treatment, including patients with P. aeruginosa infection and patients with less than 3 exacerbations per year. Implications of all the available evidence:Our data suggests that macrolide therapy is highly effective in reducing the frequency of exacerbations in bronchiectasis. Given the strong evidence that exacerbations contribute to long term morbidity and mortality in bronchiectasis macrolides should be considered in patients with frequent or severe exacerbations. Current bronchiectasis guidelines recommend inhaled antibiotics as first line treatment for patients with P. aeruginosa...