Sputum bacterial load and bacterial composition correlate with lung function and are altered by long-term azithromycin treatment in children with HIV-associated chronic lung disease.
Sputum bacterial load and bacterial composition correlate with lung function and are altered by long-term azithromycin treatment in children with HIV-associated chronic lung disease.
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DOI：
10.1186/s40168-023-01460-x
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发表时间：
2023-02-20
期刊：
影响因子：
15.5
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中科院分区：
文献类型：
--
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长期阿奇霉素 (AZM) 治疗可降低患有 HIV 相关慢性肺病 (HCLD) 的儿童和青少年急性呼吸系统恶化的频率。然而，这种治疗对呼吸道细菌组的影响尚不清楚。患有 HCLD 的非洲儿童（定义为 1 s z 分数 (FEV1z) 用力呼气量小于 - 1.0，且不可逆）参加了一项为期 48 周、每周一次 AZM 的安慰剂对照试验（BREATHE 试验）。在基线、48 周（治疗结束）和 72 周（试验结束前达到该时间点的参与者干预后 6 个月）收集痰样本。分别使用 16S rRNA 基因 qPCR 和 V4 区扩增子测序确定痰细菌载量和细菌组谱。主要结局是在基线、48 周和 72 周测量的受试者内和臂内（AZM 与安慰剂）痰细菌组的变化。还使用线性回归评估了临床或社会人口因素与细菌组概况之间的关联。总共有 347 名参与者（中位年龄：15.3 岁，四分位数范围 [12.7-17.7]）被纳入并随机分配至 AZM（173 名）或安慰剂（174 名）。 48周后，与安慰剂组相比，AZM组的参与者的痰细菌载量减少（log10中的16S rRNA拷贝数/μl，AZM与安慰剂组的平均差异和95%置信区间[CI] - 0.54 [- 0.71; - 0.36]）。在基线和 48 周之间，AZM 组中的 Shannon α 多样性保持稳定，但安慰剂组中有所下降（3.03 与 2.80，p = 0.04，Wilcoxon 配对检验）。与基线相比，AZM 组的细菌群落结构在 48 周时发生了变化（PERMANOVA 检验 p = 0.003），但在 72 周时得到解决。与基线相比，AZM 组中先前与 HCLD 相关的属的相对丰度在 48 周时下降，包括嗜血杆菌（17.9% vs. 25.8%，p < 0.05，ANCOM ω = 32）和莫拉氏菌（1% vs. 1.9%，p< 0.05，ANCOM） ω = 47）。相对于基线，这种减少持续了 72 周。肺功能 (FEV1z) 与细菌负荷呈负相关（系数，[CI]：− 0.09 [− 0.16；− 0.02]），与香农多样性呈正相关（0.19 [0.12；0.27]）。奈瑟菌的相对丰度（系数，[标准误差]：（2.85，[0.7]，q = 0.01）和嗜血杆菌（− 6.1，[1.2]，q < 0.001）分别与 FEV1z 呈正相关和负相关。从基线到 48 周，链球菌相对丰度的增加与 FEV1z 的改善相关。 FEV1z (3.2 [1.11], q = 0.01) 而莫拉氏菌的增加与 FEV1z 的下降相关 (-2.74 [0.74], q = 0.002) AZM 治疗保留了痰细菌多样性并降低了 HCLD 相关嗜血杆菌属和莫拉氏菌属的相对丰度。肺功能的改善，可能是 HCLD 儿童 AZM 治疗相关呼吸恶化减少的原因。 视频摘要 在线版本包含可在 10.1186/s40168-023-01460-x 获取的补充材料。
Long-term azithromycin (AZM) treatment reduces the frequency of acute respiratory exacerbation in children and adolescents with HIV-associated chronic lung disease (HCLD). However, the impact of this treatment on the respiratory bacteriome is unknown. African children with HCLD (defined as forced expiratory volume in 1 s z-score (FEV1z) less than − 1.0 with no reversibility) were enrolled in a placebo-controlled trial of once-weekly AZM given for 48-weeks (BREATHE trial). Sputum samples were collected at baseline, 48 weeks (end of treatment) and 72 weeks (6 months post-intervention in participants who reached this timepoint before trial conclusion). Sputum bacterial load and bacteriome profiles were determined using 16S rRNA gene qPCR and V4 region amplicon sequencing, respectively. The primary outcomes were within-participant and within-arm (AZM vs placebo) changes in the sputum bacteriome measured across baseline, 48 weeks and 72 weeks. Associations between clinical or socio-demographic factors and bacteriome profiles were also assessed using linear regression. In total, 347 participants (median age: 15.3 years, interquartile range [12.7–17.7]) were enrolled and randomised to AZM (173) or placebo (174). After 48 weeks, participants in the AZM arm had reduced sputum bacterial load vs placebo arm (16S rRNA copies/µl in log10, mean difference and 95% confidence interval [CI] of AZM vs placebo − 0.54 [− 0.71; − 0.36]). Shannon alpha diversity remained stable in the AZM arm but declined in the placebo arm between baseline and 48 weeks (3.03 vs. 2.80, p = 0.04, Wilcoxon paired test). Bacterial community structure changed in the AZM arm at 48 weeks compared with baseline (PERMANOVA test p = 0.003) but resolved at 72 weeks. The relative abundances of genera previously associated with HCLD decreased in the AZM arm at 48 weeks compared with baseline, including Haemophilus (17.9% vs. 25.8%, p < 0.05, ANCOM ω = 32) and Moraxella (1% vs. 1.9%, p < 0.05, ANCOM ω = 47). This reduction was sustained at 72 weeks relative to baseline. Lung function (FEV1z) was negatively associated with bacterial load (coefficient, [CI]: − 0.09 [− 0.16; − 0.02]) and positively associated with Shannon diversity (0.19 [0.12; 0.27]). The relative abundance of Neisseria (coefficient, [standard error]: (2.85, [0.7], q = 0.01), and Haemophilus (− 6.1, [1.2], q < 0.001) were positively and negatively associated with FEV1z, respectively. An increase in the relative abundance of Streptococcus from baseline to 48 weeks was associated with improvement in FEV1z (3.2 [1.11], q = 0.01) whilst an increase in Moraxella was associated with decline in FEV1z (-2.74 [0.74], q = 0.002). AZM treatment preserved sputum bacterial diversity and reduced the relative abundances of the HCLD-associated genera Haemophilus and Moraxella. These bacteriological effects were associated with improvement in lung function and may account for reduced respiratory exacerbations associated with AZM treatment of children with HCLD. Video Abstract The online version contains supplementary material available at 10.1186/s40168-023-01460-x.
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影响因子：
48
作者：
Callahan BJ;McMurdie PJ;Rosen MJ;Han AW;Johnson AJ;Holmes SP
通讯作者：
Holmes SP
影响因子：
3.7
作者：
Bogaert D;Keijser B;Huse S;Rossen J;Veenhoven R;van Gils E;Bruin J;Montijn R;Bonten M;Sanders E
通讯作者：
Sanders E
影响因子：
2.5
作者：
Gonzalez-Martinez, Carmen;Kranzer, Katharina;Ferrand, Rashida A.
通讯作者：
Ferrand, Rashida A.
影响因子：
6.4
作者：
Berenson, Charles S.;Kruzel, Ragina L.;Sethi, Sanjay
通讯作者：
Sethi, Sanjay
影响因子：
15.5
作者：
Davis, Nicole M;Proctor, Diana M;Callahan, Benjamin J
通讯作者：
Callahan, Benjamin J