Background

Structural lung disease and neutrophil-dominated airway inflammation is present from 3 months of age in children diagnosed with cystic fibrosis after newborn screening. We hypothesised that azithromycin, given three times weekly to infants with cystic fibrosis from diagnosis until age 36 months, would reduce the extent of structural lung disease as captured on chest CT scans.

Methods

A phase three, randomised, double-blind, placebo-controlled trial was done at eight paediatric cystic fibrosis centres in Australia and New Zealand. Infants (aged 3–6 months) diagnosed with cystic fibrosis following newborn screening were eligible. Exclusion criteria included prolonged mechanical ventilation in the first 3 months of life, clinically significant medical disease or comorbidities other than cystic fibrosis, or macrolide hypersensitivity. Participants were randomly assigned (1:1) to receive either azithromycin (10 mg/kg bodyweight orally three times per week) or matched placebo until age 36 months. Randomisation was done with a permuted block strategy and an interactive web-based response system, stratified by study site. Unblinding was done once all participants completed the trial. The two primary outcomes were the proportion of children with radiologically defined bronchiectasis, and the percentage of total lung volume affected by disease. Secondary outcomes included clinical outcomes and exploratory outcomes were inflammatory markers. Analyses were done with the intention-to-treat principle. This study is registered at ClinicalTrials.gov (NCT01270074).

Findings

Between June 15, 2012, and July 10, 2017, 281 patients were screened, of whom 130 were enrolled, randomly assigned, and received first study dose. 68 participants received azithromycin and 62 received placebo. At 36 months, 88% (n=50) of the azithromycin group and 94% (n=44) of the placebo group had bronchiectasis (odds ratio 0·49, 95% CI 0·12 to 2·00; p=0·32), and total airways disease did not differ between groups (median difference −0·02%, 95% CI −0·59 to 0·56; p=0·96). Secondary outcome results included fewer days in hospital for pulmonary exacerbations (mean difference −6·3, 95% CI −10·5 to −2·1; p=0·0037) and fewer courses of inhaled or oral antibiotics (incidence rate ratio 0·88, 95% CI 0·81 to 0·97; p=0·0088) for those in the azithromycin group. For the preplanned, exploratory analysis, concentrations of airway inflammation were lower for participants receiving azithromycin, including interleukin-8 (median difference −1·2 pg/mL, 95% CI −1·9 to −0·5; p=0·0012) and neutrophil elastase activity (−0·6 μg/mL, −1·1 to −0·2; p=0·0087) at age 36 months, although no difference was noted between the groups for interleukin-8 or neutrophil elastase activity at 12 months. There was no effect of azithromycin on body-mass index at age 36 months (mean difference 0·4, 95% CI −0·1 to 0·9; p=0·12), nor any evidence of pathogen emergence with the use of azithromycin. There were few adverse outcomes with no differences between the treatment groups.

Interpretation

Azithromycin treatment from diagnosis of cystic fibrosis did not reduce the extent of structural lung disease at 36 months of age; however, it did reduce airway inflammation, morbidity including pulmonary exacerbations in the first year of life and hospitalisations, and improved some clinical outcomes associated with cystic fibrosis lung disease. Therefore we suggest thrice-weekly azithromycin is a strategy that could be considered for the routine early management of paediatric patients with cystic fibrosis.

Funding

Cystic Fibrosis Foundation.

中文翻译：

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阿奇霉素对囊性纤维化 (COMBAT CF) 婴儿结构性肺病的影响：一项 3 期、随机、双盲、安慰剂对照临床试验

背景

新生儿筛查后诊断为囊性纤维化的儿童从 3 个月大开始出现结构性肺病和以中性粒细胞为主的气道炎症。我们假设，从诊断到 36 个月大的囊性纤维化婴儿每周给予阿奇霉素 3 次，可以减少胸部 CT 扫描显示的结构性肺疾病的程度。

方法

在澳大利亚和新西兰的八个儿科囊性纤维化中心进行了一项三期、随机、双盲、安慰剂对照试验。新生儿筛查后诊断为囊性纤维化的婴儿（3-6 个月大）符合条件。排除标准包括出生后前 3 个月的机械通气时间延长、有临床意义的内科疾病或囊性纤维化以外的合并症，或大环内酯类过敏症。参与者被随机分配（1:1）接受阿奇霉素（10 mg/kg 体重，每周口服 3 次）或匹配安慰剂，直到 36 个月大。随机化采用置换区组策略和基于网络的交互式响应系统，按研究站点分层。一旦所有参与者完成试验，就进行了揭盲。两个主要结果是放射学定义的支气管扩张儿童的比例，以及受疾病影响的总肺容积的百分比。次要结果包括临床结果，探索性结果是炎症标志物。分析采用意向治疗原则。该研究已在 ClinicalTrials.gov (NCT01270074) 注册。

发现

2012 年 6 月 15 日至 2017 年 7 月 10 日期间，筛选了 281 名患者，其中 130 名被纳入、随机分配并接受了第一次研究剂量。68 名参与者接受了阿奇霉素治疗，62 人接受了安慰剂治疗。36 个月时，阿奇霉素组 88% (n=50) 和安慰剂组 94% (n=44) 发生支气管扩张（优势比 0·49，95% CI 0·12 至 2·00；p=0 ·32)，总气道疾病在各组之间没有差异（中位数差异 -0·02%，95% CI -0·59 至 0·56；p=0·96）。次要结果包括更少的肺部恶化住院天数（平均差 -6·3，95% CI -10·5 至 -2·1；p=0·0037）和更少的吸入或口服抗生素疗程（发病率比0·88, 95% CI 0·81 至 0·97；p=0·0088) 为阿奇霉素组。对于预先计划的探索性分析，接受阿奇霉素治疗的参与者气道炎症浓度较低，包括白细胞介素 8（中位数差异 -1·2 pg/mL，95% CI -1·9 至 -0·5；p=0·0012）和中性粒细胞弹性蛋白酶活性（ -0·6 μg/mL，-1·1 至 -0·2；p=0·0087）在 36 个月大时，尽管在 12 个月时白细胞介素 8 或中性粒细胞弹性蛋白酶活性组之间没有差异。在 36 个月大时，阿奇霉素对体重指数没有影响（平均差 0·4，95% CI -0·1 到 0·9；p=0·12），也没有任何证据表明使用时出现病原体的阿奇霉素。治疗组之间几乎没有不良结果，没有差异。p=0·0087) 在 36 个月大时，尽管在 12 个月时白细胞介素 8 或中性粒细胞弹性蛋白酶活性在各组之间没有差异。在 36 个月大时，阿奇霉素对体重指数没有影响（平均差 0·4，95% CI -0·1 到 0·9；p=0·12），也没有任何证据表明使用时出现病原体的阿奇霉素。治疗组之间几乎没有不良结果，没有差异。p=0·0087) 在 36 个月大时，尽管在 12 个月时白细胞介素 8 或中性粒细胞弹性蛋白酶活性在各组之间没有差异。在 36 个月大时，阿奇霉素对体重指数没有影响（平均差 0·4，95% CI -0·1 到 0·9；p=0·12），也没有任何证据表明使用时出现病原体的阿奇霉素。治疗组之间几乎没有不良结果，没有差异。

解释

从诊断囊性纤维化开始的阿奇霉素治疗并未减少 36 个月大时结构性肺病的程度；然而，它确实减少了气道炎症、包括生命第一年的肺部恶化和住院在内的发病率，并改善了与囊性纤维化肺病相关的一些临床结果。因此，我们建议每周三次的阿奇霉素是一种可考虑用于囊性纤维化儿科患者常规早期管理的策略。

资金

囊性纤维化基金会。