AJG：粪菌移植有效治疗复发性艰难梭菌感染

难辨梭状芽孢杆菌小肠结肠炎是因使用抗生素导致肠道菌群失调，由难辨梭状芽孢杆菌在肠道大量繁殖引起的肠炎。严重者大便排出片状黏膜，曾称假膜性肠炎，本病由于广泛使用抗生素而日益增多，又称抗生素相关性肠炎，是一种常见的医院内感染性疾病。临床表现主要为腹致疾泻、血便、粪便内可见假膜，并有发热、腹痛等表现，重症患者可合并电解质紊乱、休克、DIC、低蛋白血症、肠出血、肠穿孔以及脓肿、血管栓塞、中毒性巨结 肠等。艰难梭菌肠炎多系医院内感染，几乎所有抗菌药物均可诱发本病。近年艰难梭菌感染的比例明显上升。在美国1996年至2005年10年间艰难梭菌感染 的发病率增长了3倍。基因型NAP1的高毒力027菌株的出现导病的严重程度明显上升，该菌株造成的死亡率高度6.9%。在发病率上升的同时伴随而来的是抗菌药物治疗艰难梭菌的疗效逐渐下降。从2000年至今，非复杂性艰难梭菌感染对甲硝唑的耐药性由2.5%上升至10%。抗菌药物使用的失效导致艰难梭菌感染治疗后复发率明显上升。粪菌移植是将健康人粪便中的功能菌群，移植到患者胃肠道内，重建具有正常功能的肠道菌群，实现肠道及肠道外疾病的治疗。粪菌移植在国内外主要用来治疗难治性肠病，包括炎症性肠病合并难辨梭状芽孢杆菌感染、严重菌群失调、免疫缺陷性肠病、代谢性疾病、严重肠道过敏性疾病等。1958年Eiseman首次使用粪菌移植治疗艰难梭菌感染，至今50余年的临床应用证实粪菌治疗复发性艰难梭菌感染有效率高达90%。但是目前对于粪菌移植治疗艰难梭菌感染尚缺乏已经批准通过的随机对照实验，虽然有2项系统性综述总结了粪菌移植治疗艰难梭菌感染的文献，但都存在方法学的限制和缺陷。为了弥补这一缺陷，加拿大安大略省汉密尔顿麦克马斯特大学健康科学中心胃肠病科Zain Kassam等人在前人基础上对研究方法进行了改良，重新检索了相关文献、注册临床研究等，对粪菌移植治疗艰难梭菌感染进行了系统性综述和Meta分析，，结果提示粪菌移植治疗复发性艰难梭菌感染有效率高达89.7%，且未发现任何不良反应。但仍需设计良好的并登记注册、可长期随访的临床随机对照实验进一步对其适宜人群、疗效、安全性进行评估。该结果发表在2013年4月的The American Journal of Gastroenterology。
作者检索了MEDLINE (1946年–2012年3月)，EMBASE (1974年– 2012年3月)以及在科克兰中心注册的对照实验项目。检索策略为不受语言类别限制。选择经过完整、严格的同行评审过程的完整实验数据而排除摘要数据。纳入的研究包括任何形式的粪菌移植用于治疗实验室检查或内窥镜检查确定的艰难梭菌感染的患者，以临床缓解作为初级结局指标。进一步在其中筛选样本量大于等于10例的研究。入选的文献涉及的研究进行的医疗中心的级别，研究分布的区域、国家临床技术研究所对系列案例的质量评估作为判定研究质量的参考标准。质量合格与否的评估和提取数据分别由不同的研究者进行。同时计算全部纳入研究及预先确定的亚组的未加权的混合缓解率及加权的混合缓解率，以及其95%置信区间。结果共检索出11项相关研究，其中共273名艰难梭菌感染的患者进行了粪菌移植的治疗。在发表文献中无随机对照性研究。273名患者中245名患者得到了临床缓解（未加权混合缓解率为89.7%，加权混合缓解率为89.1%，95%置信区间为84-93%）。在不同研究中不存在显著的异质性（Cocharan Q检验，P = 0.13, I2= 33.7%）。先验的亚组分析显示下消化道粪菌移植治疗效果（未加权混合缓解率为91.4%，加权混合缓解率为91.2%，95%置信区间为86-95%）优于上消化道粪菌移植（未加权混合缓解率为82.3%，加权混合缓解率为80.6%，95%置信区间为69 – 90%）。加权混合缓解率的比例差异为10.6%（95%置信区间为-0.6 – 22%）。粪菌群来自匿名捐献者和患者自己选定的捐献者的治疗效果无显著差异。在随访的期间内（随访时间数周至数年不等）均未发现粪菌移植治疗的不良反应。
综上所述，粪菌移植相当有希望成为治疗复发性艰难梭菌感染的治疗方法。但在提倡广泛推广该治疗方法之间仍需要进行设计良好的并登记注册、可长期随访的临床随机对照实验进一步对其适宜人群、疗效、安全性进行评估。
与艰难梭菌相关的拓展阅读：

• Am J Infect Control：入院时靶向筛查艰难梭菌或可识别出多数定殖患者
• AJG：肠道艰难梭菌诊治指南
• Clin Infect Dis:儿童艰难梭菌感染率明显上升
• NAT GENET :艰难梭菌全球流行原因被识别
• NEJM：非达霉素治疗艰难梭菌感染不逊于万古霉素 4周时更胜一筹
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Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis.
OBJECTIVES
The clinical and economic burden of Clostridium difficile infection (CDI) is significant. Recurrent CDI management has emerged as a major challenge with suboptimal response to standard therapy. Fecal microbiota transplantation (FMT) has been used as a treatment to reconstitute the normal microbial homeostasis and break the cycle of antibiotic agents that may further disrupt the microbiome. Given the lack of randomized-controlled trials (RCTs) and limitations in previous systematic reviews, we aimed to conduct a systematic review with robust methods to determine the efficacy and safety profile of FMT in CDI.
METHODS
An electronic search was conducted using MEDLINE (1946-March 2012), EMBASE (1974-March 2012) and Cochrane Central Register of Controlled Trials (2012). The search strategy was not limited by language. Abstract data were excluded and only completed studies that underwent the full, rigorous peer-review process were included. Studies that used FMT via any delivery modality for laboratory or endoscopically proven CDI with clinical resolution as primary outcome were included. A sample size of 10 or more patients was a further criterion. Elements of the Centre for Reviews and Dissemination checklist and the National Institute of Clinical Excellence quality assessment for case series checklist were employed to determine study quality. Eligibility assessment and data extraction were performed by two independent researchers. Both unweighted pooled resolution rates (UPR) and weighted pooled resolution rates (WPR) were calculated with corresponding 95% confidence intervals (CI) for overall studies, as well as predefined subgroups.
RESULTS
Eleven studies with a total of 273 CDI patients treated with FMT were identified; no RCTs were found as none have been published. Two-hundred and forty-five out of 273 patients experienced clinical resolution (UPR 89.7%; WPR 89.1% (95% CI 84 to 93%)). There was no statistically significant heterogeneity between studies (Cochran Q test P=0.13, I(2)=33.7%). A priori subgroup analysis suggested that lower gastrointestinal FMT delivery (UPR 91.4%; WPR 91.2% (95% CI 86 to 95%)) led to a trend towards higher clinical resolution rates than the upper gastrointestinal route (UPR 82.3%; WPR 80.6% (95% CI 69-90%)) (proportion difference of WPR was 10.6% (95% CI -0.6 to 22%)). No difference in clinical outcomes was detected between anonymous vs. patient selected donors. There were no reported adverse events associated with FMT and follow-up was variable from weeks to years.
CONCLUSIONS
FMT holds considerable promise as a therapy for recurrent CDI but well-designed, RCTs and long-term follow-up registries are still required. These are needed to identify the right patient, efficacy and safety profile of FMT before this approach can be widely advocated.