糞便菌群移植治療艱難梭菌感染有效性和安全性的Meta分析

鄭晗晗，江學(xué)良

作者單位：250000山東省濟(jì)南市，濟(jì)南軍區(qū)總醫(yī)院消化科

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糞便菌群移植治療艱難梭菌感染有效性和安全性的Meta分析

鄭晗晗，江學(xué)良

作者單位：250000山東省濟(jì)南市，濟(jì)南軍區(qū)總醫(yī)院消化科

【摘要】目的探討糞便菌群移植(FMT)治療復(fù)發(fā)性、難治性、危重性艱難梭菌感染(CDI)的有效性和安全性。方法計(jì)算機(jī)檢索PubMed、EMBase、Cochrane Library、中國(guó)期刊全文數(shù)據(jù)庫(kù)，檢索時(shí)間從建庫(kù)至2015年5月。按照PICOS原則制定檢索策略,對(duì)檢索詞同時(shí)進(jìn)行主題詞和自由詞檢索。提取文獻(xiàn)相關(guān)信息，包括樣本量、CDI類型、是否合并炎癥性腸病(IBD)、年齡、捐贈(zèng)者、移植方式、糞便制劑、隨訪時(shí)間等。采用英國(guó)國(guó)立臨床優(yōu)化研究所(NICE)推薦的對(duì)病例系列的質(zhì)量評(píng)價(jià)清單評(píng)價(jià)納入文獻(xiàn)質(zhì)量。結(jié)果納入24篇文獻(xiàn)，共743例患者，663例獲得臨床緩解，臨床緩解率為89.2%，合并緩解率為87.6%〔95%CI(84.0%，90.4%)〕。亞組分析顯示，經(jīng)上消化道實(shí)施FMT的患者合并緩解率為81.5%〔95%CI(75.3%，86.5%)〕，低于經(jīng)下消化道實(shí)施FMT患者的合并緩解率89.7%〔95%CI(85.5%，92.7%)〕，差異有統(tǒng)計(jì)學(xué)意義(P<0.05)；采用冷凍制劑實(shí)施FMT的患者合并緩解率為85.5%〔95%CI(78.4%，90.6%)〕，與采用新鮮糞便制劑實(shí)施FMT患者的合并緩解率為88.3%〔95%CI(84.1%，91.5%)〕比較，差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)；合并IBD患者合并緩解率為72.7%〔95%CI(53.1%，86.3%)〕，與未合并IBD患者的合并緩解率87.8%〔95%CI(84.6%，90.4%)〕比較，差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)。11篇文獻(xiàn)發(fā)現(xiàn)了可能與FMT治療相關(guān)的不良反應(yīng)，如嘔吐、發(fā)熱、腹脹等，多為自限性,可在短時(shí)間內(nèi)緩解。接受FMT治療后死亡的患者中，死亡原因與患者本身其他疾病有關(guān)，沒有證據(jù)證明與FMT治療相關(guān)。結(jié)論FMT治療復(fù)發(fā)性、難治性、危重CDI安全有效，且經(jīng)下消化道實(shí)施FMT較上消化道有更高的臨床緩解率。 1.3資料提取文獻(xiàn)的審查和評(píng)價(jià)由2位作者獨(dú)立完成，通過閱讀文獻(xiàn)題目及，排除無(wú)關(guān)文獻(xiàn)，對(duì)其余文獻(xiàn)進(jìn)一步閱讀和分析，決定最終是否能夠入選，最后將納入的文獻(xiàn)是否合格進(jìn)行交叉核對(duì)，出現(xiàn)分歧時(shí)討論決定是否納入。文獻(xiàn)提取內(nèi)容包括：題目、第一作者、發(fā)表時(shí)間、樣本量、CDI類型、是否合并IBD、年齡、捐贈(zèng)者、移植方式、糞便制劑、隨訪時(shí)間等。 2.1文獻(xiàn)檢索及質(zhì)量評(píng)價(jià)檢索出FMT治療CDI的相關(guān)文獻(xiàn)5 281篇，通過閱讀文獻(xiàn)題目及排除5 237篇，閱讀全文后，納入24篇[26-31,36-53]英文文獻(xiàn)，國(guó)內(nèi)尚無(wú)符合納入標(biāo)準(zhǔn)的文獻(xiàn)。文獻(xiàn)篩選流程圖見圖1。納入的24篇文獻(xiàn)中，3篇文獻(xiàn)[31,37,42]是多中心研究，4篇[27,28,36,51]沒有清楚明確地描述研究的假說(shuō)或目的、目標(biāo)，4篇[31,36,41,51]沒有清楚地報(bào)告納入和排除標(biāo)準(zhǔn)，5篇[29,44,47,50-51]沒有對(duì)測(cè)量的結(jié)局做出明確的定義，4篇[29,44-45,52]前瞻性地收集數(shù)據(jù)，9篇[26,28-29,38,41,44-45,47,52]準(zhǔn)確地描述患者是連續(xù)招募的，只有1篇[36]文獻(xiàn)沒有清楚明確地描述研究的主要發(fā)現(xiàn)，沒有文獻(xiàn)對(duì)結(jié)局進(jìn)行分層分析。多數(shù)文獻(xiàn)NICE評(píng)分≥4分，屬于高質(zhì)量文獻(xiàn)，5篇[27,36,39,50-51]在4分以下，屬于低質(zhì)量文獻(xiàn)。納入文獻(xiàn)的基本特征見表1。

全球范圍內(nèi)，復(fù)發(fā)性和難治性艱難梭菌感染(CDI)發(fā)病率、病死率不斷增加[1-4]。CDI初次發(fā)作后，30%的患者會(huì)復(fù)發(fā)，多次復(fù)發(fā)的患者，60%會(huì)再次復(fù)發(fā)[5-7]。危重CDI患者的病死率可高達(dá)58%[8-10]。而高毒菌株(NAP1/B1/027)的出現(xiàn)，使治療的失敗率繼續(xù)增加[11]。目前，傳統(tǒng)的治療方案效果并不理想，非達(dá)霉素雖能降低復(fù)發(fā)率，但其費(fèi)用較高，且對(duì)多次復(fù)發(fā)患者的療效尚不明確[12-13]。

糞便菌群移植(FMT)能夠重塑腸道菌群的多樣性，使腸道功能得以恢復(fù)，從而抵御艱難梭菌及其產(chǎn)生的毒素[14- 15]。FMT可追溯至中國(guó)的東晉時(shí)期，距今約有1 700多年的歷史[16-17]，著名醫(yī)藥學(xué)家葛洪成功地用人糞清治療食物中毒、腹瀉、發(fā)熱并瀕臨死亡的患者[18]。受藥品安全及衛(wèi)生的相關(guān)管理規(guī)定，F(xiàn)MT并未得到廣泛應(yīng)用及發(fā)展。直到1958年Eiseman等[19]報(bào)道了FMT成功治療偽膜性腸炎患者，F(xiàn)MT的價(jià)值才逐漸得到認(rèn)可。在隨后的50多年中，不斷有FMT成功治療CDI的報(bào)道[20-31]。

目前FMT治療CDI的相關(guān)研究有限，缺乏設(shè)計(jì)合理的大規(guī)模、多中心的隨機(jī)對(duì)照試驗(yàn)，對(duì)FMT的長(zhǎng)期有效性和安全性研究較少，對(duì)合適患者、糞便制劑與劑量、移植方式與次數(shù)的選擇等缺乏統(tǒng)一的標(biāo)準(zhǔn)。僅有的循證醫(yī)學(xué)證據(jù)[32]也存在主要結(jié)局指標(biāo)定義不明確、樣本量較少等缺陷。因此，本研究增大樣本量，并對(duì)主要結(jié)局指標(biāo)做出定義，進(jìn)一步探討FMT治療CDI的有效性和安全性，并對(duì)不同移植方式、不同糞便制劑、是否合并炎癥性腸病(IBD)的患者療效進(jìn)行亞組分析，為FMT的臨床應(yīng)用提供參考。

1資料與方法

1.1文獻(xiàn)納入與排除標(biāo)準(zhǔn)

1.1.1文獻(xiàn)納入標(biāo)準(zhǔn)(1)研究設(shè)計(jì)：接受FMT治療的復(fù)發(fā)性或難治性或危重CDI患者；未設(shè)有對(duì)照組；≥10例的病例系列；(2)研究對(duì)象：復(fù)發(fā)性或難治性或危重CDI患者；伴或不伴感染(如IBD)，有明確的患者臨床特征及結(jié)局；(3)干預(yù)措施：FMT治療，包括任何形式的FMT，如結(jié)腸鏡、鼻胃管、灌腸等，不限制FMT次數(shù)和糞便劑型；(4)結(jié)局指標(biāo)：以腹瀉的臨床緩解作為主要結(jié)局指標(biāo)[33]。

FMT治療后，患者的臨床癥狀一般在治療當(dāng)時(shí)或48 h內(nèi)出現(xiàn)緩解，未緩解的患者在3～7 d再次給予FMT治療，因此，本研究綜合以上原因并結(jié)合臨床相關(guān)指南[33-34]，將腹瀉的臨床緩解定義為：FMT治療后大便次數(shù)減少或性狀改善，且在7 d內(nèi)不需其他干預(yù)治療。在FMT治療7 d后，緩解的患者出現(xiàn)癥狀復(fù)發(fā)或需要聯(lián)合其他藥物治療才能控制癥狀或使用其他抗生素后再次出現(xiàn)癥狀者，也認(rèn)為已獲得了臨床緩解。

1.1.2文獻(xiàn)排除標(biāo)準(zhǔn)(1)使用非糞便來(lái)源的腸道細(xì)菌進(jìn)行移植；(2)FMT治療CDI陰性的抗生素相關(guān)性腹瀉；(3)未報(bào)告FMT治療結(jié)果；(4)會(huì)議摘要、讀者來(lái)信、問卷調(diào)查；(5)聯(lián)合其他藥物治療CDI。

1.2文獻(xiàn)檢索策略計(jì)算機(jī)檢索PubMed、EMBase、Cochrane Library、中國(guó)期刊全文數(shù)據(jù)庫(kù)，檢索時(shí)間從建庫(kù)至2015年5月。按照PICOS(Patients，Intervention，Comparisons，Outcomes，Study)原則制定檢索策略,對(duì)檢索詞同時(shí)進(jìn)行主題詞和自由詞檢索。英文檢索詞為“clostridium”“clostridium difficile”“fecal microbiota transplant”；中文檢索詞為“艱難梭菌感染”“糞便菌群移植”。語(yǔ)種限制為中、英文。

1.4文獻(xiàn)質(zhì)量評(píng)價(jià)采用英國(guó)國(guó)立臨床優(yōu)化研究所(NICE)推薦的對(duì)病例系列的質(zhì)量評(píng)價(jià)清單[32]評(píng)價(jià)納入文獻(xiàn)質(zhì)量，包括以下內(nèi)容：(1)為提高研究結(jié)果的代表性，病例系列中的病例最好來(lái)自不同級(jí)別的醫(yī)療機(jī)構(gòu)，開展多中心研究；(2)清楚明確地描述研究的假說(shuō)或目的、目標(biāo)；(3)清楚地報(bào)告納入和排除標(biāo)準(zhǔn)；(4)對(duì)測(cè)量的結(jié)局做出明確定義；(5)前瞻性收集數(shù)據(jù)；(6)準(zhǔn)確地描述患者為連續(xù)招募；(7)清楚明確地描述研究的主要發(fā)現(xiàn)；(8)將結(jié)局進(jìn)行分層分析及報(bào)告，如按照疾病分期、化驗(yàn)結(jié)果異常、患者的特征等。每項(xiàng)1分，≥4分的文獻(xiàn)為高質(zhì)量文獻(xiàn)，否則為低質(zhì)量文獻(xiàn)。

1.5統(tǒng)計(jì)學(xué)方法采用MetaAnalyst Beta 3.13進(jìn)行統(tǒng)計(jì)分析，采用I2和Q檢驗(yàn)評(píng)價(jià)各文獻(xiàn)異質(zhì)性，當(dāng)I2=0時(shí)，表明各文獻(xiàn)的變異僅由抽樣誤差引起；I2<25%表明各文獻(xiàn)存在輕度異質(zhì)性，25%～50%表明有中度異質(zhì)性，I2>50%或P<0.10時(shí)，認(rèn)為各文獻(xiàn)有較大的異質(zhì)性。以腹瀉的臨床緩解作為主要的結(jié)局指標(biāo)，采用隨機(jī)效應(yīng)模型[35]計(jì)算臨床緩解率、合并緩解率。以P<0.05為差異有統(tǒng)計(jì)學(xué)意義。

2結(jié)果

2.2Meta分析結(jié)果

2.2.1合并緩解率各文獻(xiàn)存在輕度異質(zhì)性(I2=23%，P=0.156)。納入文獻(xiàn)共743例患者，663例獲得臨床緩解，臨床緩解率為89.2%，合并緩解率為87.6%〔95%CI(84.0%，90.4%)，見圖2〕。

2.2.2不同移植方式的亞組分析9篇文獻(xiàn)[26-27,30,36,43,47,49,51-52]經(jīng)上消化道(胃鏡、鼻胃管、鼻十二指腸管、內(nèi)鏡引導(dǎo)下經(jīng)皮胃造瘺管、口服膠囊制劑)實(shí)施FMT,各文獻(xiàn)無(wú)異質(zhì)性(I2=0，P=0.933)。共192例患者，159例獲得臨床緩解，臨床緩解率為82.8%，合并緩解率為81.5%〔95%CI(75.3%，86.5%)，見圖3〕。19篇文獻(xiàn)[28-31,36-42,44-46,48-51,53]經(jīng)下消化道(腸鏡、灌腸)實(shí)施FMT，各文獻(xiàn)有輕度異質(zhì)性(I2=24%，P=0.170)。共551例患者，504例獲得臨床緩解，臨床緩解率為91.5%，合并緩解率為89.7%〔95%CI(85.5%，92.7%),見圖4〕。經(jīng)下消化道實(shí)施FMT的合并緩解率高于經(jīng)上消化道，合并緩解率之差為-8.2%〔95%CI(-14.2%，-2.2%)〕，差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。

圖1　文獻(xiàn)篩選流程圖

第一作者發(fā)表時(shí)間樣本量(例)合并IBD(例)CDI類型平均年齡(歲)捐贈(zèng)者移植方式糞便制劑隨訪時(shí)間NICE評(píng)分(分)Aas[26]2003180復(fù)發(fā)性73±9親屬、非親屬鼻胃管新鮮9年5Macconnachie[27]2009150復(fù)發(fā)性81.5非親屬鼻胃管新鮮平均16周2Yoon[38]2010120復(fù)發(fā)性、難治性66親屬結(jié)腸鏡新鮮3周～8年5Rohlke[37]2010190復(fù)發(fā)性49親屬、非親屬結(jié)腸鏡新鮮平均27.2個(gè)月5Garborg[36]2010402復(fù)發(fā)性75親屬胃鏡、結(jié)腸鏡新鮮80d1Mellow[28]2011130復(fù)發(fā)性、難治性63.5親屬結(jié)腸鏡新鮮平均5.3個(gè)月4Jorup-Ronstrom[39]2012321復(fù)發(fā)性75非親屬灌腸冷凍1～68個(gè)月3Kelly[41]2012260復(fù)發(fā)性59親屬結(jié)腸鏡新鮮平均10.7個(gè)月4Hamilton[29]20124314復(fù)發(fā)性NR非親屬結(jié)腸鏡冷凍、新鮮2個(gè)月5Kassam[40]2012270復(fù)發(fā)性、難治性69.4非親屬灌腸新鮮平均427d4Mattila[42]2012700復(fù)發(fā)性73親屬、非親屬結(jié)腸鏡新鮮12周～12個(gè)月5Rubin[43]2013750復(fù)發(fā)性63非親屬鼻胃管、胃鏡、PEG新鮮60d4Pathak[49]2014121復(fù)發(fā)性NR親屬、非親屬結(jié)腸鏡、NDT新鮮2～30個(gè)月4Russell[51]2014103復(fù)發(fā)性NR親屬鼻胃管、結(jié)腸鏡新鮮1個(gè)月～4年1Youngster[52]2014200復(fù)發(fā)性、難治性64.5非親屬口服膠囊制劑冷凍2～6個(gè)月6Zainah[30]2014140復(fù)發(fā)性、危重性73.4±11.9親屬、非親屬鼻胃管、結(jié)腸鏡新鮮7～100d4Ray[50]2014201復(fù)發(fā)性、難治性62親屬結(jié)腸鏡新鮮3.2個(gè)月3Kronman[47]2014103復(fù)發(fā)性5.4親屬、非親屬鼻胃管新鮮平均44d4Lee[48]2014940復(fù)發(fā)性、難治性71.8非親屬灌腸新鮮6～24個(gè)月4Dutta[45]2014270復(fù)發(fā)性64.5親屬、非親屬結(jié)腸鏡、小腸鏡新鮮9.7～34.0個(gè)月6Allegretti[44]2014229復(fù)發(fā)性、難治性NR親屬、非親屬結(jié)腸鏡新鮮平均3個(gè)月5Khan[46]2014200復(fù)發(fā)性、難治性NR親屬、非親屬結(jié)腸鏡新鮮3～6個(gè)月4Satokari[53]2015490復(fù)發(fā)性NR親屬、非親屬結(jié)腸鏡新鮮、冷凍12周～1年4Tvede[31]2015550復(fù)發(fā)性65.6非親屬灌腸冷凍30d4

注：CDI=艱難梭菌感染，IBD=炎癥性腸病，NR=沒有報(bào)道，PEG=內(nèi)鏡引導(dǎo)下經(jīng)皮胃造瘺管，NDT=鼻十二指腸管，NICE=英國(guó)國(guó)立臨床優(yōu)化研究所

Figure 2Forest plot for clinical remission rates of CDI patients treated by FMT

圖3　經(jīng)上消化道實(shí)施FMT治療CDI臨床緩解率的森林圖

Figure 3Forest plot of clinical remission rates of CDI patients treated by upper gastrointestinal FMT

圖4　經(jīng)下消化道實(shí)施FMT治療CDI臨床緩解率的森林圖

Figure 4Forest plot of clinical remission rates of CDI pateints treated by lower gastrointestinal FMT

2.2.3不同糞便制劑的亞組分析5篇文獻(xiàn)[29,31,39,52-53]采用冷凍制劑(冷凍的糞便混懸液、冷凍的膠囊制劑、冷凍培養(yǎng)的糞便菌株)實(shí)施FMT，各文獻(xiàn)無(wú)異質(zhì)性(I2=0，P=0.566)。共142例患者，123例獲得臨床緩解，臨床緩解率為86.6%，合并緩解率為85.5%〔95%CI(78.4%，90.6%),見圖5〕。21篇文獻(xiàn)[26-30,36-38,40-51,53]采用新鮮糞便制劑實(shí)施FMT，各文獻(xiàn)有中度異質(zhì)性(I2=26%，P=0.131)。共601例患者，540例獲得臨床緩解，合并緩解率為88.3%〔95%CI(84.1%，91.5%)，見圖6〕。采用冷凍制劑與新鮮制劑實(shí)施FMT的合并緩解率之差為-2.8%〔95%CI(-3.4%，9.0%)〕，差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)。

圖5　冷凍制劑治療CDI臨床緩解率的森林圖

Figure 5Forest plot of clinical remission rates of CDI pateints treated by frozen feces preparation

圖6　新鮮制劑治療CDI臨床緩解率的森林圖

Figure 6Forest plot of clinical remission rates of CDI patients treated by fresh feces preparation

2.2.4是否合并IBD的亞組分析8篇文獻(xiàn)[29,36,39,44,47,49-51]納入的部分患者合并IBD，各文獻(xiàn)有輕度異質(zhì)性(I2=2%，P=0.413)。共34例患者，27例患者獲得臨床緩解，臨床緩解率為79.4%，合并緩解率為72.7%〔95%CI(53.1%，86.3%)，見圖7〕。24篇文獻(xiàn)[26-31,36-53]納入的部分患者未合并IBD，各文獻(xiàn)有輕度異質(zhì)性(I2=11%，P=0.310)。共納入709例患者，636例獲得臨床緩解，臨床緩解率為89.7%，合并緩解率為87.8%〔95%CI(84.6%，90.4%)，見圖8〕。合并IBD與未合并IBD患者合并緩解率之差為-15.1%〔95%CI(-1.0%，30.3%)〕，差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)。

2.3不良反應(yīng)11篇文獻(xiàn)[26-27,29,31,44-45,47-48,50,52-53]發(fā)現(xiàn)了可能與FMT治療相關(guān)的不良反應(yīng)，如嘔吐、發(fā)熱、腹脹等，多為自限性,可在短時(shí)間內(nèi)緩解(見表2)。接受FMT治療后死亡的患者中，死亡原因與患者本身其他疾病有關(guān)，如惡性腫瘤、心血管疾病、器官功能衰竭等，沒有證據(jù)證明與FMT治療相關(guān)。在Aas等[26]研究中，1例患者經(jīng)FMT治療后，癥狀沒有改善，在FMT治療后的第3天發(fā)展為腹膜炎，并且很快死亡。該例患者在接受FMT時(shí)已患有嚴(yán)重的終末期腎病，需要腹膜透析治療，因此難以說(shuō)明其死亡與FMT有關(guān)。

圖7　FMT治療CDI合并IBD的臨床緩解率的森林圖

Figure 7Forest plot of clinical remission rates of CDI patients combined with IBD treated by FMT

圖8　FMT治療CDI未合并IBD的臨床緩解率的森林圖

Figure 8Forest plot of clinical remission rates of CDI patients without IBD treated by FMT

表2　FMT治療CDI的不良反應(yīng)

注：NR=沒有報(bào)道

3討論

本研究采用NICE質(zhì)量評(píng)價(jià)工具對(duì)納入的病例系列進(jìn)行質(zhì)量評(píng)價(jià)，雖然病例系列研究在治療療效評(píng)價(jià)中的證據(jù)級(jí)別低于隨機(jī)對(duì)照試驗(yàn)、類試驗(yàn)，但本研究納入的多數(shù)文獻(xiàn)質(zhì)量評(píng)分在4分及以上，為高質(zhì)量研究，僅5篇低于4分，文獻(xiàn)總體質(zhì)量較高。

FMT治療復(fù)發(fā)性、難治性或危重性CDI患者是有效的。本研究發(fā)現(xiàn)，F(xiàn)MT治療CDI的臨床緩解率為89.2%，合并緩解率為87.6%，與Kassam等[32]Meta分析結(jié)果(臨床緩解率為89.7%，合并緩解率為89.1%)相近，低于Sofi等[54]研究的合并緩解率91.2%，分析原因可能為本研究納入的樣本量大，部分患者合并其他胃腸道疾病等危險(xiǎn)因素有關(guān)。

FMT治療復(fù)發(fā)性、難治性或危重CDI患者是安全的。FMT通過將健康者的糞便懸液或糞便菌群注入患者胃腸道，以達(dá)到修復(fù)患者受損的腸道菌群的目的，雖有一些輕度不良反應(yīng)的發(fā)生，如腹痛、發(fā)熱、惡心、嘔吐等，但均在短時(shí)間內(nèi)得到緩解，未發(fā)生與FMT治療相關(guān)的嚴(yán)重不良反應(yīng)?；颊邔?duì)FMT的耐受性好，未見因FMT傳播疾病的報(bào)道。

本研究發(fā)現(xiàn)，經(jīng)下消化道實(shí)施FMT較上消化道有更高的臨床緩解率。分析可能的原因?yàn)椋?1)若患者病情較重，通過結(jié)腸鏡實(shí)施FMT有誘發(fā)腸穿孔的風(fēng)險(xiǎn)，因此會(huì)選擇經(jīng)上消化道實(shí)施FMT[30]。故經(jīng)上消化道實(shí)施FMT治療的患者病情通常較經(jīng)下消化道實(shí)施患者嚴(yán)重；(2)經(jīng)上消化道注入的糞便制劑量較少；(3)經(jīng)下消化道實(shí)施FMT，可以使糞便菌群免受胃酸及胰酶的破壞，且直接作用于病變的腸道黏膜，使移植的糞便菌群最大限度發(fā)揮作用。近期一項(xiàng)研究發(fā)現(xiàn)，通過結(jié)腸鏡實(shí)施FMT治療CDI比萬(wàn)古霉素或非達(dá)霉素更為經(jīng)濟(jì)有效[55]。

本研究未發(fā)現(xiàn)使用冷凍制劑與新鮮制劑的患者臨床緩解率存在差異，分析可能的原因?yàn)槔鋬鲋苿┖托迈r制劑有相同的有效菌株，雖然冷凍制劑經(jīng)過冷凍儲(chǔ)存，但其有效菌株并沒有被破壞。FMT治療CDI的有效菌株尚不明確，仍需進(jìn)一步研究。

本研究同樣未發(fā)現(xiàn)CDI合并IBD與未合并IBD患者的臨床緩解率存在差異，分析可能的原因?yàn)镃DI和IBD均涉及腸道菌群結(jié)構(gòu)的改變，F(xiàn)MT對(duì)CDI和IBD均發(fā)揮作用。最近發(fā)表的FMT治療活動(dòng)性潰瘍性結(jié)腸炎的隨機(jī)對(duì)照試驗(yàn)顯示，F(xiàn)MT治療組比安慰劑組有更高的臨床緩解率，并且差異有統(tǒng)計(jì)學(xué)意義，經(jīng)FMT治療后患者的腸道菌群多樣性較治療前增加[56]。

本研究局限性：(1)納入文獻(xiàn)均來(lái)自國(guó)外，研究對(duì)象以歐美人群居多，使研究結(jié)論在我國(guó)患者的推廣受到限制；(2)病例系列研究論證強(qiáng)度低于隨機(jī)對(duì)照試驗(yàn)，在一定程度上增加了偏倚，可能會(huì)使緩解率增大。本研究納入文獻(xiàn)的患者均為10例及以上，減少個(gè)案報(bào)道和小病例系列的偏倚，且是目前樣本量最大的FMT治療CDI有效性的Meta分析，首次探討了不同制劑、是否合并IBD患者臨床緩解率的差異。在FMT廣泛應(yīng)用于治療CDI之前，期待設(shè)計(jì)合理的大樣本隨機(jī)對(duì)照試驗(yàn)進(jìn)行進(jìn)一步研究。

作者貢獻(xiàn):鄭晗晗進(jìn)行課題設(shè)計(jì)、資料收集整理、數(shù)據(jù)分析、撰寫論文；江學(xué)良參與課題設(shè)計(jì)，進(jìn)行質(zhì)量控制及審校。各作者均對(duì)文章負(fù)責(zé)。

本文無(wú)利益沖突。

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(本文編輯：吳立波)

·醫(yī)學(xué)循證·

【關(guān)鍵詞】難辨梭菌；糞便菌群移植；有效性研究；Meta分析

鄭晗晗，江學(xué)良.糞便菌群移植治療艱難梭菌感染有效性和安全性的Meta分析[J].中國(guó)全科醫(yī)學(xué)，2016，19(2)：199-205.[www.chinagp.net]

Zheng HH,Jiang XL.Fecal microbiota transplantation for clostridium difficile infection:a meta-analysis[J].Chinese General Practice，2016，19(2)：199-205.

Fecal Microbiota Transplantation for Clostridium Difficile Infection:A Meta-analysisZHENGHan-han,JIANGXue-liang.DepartmentofGastroenterology,theGeneralHospitalofJi′nanMilitaryCommand,Ji′nan250000,China

【Abstract】ObjectiveTo investigate the efficacy and safety of fecal microbiota transplantation(FMT) in recurrent,refractory and severe clostridium difficile infection(CDI).MethodsA computer-based research was conducted on PubMed,EMBase,Cochrane Library and CNKI,with the research time set from database establishment to May 2015.Searching strategy was made based on PICOS principle,and keywords were searched as both subject term and free term.Relevant information was extracted from literatures,including sample volume,CDI type,whether combined with IBD,age,donator,transplanting methods,feces preparation,follow-up period,etc.The quality evaluation inventory for cases recommended by National Institute for Health and Clinical Excellence (NICE) of Britain was employed in the literature quality evaluation.ResultsA total of 24 pieces of literature were included,and there were 743 patients concerned,of which 663 patients had clinical remission with a clinical remission rate of 89.2% and a merged remission rate of 87.6%〔95%CI(84.0%，90.4%)〕.The subgroup analysis showed that the merging remission rate of patients who received FMT through upper gastrointestinal tract was 81.5%〔95%CI(75.3%，86.5%)〕,lower (P<0.05) than that of patients who received FMT through lower gastrointestinal tract,which was 89.7%〔95%CI(85.5%，92.7%)〕;the merging remission rate of patients who underwent FMT using frozen feces preparation was 85.5%〔95%CI(78.4%，90.6%)〕,and the merging remission rate of patients who underwent FMT using fresh feces preparation was 88.3%〔95%CI(84.1%，91.5%)〕,without significant difference between them(P>0.05).The merging remission rate of patients combined with IBD was 72.7%〔95%CI(53.1%，86.3%)〕,and that of patients without IBD combined was 87.8%〔95%CI(84.6%，90.4%)〕,without significant differences between them (P>0.05).Adverse reactions that may be related with FMT treatment were found in 11 pieces of literatures,such as vomit,fever,abdominal distension,and most symptoms were self-confined and could remit soon.Among patients who died after FMT treatment,the cause of death was related with other diseases of these patients,and there were no evidences of the relation between FMT treatment and their death.ConclusionFMT is safe and effective for treating recurrent,refractory,and severe CDI.Lower gastrointestinal FMT delivery lead to higher clinical remission rate.

【Key words】Clostridium difficile；Fecal microbiota transplantation；Validation studies；Meta-analysis

收稿日期：(2015-06-23；修回日期：2015-11-25)

【中圖分類號(hào)】R 378.8

【文獻(xiàn)標(biāo)識(shí)碼】A

doi：10.3969/j.issn.1007-9572.2016.02.016

通信作者：江學(xué)良，250000山東省濟(jì)南市，濟(jì)南軍區(qū)總醫(yī)院消化科；E-mail：jiangxueliang678@126.com