Coffey Michael J, Garg Millie, Homaira Nusrat, Jaffe Adam, Ooi Chee Y
University of New South Wales, School of Women's and Children's Health, Level 8, Centre for Child Health Research & Innovation Bright Alliance Building Cnr Avoca & High Streets, Randwick, Sydney, NSW, Australia, 2031.
Sydney Children's Hospital, Junior Medical Officers Department, High Street, Randwick, Sydney, NSW, Australia, 2031.
Cochrane Database Syst Rev. 2020 Jan 22;1(1):CD012949. doi: 10.1002/14651858.CD012949.pub2.
Cystic fibrosis (CF) is a multisystem disease and the importance of growth and nutrition has been well established, given its implications for lung function and overall survival. It has been established that intestinal dysbiosis (i.e. microbial imbalance) and inflammation is present in people with CF. Probiotics are commercially available (over-the-counter) and may improve both intestinal and overall health.
To assess the efficacy and safety of probiotics for improving health outcomes in children and adults with CF.
We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Date of last register search: 20 January 2020. We also searched ongoing trials registries and the reference lists of relevant articles and reviews. Date of last search: 29 January 2019.
Randomised or quasi-randomised controlled trials (RCTs) assessing efficacies and safety of probiotics in children and adults with CF. Cross-over RCTs with a washout phase were included and for those without a washout period, only the first phase of each trial was analysed.
We independently extracted data and assessed the risk of bias of the included trials; we used GRADE to assess the certainty of the evidence. We contacted trial authors for additional data. Meta-analyses were undertaken on outcomes at several time points.
We identified 17 trials and included 12 RCTs (11 completed and one trial protocol - this trial was terminated early) (464 participants). Eight trials included only children, whilst four trials included both children and adults. Trial duration ranged from one to 12 months. Nine trials compared a probiotic (seven single strain and three multistrain preparations) with a placebo preparation, two trials compared a synbiotic (multistrain) with a placebo preparation and one trial compared two probiotic preparations. Overall we judged the risk of bias in the 12 trials to be low. Three trials had a high risk of performance bias, two trials a high risk of attrition bias and six trials a high risk of reporting bias. Only two trials were judged to have low or unclear risk of bias for all domains. Four trials were sponsored by grants only, two trials by industry only, two trials by both grants and industry and three trials had an unknown funding source. Combined data from four trials (225 participants) suggested probiotics may reduce the number of pulmonary exacerbations during a four to 12 month time-frame, mean difference (MD) -0.32 episodes per participant (95% confidence interval (CI) -0.68 to 0.03; P = 0.07) (low-certainty evidence); however, the 95% CI includes the possibility of both an increased and a reduced number of exacerbations. Additionally, two trials (127 participants) found no evidence of an effect on the duration of antibiotic therapy during the same time period. Combined data from four trials (177 participants) demonstrated probiotics may reduce faecal calprotectin, MD -47.4 µg/g (95% CI -93.28 to -1.54; P = 0.04) (low-certainty evidence), but the results for other biomarkers mainly did not show any difference between probiotics and placebo. Two trials (91 participants) found no evidence of effect on height, weight or body mass index (low-certainty evidence). Combined data from five trials (284 participants) suggested there was no difference in lung function (forced expiratory volume at one second (FEV) % predicted) during a three- to 12-month time frame, MD 1.36% (95% CI -1.20 to 3.91; P = 0.30) (low-certainty evidence). Combined data from two trials (115 participants) suggested there was no difference in hospitalisation rates during a three- to 12-month time frame, MD -0.44 admissions per participant (95% CI -1.41 to 0.54; P = 0.38) (low-certainty evidence). One trial (37 participants) reported health-related quality of life and while the parent report favoured probiotics, SMD 0.87 (95% CI 0.19 to 1.55) the child self-report did not identify any effect, SMD 0.59 (95% CI -0.07 to 1.26) (low-certainty evidence). There were limited results for gastrointestinal symptoms and intestinal microbial profile which were not analysable. Only four trials and one trial protocol (298 participants) reported adverse events as a priori hypotheses. No trials reported any deaths. One terminated trial (12 participants and available as a protocol only) reported a severe allergic reaction (severe urticaria) for one participant in the probiotic group. Two trials reported a single adverse event each (vomiting in one child and diarrhoea in one child). The estimated number needed to harm for any adverse reaction (serious or not) is 52 people (low-certainty evidence).
AUTHORS' CONCLUSIONS: Probiotics significantly reduce faecal calprotectin (a marker of intestinal inflammation) in children and adults with CF, however the clinical implications of this require further investigation. Probiotics may make little or no difference to pulmonary exacerbation rates, however, further evidence is required before firm conclusions can be made. Probiotics are associated with a small number of adverse events including vomiting, diarrhoea and allergic reactions. In children and adults with CF, probiotics may be considered by patients and their healthcare providers. Given the variability of probiotic composition and dosage, further adequately-powered multicentre RCTs of at least 12 months duration are required to best assess the efficacy and safety of probiotics for children and adults with CF.
囊性纤维化（CF）是一种多系统疾病，鉴于其对肺功能和总体生存率的影响，生长和营养的重要性已得到充分证实。已证实CF患者存在肠道菌群失调（即微生物失衡）和炎症。益生菌可通过非处方方式购买，可能改善肠道和整体健康状况。
评估益生菌对改善CF儿童和成人健康结局的疗效和安全性。
我们检索了Cochrane囊性纤维化试验注册库，该注册库通过电子数据库检索以及对期刊和会议摘要书籍的手工检索编制而成。最后一次注册库检索日期：2020年1月20日。我们还检索了正在进行的试验注册库以及相关文章和综述的参考文献列表。最后一次检索日期：2019年1月29日。
评估益生菌对CF儿童和成人疗效及安全性的随机或半随机对照试验（RCT）。纳入了有洗脱期的交叉RCT，对于没有洗脱期的试验，仅分析每个试验的第一阶段。
我们独立提取数据并评估纳入试验的偏倚风险；我们使用GRADE评估证据的确定性。我们与试验作者联系以获取更多数据。对几个时间点的结局进行了荟萃分析。
我们识别出17项试验，纳入12项RCT（11项完成，1项试验方案——该试验提前终止）（464名参与者）。8项试验仅纳入儿童，4项试验同时纳入儿童和成人。试验持续时间为1至12个月。9项试验将一种益生菌（7种单菌株和3种多菌株制剂）与一种安慰剂制剂进行比较，2项试验将一种合生元（多菌株）与一种安慰剂制剂进行比较，1项试验将两种益生菌制剂进行比较。总体而言，我们判断这12项试验中的偏倚风险较低。3项试验存在较高的实施偏倚风险，2项试验存在较高的失访偏倚风险，6项试验存在较高的报告偏倚风险。只有2项试验在所有领域的偏倚风险被判定为低或不明确。4项试验仅由资助支持，2项试验仅由行业支持，2项试验由资助和行业共同支持，3项试验的资金来源不明。来自4项试验（2名参与者）的合并数据表明，益生菌可能在4至12个月的时间范围内减少肺部加重发作的次数，平均差（MD）为每位参与者-0.32次发作（95%置信区间（CI）-0.68至0.03；P = 0.07）（低确定性证据）；然而，95%CI包括加重发作次数增加和减少的可能性。此外，2项试验（127名参与者）未发现同期对抗生素治疗持续时间有影响的证据。来自4项试验（177名参与者）的数据表明，益生菌可能降低粪便钙卫蛋白水平，MD为-47.4μg/g（95%CI -93.28至-1.54；P = 0.04）（低确定性证据），但其他生物标志物的结果主要未显示益生菌与安慰剂之间有任何差异。2项试验（91名参与者）未发现对身高、体重或体重指数有影响的证据（低确定性证据）。来自5项试验（284名参与者）的合并数据表明，在3至12个月的时间范围内肺功能（一秒用力呼气量（FEV）占预计值的百分比）无差异，MD为1.36%（95%CI -1.20至3.91；P = 0.三十年）（低确定性证据）。来自2项试验（115名参与者）的合并数据表明，在3至12个月的时间范围内住院率无差异，MD为每位参与者-0.44次入院（95%CI -1.41至0.54；P = 0.38）（低确定性证据）。1项试验（37名参与者）报告了与健康相关的生活质量，虽然家长报告倾向于益生菌，标准化均数差（SMD）为0.87（95%CI 0.19至1.55），但儿童自我报告未发现任何影响，SMD为0.59（95%CI -0.07至1.26）（低确定性证据）。关于胃肠道症状和肠道微生物谱的结果有限，无法进行分析。只有4项试验和1项试验方案（298名参与者）将不良事件作为预先设定的假设进行报告。没有试验报告任何死亡事件。1项提前终止的试验（12名参与者，仅以试验方案形式提供）报告益生菌组有一名参与者发生严重过敏反应（严重荨麻疹）。2项试验各报告了1例不良事件（1名儿童呕吐，1名儿童腹泻）。任何不良反应（严重或不严重）的估计伤害人数为52人（低确定性证据）。
益生菌可显著降低CF儿童和成人的粪便钙卫蛋白（肠道炎症标志物）水平，然而其临床意义需要进一步研究。益生菌对肺部加重发作率可能影响甚微或无影响，不过在得出确切结论之前还需要更多证据。益生菌与少数不良事件相关，包括呕吐、腹泻和过敏反应。对于CF儿童和成人，患者及其医疗服务提供者可考虑使用益生菌。鉴于益生菌成分和剂量的变异性，需要进一步开展至少持续12个月、样本量充足的多中心RCT，以最佳评估益生菌对CF儿童和成人的疗效和安全性。
