Effect of Faecal Microbiota Transplantation for Treatment of Clostridium difficile Infection in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis of Cohort Studies

Effect of Faecal Microbiota Transplantation for Treatment of Clostridium difficile Infection in... Abstract Background Evidence concerning the effect of faecal microbiota transplantation [FMT] in Clostridium difficile infection [CDI] patients with inflammatory bowel disease [IBD] has not been firmly established. Therefore, we performed a systematic review and meta-analysis to evaluate FMT treatment outcomes in patients with IBD treated for CDI. Methods An electronic search of four databases was conducted until November 1, 2017. Cohort studies of FMT efficacy and safety in CDI patients with IBD were included. Pooled effect sizes were calculated with 95% confidence intervals [CI] using a random-effects model. Results Nine cohort studies comprising a total of 346 CDI patients with IBD were included. The initial cure rate was 81% [95% CI = 76%-85%] and the overall cure rate was up to 89% [95% CI = 83%-93%], both with no significant heterogeneity. The recurrence rate was 19% [95% CI = 13%-27%] with moderate heterogeneity [Cochran’s Q, p = 0.19; I2 = 33%]. There was no significant difference in the CDI cure rate after FMT in patients with and without IBD (risk ratio [RR] = 0.92; 95% CI = 0.81-1.05; Cochran’s Q, p = 0.06; I2 = 53%). Subgroup analysis revealed a similar CDI treatment effects after FMT in patients with Crohn’s disease and in those with ulcerative colitis [p = 0.1804]. Four studies reported adverse events of IBD flares. Conclusions FMT is an effective therapy for CDI in patients with IBD. Well-designed randomised controlled trials and well-conducted microbiological studies are needed to validate its efficacy and safety. Faecal microbiota transplantation, Clostridium difficile infection, inflammatory bowel disease, systematic review, meta-analysis 1. Introduction Clostridium difficile infection [CDI], accompanied by community- and hospital-acquired diarrhoea, has become a major clinical and economic burden. The incidence of CDI has increased from 50 cases per 100000 people in 2001 to 120 cases per 100000 people in 2011, and a large increase has been demonstrated in patients with inflammatory bowel disease [IBD].1–3 In 2004, 7% of patients with CDI had concomitant IBD, and this proportion grew to 16% in 2005.4 Notably, CDI patients with concurrent IBD have an increased risk for numerous adverse events, which include higher mortality, prolonged hospital stay, and higher health care costs.4–6 The treatment of CDI patients with IBD is challenging because these individuals are less likely to respond to medical therapy for CDI.5,7 These cases are typically managed using antibiotic therapy. However, treatment with metronidazole or vancomycin, the current treatment options for CDI, results in recurrence rates ranging from 22% to 34%.8,9 After a first episode of CDI, over 70% of patients are at risk of recurrence despite receiving standard treatment.10 Furthermore, the risk of CDI is increased in patients receiving prolonged corticosteroid therapy for IBD,11 and patients in this population who develop CDI have an associated risk of colectomy, bowel perforation, shock, respiratory failure, and death.12,13 Therefore, some investigators have turned to faecal microbiota transplantation [FMT], a microbiome-based therapy, in seeking an effective treatment that normalises gut dysbiosis and thus confers resistance to C. difficile colonisation. Although FMT is not a new technique, it is regarded as an effective and safe treatment for gastrointestinal disease, especially for CDI.14,15 A previous meta-analysis revealed that after treatment with FMT, approximately 90% of patients with CDI were cured.16 Several cohort studies suggested that FMT was a beneficial treatment for CDI patients with IBD, but the exact effect of FMT in these patients has not been confirmed. Accordingly, we performed a systematic literature review and meta-analysis to evaluate the efficacy and safety of FMT for the treatment of CDI in patients with IBD. 2. Methods 2.1 Search and selection We designed our systematic review and meta-analysis in accordance with the guidelines of the 2009 Preferred Reporting Items for Systematic Reviews and Meta-analysis [PRISMA] statement.17 We performed an electronic search of four databases [Pubmed, Embase, Medline, and the Cochrane Library] from the date of inception to November , 2017. The medical subject heading [MeSH] terms we used to search titles and abstracts were: ‘Clostridium difficile’, ‘C. difficile’, ‘Clostridium difficile infection’, ‘antibiotic diarrhoea’, ‘pseudomembranous’, ‘CDI’, ‘inflammatory bowel disease’, ‘Crohn’s disease’, ‘ulcerative colitis’, ‘colitis’, ‘IBD’, ‘CD’, ‘UC’ AND ‘faecal microbiota transplantation’, ‘fecal’, ‘flora’, ‘microbiota’, ‘donor’, ‘bacteriotherapy’, ‘transplant’, ‘transfusion’, ‘enema’, ‘infusion’, ‘reconstitution’, ‘FMT’. No language restrictions were applied, but only studies in human subjects were included. Two reviewers [TC and QZ] examined the reference list of each identified study and reviewed articles to identify additional relevant publications. 2.2 Study selection We included studies designed according to the PICO [Patients-Intervention-Comparison-Outcome] model and met the following conditions: [1] CDI patients with IBD were enrolled by authors’ criteria where clinical symptoms and laboratory testing were confirmed; [2] patients in the intervention group [with or without a control group] received FMT administered by any delivery modality; [3] the primary outcomes were CDI initial cure, overall cure, and recurrence rate, and FMT safety was evaluated based on reported adverse events. Case reports, animal studies, general reviews, conference abstracts, and letters were excluded. Additionally, any cohort studies with less than 10 participants were excluded to minimise bias. 2.3 Quality assessment For observational studies, we assessed the methodological quality using the Newcastle-Ottawa Scale [NOS].18 According to the instrument, we graded the selection of study groups, comparability of study groups, and ascertainment of exposure or outcome, for each report. Within each main category, individual items were assessed as having a low [one star awarded] or high [no star awarded] risk of bias, and the maximum score was nine. Studies with six or more stars were considered to have a low risk of bias, those with four or five stars as a moderate risk, and those with less than four stars as a high risk of bias. 2.4 Data extraction Two investigators [TC and QZ] independently evaluated the reports and determined study eligibility based on our predefined inclusion criteria. Any discrepancies were resolved by discussion with a third reviewer [Y-GC]. We recorded the first author’s name, year of publication, study design, number of participants, country, patient characteristics, FMT donor type and delivery procedure, length of follow-up, and adverse events, for each study included in our analysis. 2.5 Data synthesis and analysis We used the Metaprop module in R-3.4.1 statistical software package for data analysis. Pooled effect sizes with 95% confidence intervals [CI] were calculated for outcomes evaluating the efficacy of FMT therapy in CDI patients with IBD. Risk ratios [RR] with 95% CI were used for dichotomous outcomes. Subgroup analyses were constructed based on data availability. We analysed heterogeneity using the Cochran Q and I2 tests. Heterogeneity was assessed using the Cochran Q test when the p-value was less than 0.1. I2 values of 25%, 50%, and 75% corresponded to low, moderate, and high levels of statistical heterogeneity.19 All analyses were performed using a random-effects model.20 We applied the funnel plot and Egger’s test to evaluate publication bias if the same outcome measures [i.e. ≥9] were identified. A p-value less than 0.05 was considered statistically significant. 3. Results 3.1 Results of the literature search Our search identified 568 studies in the four electronic databases. After screening titles and abstracts, 19 articles were retrieved. Subsequently, 10 articles were excluded after a full-text review. Of these, two were case reports,21,22 three were conference summaries,23–25 three were reviews,26–28 and two were studies that did not have a fully justified pre-defined sample size.29,30 Ultimately, a total of nine cohort studies met our inclusion criteria and were selected. The summary of the study selection process is shown in Figure 1. Figure 1. View largeDownload slide Flow chart of study selection. Figure 1. View largeDownload slide Flow chart of study selection. 3.2 Study characteristics Of the nine cohort studies analysed, four were prospective31,33,36,39 and five were retrospective.32,34,35,37,38 A total of 346 CDI patients with IBD were enrolled in the nine studies, and the number included in each ranged from 12 to 67. Six studies included a control group and enrolled 188 CDI patients with IBD to receive FMT in an experimental group. In these investigations, 774 CDI patients without IBD received FMT and served as controls.31-33,35,37,39 The studies were published between 2012 and 2017, and conducted in the USA, Canada, Australia, and Europe. The combined proportion of female patients in eight studies was 56.8% [176/310], and the mean age ranged from 27.60 to 61.45.31,33-39 Five studies enrolled patients with recurrent CDI,31,33,35,36,39 and the other four included both recurrent and refractory cases.32,34,37,38 Eight studies included patients with ulcerative colitis [UC], Crohn’s disease [CD], or a combination of these IBD subtypes. Two studies used screened unrelated FMT donors,36,39 and five used both related and unrelated donors.31,34,35,37,38 The remaining two studies did not clearly identify the origin of the FMT donors.32,33 Lower gastrointestinal FMT delivery [colonoscopy, sigmoidoscopy, and enema] was performed in seven studies,31-35,38,39 and two used both lower and upper gastrointestinal FMT delivery [nasogastric tube and capsule] methods.36,37Table 1 summarises the characteristics of the studies. Table 1. Study characteristics. Study [year]  Study design  Cases  Country  Age [years] nean [range]  Female [%]  Type of CDI [recurrent, refractory, both]  Type of IBD [UC, CD, both]  Donor [related, unrelated, both]  FMT delivery  Follow-up  Hamilton et al. 201231  PCS  14  USA  44.6  79  Recurrent  Both  Both  Colonoscopy  2 months  Kelly et al. 201432  RCS  36  USA, Canada, Australia  NS  NS  Both  Both  NS  Colonoscopy or Sigmoidoscopy  3 months  Khoruts et al. 201633  PCS  43  USA  38.80 [16–84]  51.2  Recurrent  Both  NS  Colonoscopy  2 months  Fischer et al. 2016a34  RCS  67  USA, Canada, Europe  45.40  58.2  Both  Both  Both  Colonoscopy or Sigmoidoscopy  3 months  Fischer et al. 2016b35  RCS  63  USA, Canada  61.45  73.5  Recurrent  Both  Both  Colonoscopy  1 month  Chin et al. 201736  PCS  35  USA  43.00 [8–93]  46  Recurrent  Both  Unrelated  Colonoscopy, NG, and capsule  2 months  Meighani et al. 201737  RCS  20  USA  46.90  50  Both  NS  Both  Colonoscopy, NG, and enema.  7 days  Newman et al. 201738  RCS  56  USA  38.20  42.9  Both  Both  Both  Colonoscopy  2 months  Khanna et al. 201739  PCS  12  USA  27.60 [23–75]  66.7  Recurrent  Both  Unrelated  Colonoscopy  >1 year  Study [year]  Study design  Cases  Country  Age [years] nean [range]  Female [%]  Type of CDI [recurrent, refractory, both]  Type of IBD [UC, CD, both]  Donor [related, unrelated, both]  FMT delivery  Follow-up  Hamilton et al. 201231  PCS  14  USA  44.6  79  Recurrent  Both  Both  Colonoscopy  2 months  Kelly et al. 201432  RCS  36  USA, Canada, Australia  NS  NS  Both  Both  NS  Colonoscopy or Sigmoidoscopy  3 months  Khoruts et al. 201633  PCS  43  USA  38.80 [16–84]  51.2  Recurrent  Both  NS  Colonoscopy  2 months  Fischer et al. 2016a34  RCS  67  USA, Canada, Europe  45.40  58.2  Both  Both  Both  Colonoscopy or Sigmoidoscopy  3 months  Fischer et al. 2016b35  RCS  63  USA, Canada  61.45  73.5  Recurrent  Both  Both  Colonoscopy  1 month  Chin et al. 201736  PCS  35  USA  43.00 [8–93]  46  Recurrent  Both  Unrelated  Colonoscopy, NG, and capsule  2 months  Meighani et al. 201737  RCS  20  USA  46.90  50  Both  NS  Both  Colonoscopy, NG, and enema.  7 days  Newman et al. 201738  RCS  56  USA  38.20  42.9  Both  Both  Both  Colonoscopy  2 months  Khanna et al. 201739  PCS  12  USA  27.60 [23–75]  66.7  Recurrent  Both  Unrelated  Colonoscopy  >1 year  CDI, Clostridium difficile infection; IBD, inflammatory bowel disease; UC, ulcerative colitis; CD, Crohn’s disease; FMT, faecal microbiota transplantation; NS, not stated; PCS, prospective cohort study; RCS, retrospective cohort study; NG, nasogastric tube. View Large Table 1. Study characteristics. Study [year]  Study design  Cases  Country  Age [years] nean [range]  Female [%]  Type of CDI [recurrent, refractory, both]  Type of IBD [UC, CD, both]  Donor [related, unrelated, both]  FMT delivery  Follow-up  Hamilton et al. 201231  PCS  14  USA  44.6  79  Recurrent  Both  Both  Colonoscopy  2 months  Kelly et al. 201432  RCS  36  USA, Canada, Australia  NS  NS  Both  Both  NS  Colonoscopy or Sigmoidoscopy  3 months  Khoruts et al. 201633  PCS  43  USA  38.80 [16–84]  51.2  Recurrent  Both  NS  Colonoscopy  2 months  Fischer et al. 2016a34  RCS  67  USA, Canada, Europe  45.40  58.2  Both  Both  Both  Colonoscopy or Sigmoidoscopy  3 months  Fischer et al. 2016b35  RCS  63  USA, Canada  61.45  73.5  Recurrent  Both  Both  Colonoscopy  1 month  Chin et al. 201736  PCS  35  USA  43.00 [8–93]  46  Recurrent  Both  Unrelated  Colonoscopy, NG, and capsule  2 months  Meighani et al. 201737  RCS  20  USA  46.90  50  Both  NS  Both  Colonoscopy, NG, and enema.  7 days  Newman et al. 201738  RCS  56  USA  38.20  42.9  Both  Both  Both  Colonoscopy  2 months  Khanna et al. 201739  PCS  12  USA  27.60 [23–75]  66.7  Recurrent  Both  Unrelated  Colonoscopy  >1 year  Study [year]  Study design  Cases  Country  Age [years] nean [range]  Female [%]  Type of CDI [recurrent, refractory, both]  Type of IBD [UC, CD, both]  Donor [related, unrelated, both]  FMT delivery  Follow-up  Hamilton et al. 201231  PCS  14  USA  44.6  79  Recurrent  Both  Both  Colonoscopy  2 months  Kelly et al. 201432  RCS  36  USA, Canada, Australia  NS  NS  Both  Both  NS  Colonoscopy or Sigmoidoscopy  3 months  Khoruts et al. 201633  PCS  43  USA  38.80 [16–84]  51.2  Recurrent  Both  NS  Colonoscopy  2 months  Fischer et al. 2016a34  RCS  67  USA, Canada, Europe  45.40  58.2  Both  Both  Both  Colonoscopy or Sigmoidoscopy  3 months  Fischer et al. 2016b35  RCS  63  USA, Canada  61.45  73.5  Recurrent  Both  Both  Colonoscopy  1 month  Chin et al. 201736  PCS  35  USA  43.00 [8–93]  46  Recurrent  Both  Unrelated  Colonoscopy, NG, and capsule  2 months  Meighani et al. 201737  RCS  20  USA  46.90  50  Both  NS  Both  Colonoscopy, NG, and enema.  7 days  Newman et al. 201738  RCS  56  USA  38.20  42.9  Both  Both  Both  Colonoscopy  2 months  Khanna et al. 201739  PCS  12  USA  27.60 [23–75]  66.7  Recurrent  Both  Unrelated  Colonoscopy  >1 year  CDI, Clostridium difficile infection; IBD, inflammatory bowel disease; UC, ulcerative colitis; CD, Crohn’s disease; FMT, faecal microbiota transplantation; NS, not stated; PCS, prospective cohort study; RCS, retrospective cohort study; NG, nasogastric tube. View Large 3.3 Data quality According to the NOS, the cohort studies were all of moderate methodological quality and had a score ranging from four to seven. Six studies included a control group.31-33,35,37,39 All cohort studies ascertained FMT exposure and performed adequate follow-up. However, there was a lack of evidence related to the outcome of FMT exposure at the start of experiment. With one exception,37 all studies satisfied the length of follow-up requirement. A summary of risk bias is shown in Table 2. Table 2. Newcastle-Ottawa Scale for assessing quality of cohort studies. Study (year)  Representative community population of exposure cohort  Ascertainment of FMT exposure  Resemblance of control cohort populations and exposure  Evidence outcome of FMT exposure at start of experiment  Study controls for severity of CDI  Study controls for age, gender, and antibiotic application  Outcome assessment  Complete follow-up period for end outcome [30 to 40 days]  Adequacy follow-up of cohort study  NOS score  Hamilton et al. 201231  -  *  -  -  -  -  *  *  *  4  Kelly et al. 201432  -  *  -  -  -  -  *  *  *  4  Khoruts et al. 201633  *  *  *  -  *  -  *  *  *  7  Fischer et al. 2016a34  -  *  -  -  -  -  *  *  *  4  Fischer et al. 2016b35  -  *  -  -  -  -  *  *  *  4  Chin et al. 201736  *  *  -  -  -  -  *  *  *  5  Meighani et al. 201737  -  *  -  -  *  -  *  -  *  4  Newman et al. 201738  *  *  -  -  -  -  *  *  *  5  Khanna et al. 201739  -  *  -  -  -  -  *  *  *  4  Study (year)  Representative community population of exposure cohort  Ascertainment of FMT exposure  Resemblance of control cohort populations and exposure  Evidence outcome of FMT exposure at start of experiment  Study controls for severity of CDI  Study controls for age, gender, and antibiotic application  Outcome assessment  Complete follow-up period for end outcome [30 to 40 days]  Adequacy follow-up of cohort study  NOS score  Hamilton et al. 201231  -  *  -  -  -  -  *  *  *  4  Kelly et al. 201432  -  *  -  -  -  -  *  *  *  4  Khoruts et al. 201633  *  *  *  -  *  -  *  *  *  7  Fischer et al. 2016a34  -  *  -  -  -  -  *  *  *  4  Fischer et al. 2016b35  -  *  -  -  -  -  *  *  *  4  Chin et al. 201736  *  *  -  -  -  -  *  *  *  5  Meighani et al. 201737  -  *  -  -  *  -  *  -  *  4  Newman et al. 201738  *  *  -  -  -  -  *  *  *  5  Khanna et al. 201739  -  *  -  -  -  -  *  *  *  4  NOS, Newcastle-Ottawa Scale; FMT, faecal microbiota transplantation; CDI, Clostridium difficile infection. View Large Table 2. Newcastle-Ottawa Scale for assessing quality of cohort studies. Study (year)  Representative community population of exposure cohort  Ascertainment of FMT exposure  Resemblance of control cohort populations and exposure  Evidence outcome of FMT exposure at start of experiment  Study controls for severity of CDI  Study controls for age, gender, and antibiotic application  Outcome assessment  Complete follow-up period for end outcome [30 to 40 days]  Adequacy follow-up of cohort study  NOS score  Hamilton et al. 201231  -  *  -  -  -  -  *  *  *  4  Kelly et al. 201432  -  *  -  -  -  -  *  *  *  4  Khoruts et al. 201633  *  *  *  -  *  -  *  *  *  7  Fischer et al. 2016a34  -  *  -  -  -  -  *  *  *  4  Fischer et al. 2016b35  -  *  -  -  -  -  *  *  *  4  Chin et al. 201736  *  *  -  -  -  -  *  *  *  5  Meighani et al. 201737  -  *  -  -  *  -  *  -  *  4  Newman et al. 201738  *  *  -  -  -  -  *  *  *  5  Khanna et al. 201739  -  *  -  -  -  -  *  *  *  4  Study (year)  Representative community population of exposure cohort  Ascertainment of FMT exposure  Resemblance of control cohort populations and exposure  Evidence outcome of FMT exposure at start of experiment  Study controls for severity of CDI  Study controls for age, gender, and antibiotic application  Outcome assessment  Complete follow-up period for end outcome [30 to 40 days]  Adequacy follow-up of cohort study  NOS score  Hamilton et al. 201231  -  *  -  -  -  -  *  *  *  4  Kelly et al. 201432  -  *  -  -  -  -  *  *  *  4  Khoruts et al. 201633  *  *  *  -  *  -  *  *  *  7  Fischer et al. 2016a34  -  *  -  -  -  -  *  *  *  4  Fischer et al. 2016b35  -  *  -  -  -  -  *  *  *  4  Chin et al. 201736  *  *  -  -  -  -  *  *  *  5  Meighani et al. 201737  -  *  -  -  *  -  *  -  *  4  Newman et al. 201738  *  *  -  -  -  -  *  *  *  5  Khanna et al. 201739  -  *  -  -  -  -  *  *  *  4  NOS, Newcastle-Ottawa Scale; FMT, faecal microbiota transplantation; CDI, Clostridium difficile infection. View Large 3.4 Treatment effect As shown in Figure 2A, in nine cohort studies, comprising a total of 346 patients, 81% [95% CI = 76%-85%] patients achieved initial cure based on authors’ criteria, with no significant heterogeneity between studies [Cochran’s Q, p = 0.47; I2 = 0%] and no publication bias [Supplementary Figures 1 and 2, available as Supplementary data at ECCO-JCC online]. Due to a CDI relapse after one FMT treatment, some patients underwent treatment two or more times. Therefore, we defined overall cure as patients who achieved cure in more than one session of FMT. As shown in Figure 2B, the pooled results of four cohort studies, comprising an aggregate total of 160 patients, showed an overall cure rate of 89% [95% CI = 83%-93%], with no significant heterogeneity between studies [Cochran’s Q, p = 0.38; I2 = 2%]. Further, as shown in Figure 2C, in six cohort studies, after one FMT administration in an aggregate total of 213 patients, the recurrence rate was 19% [95% CI = 13%-27%], with moderate between-study heterogeneity [Cochran’s Q, p = 0.19; I2 = 33%]. Moreover, in six studies, as shown in Figure 2D, there was no significant difference in cure rate after FMT in CDI patients with IBD and those without IBD [RR = 0.92; 95% CI = 0.81-1.05; Cochran’s Q, p = 0.06; I2 = 53%]. Figure 2. View largeDownload slide Meta-analysis of treatment effect. [A] Forest plot of initial cure rate. [B] Forest plot of overall cure rate. [C] Forest plot of recurrence rate. [D] Forest plot of cure rate in patients with inflammatory bowel disease [IBD] versus without IBD. Figure 2. View largeDownload slide Meta-analysis of treatment effect. [A] Forest plot of initial cure rate. [B] Forest plot of overall cure rate. [C] Forest plot of recurrence rate. [D] Forest plot of cure rate in patients with inflammatory bowel disease [IBD] versus without IBD. 3.5 Subgroup analysis As shown in Figure 3, our subgroup analysis compared the efficacy of FMT in CDI patients with CD with those with UC. We included five cohort studies that evaluated FMT in CDI patients with CD. These studies reported an initial cure rate of 78% in an aggregate total of 124 patients [95% CI = 70%-84%], with no significant between-study heterogeneity [Cochran’s Q, p = 0.79; I2 = 0%]. In five studies of FMT treatment in CDI patients with UC, comprising a total of 109 patients, the rate of initial cure was 85% [95% CI = 77%-91%], with no significant heterogeneity between studies [Cochran’s Q, p = 0.43; I2 = 0%]. Although the initial cure rate was higher in CDI patients with UC than in patients with CD, this difference was not statistically significant [p = 0.1804]. Figure 3. View largeDownload slide Analysis of subgroups by faecal microbiota transplantation [FMT] in Crohn’s disease [CD] and ulcerative colitis [UC]. Figure 3. View largeDownload slide Analysis of subgroups by faecal microbiota transplantation [FMT] in Crohn’s disease [CD] and ulcerative colitis [UC]. 3.6 Intestinal microbiota analysis Intestinal microbiota analysis was only reported in one of the studies we analysed.39 In this study, faecal samples from 38 patients with CDI [12 with IBD and 26 without IBD] were collected and analysed before and after FMT. After treatment, in all patients, 16S rRNA gene sequencing revealed higher alpha diversity based on Faith’s phylogenetic diversity, Shannon’s diversity index, and observed species, than was present before FMT administration. However, CDI patients with IBD lacked recovery of phylogenetic diversity and contained a higher proportion of the original pre-FMT microbial communities on Days 7 and 28. 3.7 Adverse events Of all the included studies, five studies reported adverse events.31-34,38 One indicated that approximately one-third of enrolled patients experienced gastrointestinal symptoms including irregular bowel movements and excessive flatulence after FMT, but these symptoms resolved during clinical follow-up.31 Moreover, seven patients required colectomy after FMT due to the severity of their underlying IBD, in three studies.32–34 Notably, an IBD flare, despite CDI clearance, was the most commonly observed side effect in four studies.32-34,38 4. Discussion To our knowledge, this systematic review and meta-analysis is the first to evaluate the current evidence from cohort studies investigating the efficacy of FMT for the treatment of CDI in patients with IBD. Our systematic review of nine cohort studies indicated that the initial FMT cure rate was 81% [95% CI = 76%-85%] based on clinical responses and laboratory tests for CDI. The overall rate of CDI cure after treatment in patients with IBD, who underwent repeated administration of FMT when the first application failed, was up to 89% [95% CI = 83%-93%]. The presence of IBD is considered a significant risk factor for FMT failure in CDI patients.33 A reduced efficacy of FMT for CDI in IBD patients has been hypothesised because of the underlying dysbiosis, which may enhance the colonisation of C. difficile.40–42 In contrast, our pooled results showed that the CDI cure rate after FMT in patients with IBD was not significantly different from that found in patients without IBD [RR = 0.92; 95% CI = 0.81–1.05; Cochran’s Q, p = 0.06; I2 = 53%]. Furthermore, our subgroup analysis demonstrated that the FMT treatment effect was similar in CDI patients with UC and those with CD [p = 0.1804]. There has been rapid advancement in the understanding of the mechanisms by which FMT eliminates CDI in the general patient population. However, the same process in CDI patients with IBD is not well described. Previous studies revealed that FMT could re-establish a rich microbiota and promote the production of bactericidal proteins that inhibit the proliferation of C. difficile.43–45 Moreover, FMT restored the microbial community structure and functionality, thus reducing the risk of recurrent CDI.46 However, according to one study, although FMT resulted in increased microbiota diversity in CDI patients with IBD, there was a lack of recovery of phylogenetic diversity after treatment, and a high proportion of pre-FMT microbial communities were identified shortly thereafter.39 On the other hand, another study reported that microbiota diversity returned to pre-FMT levels over time.30 Notably, we found a CDI recurrence rate of 19% [95% CI = 13%-27%] after FMT in patients with IBD. A lack of improvement in the intestinal ecology could lead to a high CDI recurrence rate during a long follow-up. An IBD flare was the most commonly observed adverse effect in four studies.31–34 In these investigations, some patients underwent two or more FMTs after the first had failed. One study suggested that as FMT introduces a novel bacterial population, this treatment might lead to an exaggerated immunological response and reduced mucosal integrity, resulting in an IBD flare.21 However, toxins produced by C. difficile might incite IBD flares.47,48 The studies we evaluated did not clarify whether IBD flares that occurred after FMT were triggered by CDI, FMT administration, or the natural course of IBD. A thorough analysis that compares pre- and post-FMT intestinal microbiota in CDI patients with IBD could contribute to a better understanding of the underlying mechanism of IBD flares in this population. Our meta-analysis had some limitations. First, although results of the funnel plot and Egger’s test did not show any sign of publication bias, the number of cohort studies we included was relatively small. Consequently, more randomised controlled trials should be implemented to avoid reporting and publication biases. Second, the meaningful variables data were inadequate [e.g. patients selected, FMT delivery, donor screening] and methodological quality of the included studies was moderate overall. These deficits restricted our study’s power to be conclusive. Third, most of the studies we analysed did not include Asian patients, limiting the relevance of our meta-analysis in Asian and other countries. Future trials in various patient populations could confirm the effect of FMT in CDI patients with IBD in different ethnic groups. 5. Conclusion In conclusion, our meta-analysis of cohort studies demonstrates that FMT is a highly effective therapy for CDI in patients with IBD. However, the studies we included had limitations, including moderate methodological quality. Further, after FMT, some studies identified a high CDI recurrence rate and adverse events including IBD flare. Therefore, well-designed randomised controlled trials and well-conducted microbiological studies are needed to verify the efficacy and safety of FMT in patients with IBD. Funding This work was supported by National Natural Science Foundation of China [NSFC] [no. 81573978] and also by Jiangsu Provincial Special Program of Medical Science [no. BL2014100]. Conflict of Interest None. Author Contributions The experiment was conceived and designed by Y-GC and TC. TC and QZ independently screened literature, extracted data, performed the statistical analysis, and drafted the paper. DZ, FJ, JW, J-Z, and XZ checked this work again and critically revised the paper. All authors read and approved the final paper. Supplementary Data Supplementary data to this article can be found online at ECCO-JCC online. References 1. Lessa FC, Mu Y, Bamberg WM, et al.   Burden of clostridium difficile infection in the United States. N Engl J Med  2015; 372: 825– 34. Google Scholar CrossRef Search ADS PubMed  2. Kelly CP, LaMont JT. Clostridium difficile - more difficult than ever. N Engl J Med  2008; 359: 1932– 40. Google Scholar CrossRef Search ADS PubMed  3. Bossuyt P, Verhaegen J, Van Assche G, Rutgeerts P, Vermeire S. Increasing incidence of Clostridium difficile-associated diarrhoea in inflammatory bowel disease. J Crohns Colitis  2009; 3: 4– 7. Google Scholar CrossRef Search ADS PubMed  4. Issa M, Vijayapal A, Graham MB, et al.   Impact of clostridium difficile on inflammatory bowel disease. Clin Gastroenterol Hepatol  2007; 5: 345– 51. Google Scholar CrossRef Search ADS PubMed  5. Ananthakrishnan AN, McGinley EL, Binion DG. 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Systematic review with meta-analysis: long-term outcomes of faecal microbiota transplantation for clostridium difficile infection. Aliment Pharmacol Ther  2016; 43: 445– 57. Google Scholar CrossRef Search ADS PubMed  17. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ  2009; 339: b2535. Google Scholar CrossRef Search ADS PubMed  18. Wells GA, Shea B, O’connell D, et al. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses. Canada: Department of Epidemiology and Community Medicine, University of Ottawa; 2011. 19. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med  2002; 21: 1539– 58. Google Scholar CrossRef Search ADS PubMed  20. Higgins J, Green SE, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 . Hoboken, NJ: John Wiley; 2011. 21. De Leon LM, Watson JB, Kelly CR. Transient flare of ulcerative colitis after fecal microbiota transplantation for recurrent clostridium difficile infection. Clin Gastroenterol Hepatol  2013; 11: 1036– 8. Google Scholar CrossRef Search ADS PubMed  22. Gravito-Soares M, Gravito-Soares E, Portela F, Ferreira M, Sofia C. Fecal microbiota transplantation in recurrent clostridium difficile infection in a patient with concomitant inflammatory bowel disease. Rev Esp Enferm Dig  2017; 109: 473– 6. Google Scholar CrossRef Search ADS PubMed  23. Patel P, Goyal A. Comparative analysis of the efficacy of fecal transplantation in pediatric inflammatory bowel disease patients with and without clostridium difficile infection. Inflamm Bowel Dis  2016; 22: S68– 9. Google Scholar CrossRef Search ADS   24. Luo Y, Yang N, Roediger R, Ungaro RC, Grinspan A. Outcomes of fecal microbiota transplantation for clostridium difficile infections in inflammatory bowel disease patients. Gastroenterology  2017; 152: S342. Google Scholar CrossRef Search ADS   25. Jain A, Parian AM, Dudley-Brown S, Lazarev M. Fecal microbiota transplantation is safe and effective for treatment of recurrent clostridium difficile infection in inflammatory bowel disease patients. Gastroenterology  2015; 148: S869. Google Scholar CrossRef Search ADS   26. Carlucci C, Petrof EO, Allen-Vercoe E. Fecal microbiota-based therapeutics for recurrent clostridium difficile infection, ulcerative colitis and obesity. EBioMedicine  2016; 13: 37– 45. Google Scholar CrossRef Search ADS PubMed  27. Di Bella S, Gouliouris T, Petrosillo N. Fecal microbiota transplantation [FMT] for clostridium difficile infection: focus on immunocompromised patients. J Infect Chemother  2015; 21: 230– 7. Google Scholar CrossRef Search ADS PubMed  28. Juszczuk K, Grudlewska K, Mikucka A, Gospodarek E. Fecal microbiota transplantation-methods of treatment of recurrent clostridium difficile infections and other diseases. 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Khanna S, Vazquez-Baeza Y, González A, et al.   Changes in microbial ecology after fecal microbiota transplantation for recurrent C. difficile infection affected by underlying inflammatory bowel disease. Microbiome  2017; 5: 55. Google Scholar CrossRef Search ADS PubMed  40. Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology  2014; 146: 1489– 99. Google Scholar CrossRef Search ADS PubMed  41. Machiels K, Joossens M, Sabino J, et al.   A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut  2014; 63: 1275– 83. Google Scholar CrossRef Search ADS PubMed  42. Clayton EM, Rea MC, Shanahan F, et al.   The vexed relationship between clostridium difficile and inflammatory bowel disease: an assessment of carriage in an outpatient setting among patients in remission. Am J Gastroenterol  2009; 104: 1162– 9. 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Kelsen JR, Kim J, Latta D, et al.   Recurrence rate of clostridium difficile infection in hospitalized pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis  2011; 17: 50– 5. Google Scholar CrossRef Search ADS PubMed  48. LaMont JT, Trnka YM. Therapeutic implications of clostridium difficile toxin during relapse of chronic inflammatory bowel disease. Lancet  1980; 1: 381– 3. Google Scholar CrossRef Search ADS PubMed  Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Crohn's and Colitis Oxford University Press

Effect of Faecal Microbiota Transplantation for Treatment of Clostridium difficile Infection in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis of Cohort Studies

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Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
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10.1093/ecco-jcc/jjy031
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Abstract

Abstract Background Evidence concerning the effect of faecal microbiota transplantation [FMT] in Clostridium difficile infection [CDI] patients with inflammatory bowel disease [IBD] has not been firmly established. Therefore, we performed a systematic review and meta-analysis to evaluate FMT treatment outcomes in patients with IBD treated for CDI. Methods An electronic search of four databases was conducted until November 1, 2017. Cohort studies of FMT efficacy and safety in CDI patients with IBD were included. Pooled effect sizes were calculated with 95% confidence intervals [CI] using a random-effects model. Results Nine cohort studies comprising a total of 346 CDI patients with IBD were included. The initial cure rate was 81% [95% CI = 76%-85%] and the overall cure rate was up to 89% [95% CI = 83%-93%], both with no significant heterogeneity. The recurrence rate was 19% [95% CI = 13%-27%] with moderate heterogeneity [Cochran’s Q, p = 0.19; I2 = 33%]. There was no significant difference in the CDI cure rate after FMT in patients with and without IBD (risk ratio [RR] = 0.92; 95% CI = 0.81-1.05; Cochran’s Q, p = 0.06; I2 = 53%). Subgroup analysis revealed a similar CDI treatment effects after FMT in patients with Crohn’s disease and in those with ulcerative colitis [p = 0.1804]. Four studies reported adverse events of IBD flares. Conclusions FMT is an effective therapy for CDI in patients with IBD. Well-designed randomised controlled trials and well-conducted microbiological studies are needed to validate its efficacy and safety. Faecal microbiota transplantation, Clostridium difficile infection, inflammatory bowel disease, systematic review, meta-analysis 1. Introduction Clostridium difficile infection [CDI], accompanied by community- and hospital-acquired diarrhoea, has become a major clinical and economic burden. The incidence of CDI has increased from 50 cases per 100000 people in 2001 to 120 cases per 100000 people in 2011, and a large increase has been demonstrated in patients with inflammatory bowel disease [IBD].1–3 In 2004, 7% of patients with CDI had concomitant IBD, and this proportion grew to 16% in 2005.4 Notably, CDI patients with concurrent IBD have an increased risk for numerous adverse events, which include higher mortality, prolonged hospital stay, and higher health care costs.4–6 The treatment of CDI patients with IBD is challenging because these individuals are less likely to respond to medical therapy for CDI.5,7 These cases are typically managed using antibiotic therapy. However, treatment with metronidazole or vancomycin, the current treatment options for CDI, results in recurrence rates ranging from 22% to 34%.8,9 After a first episode of CDI, over 70% of patients are at risk of recurrence despite receiving standard treatment.10 Furthermore, the risk of CDI is increased in patients receiving prolonged corticosteroid therapy for IBD,11 and patients in this population who develop CDI have an associated risk of colectomy, bowel perforation, shock, respiratory failure, and death.12,13 Therefore, some investigators have turned to faecal microbiota transplantation [FMT], a microbiome-based therapy, in seeking an effective treatment that normalises gut dysbiosis and thus confers resistance to C. difficile colonisation. Although FMT is not a new technique, it is regarded as an effective and safe treatment for gastrointestinal disease, especially for CDI.14,15 A previous meta-analysis revealed that after treatment with FMT, approximately 90% of patients with CDI were cured.16 Several cohort studies suggested that FMT was a beneficial treatment for CDI patients with IBD, but the exact effect of FMT in these patients has not been confirmed. Accordingly, we performed a systematic literature review and meta-analysis to evaluate the efficacy and safety of FMT for the treatment of CDI in patients with IBD. 2. Methods 2.1 Search and selection We designed our systematic review and meta-analysis in accordance with the guidelines of the 2009 Preferred Reporting Items for Systematic Reviews and Meta-analysis [PRISMA] statement.17 We performed an electronic search of four databases [Pubmed, Embase, Medline, and the Cochrane Library] from the date of inception to November , 2017. The medical subject heading [MeSH] terms we used to search titles and abstracts were: ‘Clostridium difficile’, ‘C. difficile’, ‘Clostridium difficile infection’, ‘antibiotic diarrhoea’, ‘pseudomembranous’, ‘CDI’, ‘inflammatory bowel disease’, ‘Crohn’s disease’, ‘ulcerative colitis’, ‘colitis’, ‘IBD’, ‘CD’, ‘UC’ AND ‘faecal microbiota transplantation’, ‘fecal’, ‘flora’, ‘microbiota’, ‘donor’, ‘bacteriotherapy’, ‘transplant’, ‘transfusion’, ‘enema’, ‘infusion’, ‘reconstitution’, ‘FMT’. No language restrictions were applied, but only studies in human subjects were included. Two reviewers [TC and QZ] examined the reference list of each identified study and reviewed articles to identify additional relevant publications. 2.2 Study selection We included studies designed according to the PICO [Patients-Intervention-Comparison-Outcome] model and met the following conditions: [1] CDI patients with IBD were enrolled by authors’ criteria where clinical symptoms and laboratory testing were confirmed; [2] patients in the intervention group [with or without a control group] received FMT administered by any delivery modality; [3] the primary outcomes were CDI initial cure, overall cure, and recurrence rate, and FMT safety was evaluated based on reported adverse events. Case reports, animal studies, general reviews, conference abstracts, and letters were excluded. Additionally, any cohort studies with less than 10 participants were excluded to minimise bias. 2.3 Quality assessment For observational studies, we assessed the methodological quality using the Newcastle-Ottawa Scale [NOS].18 According to the instrument, we graded the selection of study groups, comparability of study groups, and ascertainment of exposure or outcome, for each report. Within each main category, individual items were assessed as having a low [one star awarded] or high [no star awarded] risk of bias, and the maximum score was nine. Studies with six or more stars were considered to have a low risk of bias, those with four or five stars as a moderate risk, and those with less than four stars as a high risk of bias. 2.4 Data extraction Two investigators [TC and QZ] independently evaluated the reports and determined study eligibility based on our predefined inclusion criteria. Any discrepancies were resolved by discussion with a third reviewer [Y-GC]. We recorded the first author’s name, year of publication, study design, number of participants, country, patient characteristics, FMT donor type and delivery procedure, length of follow-up, and adverse events, for each study included in our analysis. 2.5 Data synthesis and analysis We used the Metaprop module in R-3.4.1 statistical software package for data analysis. Pooled effect sizes with 95% confidence intervals [CI] were calculated for outcomes evaluating the efficacy of FMT therapy in CDI patients with IBD. Risk ratios [RR] with 95% CI were used for dichotomous outcomes. Subgroup analyses were constructed based on data availability. We analysed heterogeneity using the Cochran Q and I2 tests. Heterogeneity was assessed using the Cochran Q test when the p-value was less than 0.1. I2 values of 25%, 50%, and 75% corresponded to low, moderate, and high levels of statistical heterogeneity.19 All analyses were performed using a random-effects model.20 We applied the funnel plot and Egger’s test to evaluate publication bias if the same outcome measures [i.e. ≥9] were identified. A p-value less than 0.05 was considered statistically significant. 3. Results 3.1 Results of the literature search Our search identified 568 studies in the four electronic databases. After screening titles and abstracts, 19 articles were retrieved. Subsequently, 10 articles were excluded after a full-text review. Of these, two were case reports,21,22 three were conference summaries,23–25 three were reviews,26–28 and two were studies that did not have a fully justified pre-defined sample size.29,30 Ultimately, a total of nine cohort studies met our inclusion criteria and were selected. The summary of the study selection process is shown in Figure 1. Figure 1. View largeDownload slide Flow chart of study selection. Figure 1. View largeDownload slide Flow chart of study selection. 3.2 Study characteristics Of the nine cohort studies analysed, four were prospective31,33,36,39 and five were retrospective.32,34,35,37,38 A total of 346 CDI patients with IBD were enrolled in the nine studies, and the number included in each ranged from 12 to 67. Six studies included a control group and enrolled 188 CDI patients with IBD to receive FMT in an experimental group. In these investigations, 774 CDI patients without IBD received FMT and served as controls.31-33,35,37,39 The studies were published between 2012 and 2017, and conducted in the USA, Canada, Australia, and Europe. The combined proportion of female patients in eight studies was 56.8% [176/310], and the mean age ranged from 27.60 to 61.45.31,33-39 Five studies enrolled patients with recurrent CDI,31,33,35,36,39 and the other four included both recurrent and refractory cases.32,34,37,38 Eight studies included patients with ulcerative colitis [UC], Crohn’s disease [CD], or a combination of these IBD subtypes. Two studies used screened unrelated FMT donors,36,39 and five used both related and unrelated donors.31,34,35,37,38 The remaining two studies did not clearly identify the origin of the FMT donors.32,33 Lower gastrointestinal FMT delivery [colonoscopy, sigmoidoscopy, and enema] was performed in seven studies,31-35,38,39 and two used both lower and upper gastrointestinal FMT delivery [nasogastric tube and capsule] methods.36,37Table 1 summarises the characteristics of the studies. Table 1. Study characteristics. Study [year]  Study design  Cases  Country  Age [years] nean [range]  Female [%]  Type of CDI [recurrent, refractory, both]  Type of IBD [UC, CD, both]  Donor [related, unrelated, both]  FMT delivery  Follow-up  Hamilton et al. 201231  PCS  14  USA  44.6  79  Recurrent  Both  Both  Colonoscopy  2 months  Kelly et al. 201432  RCS  36  USA, Canada, Australia  NS  NS  Both  Both  NS  Colonoscopy or Sigmoidoscopy  3 months  Khoruts et al. 201633  PCS  43  USA  38.80 [16–84]  51.2  Recurrent  Both  NS  Colonoscopy  2 months  Fischer et al. 2016a34  RCS  67  USA, Canada, Europe  45.40  58.2  Both  Both  Both  Colonoscopy or Sigmoidoscopy  3 months  Fischer et al. 2016b35  RCS  63  USA, Canada  61.45  73.5  Recurrent  Both  Both  Colonoscopy  1 month  Chin et al. 201736  PCS  35  USA  43.00 [8–93]  46  Recurrent  Both  Unrelated  Colonoscopy, NG, and capsule  2 months  Meighani et al. 201737  RCS  20  USA  46.90  50  Both  NS  Both  Colonoscopy, NG, and enema.  7 days  Newman et al. 201738  RCS  56  USA  38.20  42.9  Both  Both  Both  Colonoscopy  2 months  Khanna et al. 201739  PCS  12  USA  27.60 [23–75]  66.7  Recurrent  Both  Unrelated  Colonoscopy  >1 year  Study [year]  Study design  Cases  Country  Age [years] nean [range]  Female [%]  Type of CDI [recurrent, refractory, both]  Type of IBD [UC, CD, both]  Donor [related, unrelated, both]  FMT delivery  Follow-up  Hamilton et al. 201231  PCS  14  USA  44.6  79  Recurrent  Both  Both  Colonoscopy  2 months  Kelly et al. 201432  RCS  36  USA, Canada, Australia  NS  NS  Both  Both  NS  Colonoscopy or Sigmoidoscopy  3 months  Khoruts et al. 201633  PCS  43  USA  38.80 [16–84]  51.2  Recurrent  Both  NS  Colonoscopy  2 months  Fischer et al. 2016a34  RCS  67  USA, Canada, Europe  45.40  58.2  Both  Both  Both  Colonoscopy or Sigmoidoscopy  3 months  Fischer et al. 2016b35  RCS  63  USA, Canada  61.45  73.5  Recurrent  Both  Both  Colonoscopy  1 month  Chin et al. 201736  PCS  35  USA  43.00 [8–93]  46  Recurrent  Both  Unrelated  Colonoscopy, NG, and capsule  2 months  Meighani et al. 201737  RCS  20  USA  46.90  50  Both  NS  Both  Colonoscopy, NG, and enema.  7 days  Newman et al. 201738  RCS  56  USA  38.20  42.9  Both  Both  Both  Colonoscopy  2 months  Khanna et al. 201739  PCS  12  USA  27.60 [23–75]  66.7  Recurrent  Both  Unrelated  Colonoscopy  >1 year  CDI, Clostridium difficile infection; IBD, inflammatory bowel disease; UC, ulcerative colitis; CD, Crohn’s disease; FMT, faecal microbiota transplantation; NS, not stated; PCS, prospective cohort study; RCS, retrospective cohort study; NG, nasogastric tube. View Large Table 1. Study characteristics. Study [year]  Study design  Cases  Country  Age [years] nean [range]  Female [%]  Type of CDI [recurrent, refractory, both]  Type of IBD [UC, CD, both]  Donor [related, unrelated, both]  FMT delivery  Follow-up  Hamilton et al. 201231  PCS  14  USA  44.6  79  Recurrent  Both  Both  Colonoscopy  2 months  Kelly et al. 201432  RCS  36  USA, Canada, Australia  NS  NS  Both  Both  NS  Colonoscopy or Sigmoidoscopy  3 months  Khoruts et al. 201633  PCS  43  USA  38.80 [16–84]  51.2  Recurrent  Both  NS  Colonoscopy  2 months  Fischer et al. 2016a34  RCS  67  USA, Canada, Europe  45.40  58.2  Both  Both  Both  Colonoscopy or Sigmoidoscopy  3 months  Fischer et al. 2016b35  RCS  63  USA, Canada  61.45  73.5  Recurrent  Both  Both  Colonoscopy  1 month  Chin et al. 201736  PCS  35  USA  43.00 [8–93]  46  Recurrent  Both  Unrelated  Colonoscopy, NG, and capsule  2 months  Meighani et al. 201737  RCS  20  USA  46.90  50  Both  NS  Both  Colonoscopy, NG, and enema.  7 days  Newman et al. 201738  RCS  56  USA  38.20  42.9  Both  Both  Both  Colonoscopy  2 months  Khanna et al. 201739  PCS  12  USA  27.60 [23–75]  66.7  Recurrent  Both  Unrelated  Colonoscopy  >1 year  Study [year]  Study design  Cases  Country  Age [years] nean [range]  Female [%]  Type of CDI [recurrent, refractory, both]  Type of IBD [UC, CD, both]  Donor [related, unrelated, both]  FMT delivery  Follow-up  Hamilton et al. 201231  PCS  14  USA  44.6  79  Recurrent  Both  Both  Colonoscopy  2 months  Kelly et al. 201432  RCS  36  USA, Canada, Australia  NS  NS  Both  Both  NS  Colonoscopy or Sigmoidoscopy  3 months  Khoruts et al. 201633  PCS  43  USA  38.80 [16–84]  51.2  Recurrent  Both  NS  Colonoscopy  2 months  Fischer et al. 2016a34  RCS  67  USA, Canada, Europe  45.40  58.2  Both  Both  Both  Colonoscopy or Sigmoidoscopy  3 months  Fischer et al. 2016b35  RCS  63  USA, Canada  61.45  73.5  Recurrent  Both  Both  Colonoscopy  1 month  Chin et al. 201736  PCS  35  USA  43.00 [8–93]  46  Recurrent  Both  Unrelated  Colonoscopy, NG, and capsule  2 months  Meighani et al. 201737  RCS  20  USA  46.90  50  Both  NS  Both  Colonoscopy, NG, and enema.  7 days  Newman et al. 201738  RCS  56  USA  38.20  42.9  Both  Both  Both  Colonoscopy  2 months  Khanna et al. 201739  PCS  12  USA  27.60 [23–75]  66.7  Recurrent  Both  Unrelated  Colonoscopy  >1 year  CDI, Clostridium difficile infection; IBD, inflammatory bowel disease; UC, ulcerative colitis; CD, Crohn’s disease; FMT, faecal microbiota transplantation; NS, not stated; PCS, prospective cohort study; RCS, retrospective cohort study; NG, nasogastric tube. View Large 3.3 Data quality According to the NOS, the cohort studies were all of moderate methodological quality and had a score ranging from four to seven. Six studies included a control group.31-33,35,37,39 All cohort studies ascertained FMT exposure and performed adequate follow-up. However, there was a lack of evidence related to the outcome of FMT exposure at the start of experiment. With one exception,37 all studies satisfied the length of follow-up requirement. A summary of risk bias is shown in Table 2. Table 2. Newcastle-Ottawa Scale for assessing quality of cohort studies. Study (year)  Representative community population of exposure cohort  Ascertainment of FMT exposure  Resemblance of control cohort populations and exposure  Evidence outcome of FMT exposure at start of experiment  Study controls for severity of CDI  Study controls for age, gender, and antibiotic application  Outcome assessment  Complete follow-up period for end outcome [30 to 40 days]  Adequacy follow-up of cohort study  NOS score  Hamilton et al. 201231  -  *  -  -  -  -  *  *  *  4  Kelly et al. 201432  -  *  -  -  -  -  *  *  *  4  Khoruts et al. 201633  *  *  *  -  *  -  *  *  *  7  Fischer et al. 2016a34  -  *  -  -  -  -  *  *  *  4  Fischer et al. 2016b35  -  *  -  -  -  -  *  *  *  4  Chin et al. 201736  *  *  -  -  -  -  *  *  *  5  Meighani et al. 201737  -  *  -  -  *  -  *  -  *  4  Newman et al. 201738  *  *  -  -  -  -  *  *  *  5  Khanna et al. 201739  -  *  -  -  -  -  *  *  *  4  Study (year)  Representative community population of exposure cohort  Ascertainment of FMT exposure  Resemblance of control cohort populations and exposure  Evidence outcome of FMT exposure at start of experiment  Study controls for severity of CDI  Study controls for age, gender, and antibiotic application  Outcome assessment  Complete follow-up period for end outcome [30 to 40 days]  Adequacy follow-up of cohort study  NOS score  Hamilton et al. 201231  -  *  -  -  -  -  *  *  *  4  Kelly et al. 201432  -  *  -  -  -  -  *  *  *  4  Khoruts et al. 201633  *  *  *  -  *  -  *  *  *  7  Fischer et al. 2016a34  -  *  -  -  -  -  *  *  *  4  Fischer et al. 2016b35  -  *  -  -  -  -  *  *  *  4  Chin et al. 201736  *  *  -  -  -  -  *  *  *  5  Meighani et al. 201737  -  *  -  -  *  -  *  -  *  4  Newman et al. 201738  *  *  -  -  -  -  *  *  *  5  Khanna et al. 201739  -  *  -  -  -  -  *  *  *  4  NOS, Newcastle-Ottawa Scale; FMT, faecal microbiota transplantation; CDI, Clostridium difficile infection. View Large Table 2. Newcastle-Ottawa Scale for assessing quality of cohort studies. Study (year)  Representative community population of exposure cohort  Ascertainment of FMT exposure  Resemblance of control cohort populations and exposure  Evidence outcome of FMT exposure at start of experiment  Study controls for severity of CDI  Study controls for age, gender, and antibiotic application  Outcome assessment  Complete follow-up period for end outcome [30 to 40 days]  Adequacy follow-up of cohort study  NOS score  Hamilton et al. 201231  -  *  -  -  -  -  *  *  *  4  Kelly et al. 201432  -  *  -  -  -  -  *  *  *  4  Khoruts et al. 201633  *  *  *  -  *  -  *  *  *  7  Fischer et al. 2016a34  -  *  -  -  -  -  *  *  *  4  Fischer et al. 2016b35  -  *  -  -  -  -  *  *  *  4  Chin et al. 201736  *  *  -  -  -  -  *  *  *  5  Meighani et al. 201737  -  *  -  -  *  -  *  -  *  4  Newman et al. 201738  *  *  -  -  -  -  *  *  *  5  Khanna et al. 201739  -  *  -  -  -  -  *  *  *  4  Study (year)  Representative community population of exposure cohort  Ascertainment of FMT exposure  Resemblance of control cohort populations and exposure  Evidence outcome of FMT exposure at start of experiment  Study controls for severity of CDI  Study controls for age, gender, and antibiotic application  Outcome assessment  Complete follow-up period for end outcome [30 to 40 days]  Adequacy follow-up of cohort study  NOS score  Hamilton et al. 201231  -  *  -  -  -  -  *  *  *  4  Kelly et al. 201432  -  *  -  -  -  -  *  *  *  4  Khoruts et al. 201633  *  *  *  -  *  -  *  *  *  7  Fischer et al. 2016a34  -  *  -  -  -  -  *  *  *  4  Fischer et al. 2016b35  -  *  -  -  -  -  *  *  *  4  Chin et al. 201736  *  *  -  -  -  -  *  *  *  5  Meighani et al. 201737  -  *  -  -  *  -  *  -  *  4  Newman et al. 201738  *  *  -  -  -  -  *  *  *  5  Khanna et al. 201739  -  *  -  -  -  -  *  *  *  4  NOS, Newcastle-Ottawa Scale; FMT, faecal microbiota transplantation; CDI, Clostridium difficile infection. View Large 3.4 Treatment effect As shown in Figure 2A, in nine cohort studies, comprising a total of 346 patients, 81% [95% CI = 76%-85%] patients achieved initial cure based on authors’ criteria, with no significant heterogeneity between studies [Cochran’s Q, p = 0.47; I2 = 0%] and no publication bias [Supplementary Figures 1 and 2, available as Supplementary data at ECCO-JCC online]. Due to a CDI relapse after one FMT treatment, some patients underwent treatment two or more times. Therefore, we defined overall cure as patients who achieved cure in more than one session of FMT. As shown in Figure 2B, the pooled results of four cohort studies, comprising an aggregate total of 160 patients, showed an overall cure rate of 89% [95% CI = 83%-93%], with no significant heterogeneity between studies [Cochran’s Q, p = 0.38; I2 = 2%]. Further, as shown in Figure 2C, in six cohort studies, after one FMT administration in an aggregate total of 213 patients, the recurrence rate was 19% [95% CI = 13%-27%], with moderate between-study heterogeneity [Cochran’s Q, p = 0.19; I2 = 33%]. Moreover, in six studies, as shown in Figure 2D, there was no significant difference in cure rate after FMT in CDI patients with IBD and those without IBD [RR = 0.92; 95% CI = 0.81-1.05; Cochran’s Q, p = 0.06; I2 = 53%]. Figure 2. View largeDownload slide Meta-analysis of treatment effect. [A] Forest plot of initial cure rate. [B] Forest plot of overall cure rate. [C] Forest plot of recurrence rate. [D] Forest plot of cure rate in patients with inflammatory bowel disease [IBD] versus without IBD. Figure 2. View largeDownload slide Meta-analysis of treatment effect. [A] Forest plot of initial cure rate. [B] Forest plot of overall cure rate. [C] Forest plot of recurrence rate. [D] Forest plot of cure rate in patients with inflammatory bowel disease [IBD] versus without IBD. 3.5 Subgroup analysis As shown in Figure 3, our subgroup analysis compared the efficacy of FMT in CDI patients with CD with those with UC. We included five cohort studies that evaluated FMT in CDI patients with CD. These studies reported an initial cure rate of 78% in an aggregate total of 124 patients [95% CI = 70%-84%], with no significant between-study heterogeneity [Cochran’s Q, p = 0.79; I2 = 0%]. In five studies of FMT treatment in CDI patients with UC, comprising a total of 109 patients, the rate of initial cure was 85% [95% CI = 77%-91%], with no significant heterogeneity between studies [Cochran’s Q, p = 0.43; I2 = 0%]. Although the initial cure rate was higher in CDI patients with UC than in patients with CD, this difference was not statistically significant [p = 0.1804]. Figure 3. View largeDownload slide Analysis of subgroups by faecal microbiota transplantation [FMT] in Crohn’s disease [CD] and ulcerative colitis [UC]. Figure 3. View largeDownload slide Analysis of subgroups by faecal microbiota transplantation [FMT] in Crohn’s disease [CD] and ulcerative colitis [UC]. 3.6 Intestinal microbiota analysis Intestinal microbiota analysis was only reported in one of the studies we analysed.39 In this study, faecal samples from 38 patients with CDI [12 with IBD and 26 without IBD] were collected and analysed before and after FMT. After treatment, in all patients, 16S rRNA gene sequencing revealed higher alpha diversity based on Faith’s phylogenetic diversity, Shannon’s diversity index, and observed species, than was present before FMT administration. However, CDI patients with IBD lacked recovery of phylogenetic diversity and contained a higher proportion of the original pre-FMT microbial communities on Days 7 and 28. 3.7 Adverse events Of all the included studies, five studies reported adverse events.31-34,38 One indicated that approximately one-third of enrolled patients experienced gastrointestinal symptoms including irregular bowel movements and excessive flatulence after FMT, but these symptoms resolved during clinical follow-up.31 Moreover, seven patients required colectomy after FMT due to the severity of their underlying IBD, in three studies.32–34 Notably, an IBD flare, despite CDI clearance, was the most commonly observed side effect in four studies.32-34,38 4. Discussion To our knowledge, this systematic review and meta-analysis is the first to evaluate the current evidence from cohort studies investigating the efficacy of FMT for the treatment of CDI in patients with IBD. Our systematic review of nine cohort studies indicated that the initial FMT cure rate was 81% [95% CI = 76%-85%] based on clinical responses and laboratory tests for CDI. The overall rate of CDI cure after treatment in patients with IBD, who underwent repeated administration of FMT when the first application failed, was up to 89% [95% CI = 83%-93%]. The presence of IBD is considered a significant risk factor for FMT failure in CDI patients.33 A reduced efficacy of FMT for CDI in IBD patients has been hypothesised because of the underlying dysbiosis, which may enhance the colonisation of C. difficile.40–42 In contrast, our pooled results showed that the CDI cure rate after FMT in patients with IBD was not significantly different from that found in patients without IBD [RR = 0.92; 95% CI = 0.81–1.05; Cochran’s Q, p = 0.06; I2 = 53%]. Furthermore, our subgroup analysis demonstrated that the FMT treatment effect was similar in CDI patients with UC and those with CD [p = 0.1804]. There has been rapid advancement in the understanding of the mechanisms by which FMT eliminates CDI in the general patient population. However, the same process in CDI patients with IBD is not well described. Previous studies revealed that FMT could re-establish a rich microbiota and promote the production of bactericidal proteins that inhibit the proliferation of C. difficile.43–45 Moreover, FMT restored the microbial community structure and functionality, thus reducing the risk of recurrent CDI.46 However, according to one study, although FMT resulted in increased microbiota diversity in CDI patients with IBD, there was a lack of recovery of phylogenetic diversity after treatment, and a high proportion of pre-FMT microbial communities were identified shortly thereafter.39 On the other hand, another study reported that microbiota diversity returned to pre-FMT levels over time.30 Notably, we found a CDI recurrence rate of 19% [95% CI = 13%-27%] after FMT in patients with IBD. A lack of improvement in the intestinal ecology could lead to a high CDI recurrence rate during a long follow-up. An IBD flare was the most commonly observed adverse effect in four studies.31–34 In these investigations, some patients underwent two or more FMTs after the first had failed. One study suggested that as FMT introduces a novel bacterial population, this treatment might lead to an exaggerated immunological response and reduced mucosal integrity, resulting in an IBD flare.21 However, toxins produced by C. difficile might incite IBD flares.47,48 The studies we evaluated did not clarify whether IBD flares that occurred after FMT were triggered by CDI, FMT administration, or the natural course of IBD. A thorough analysis that compares pre- and post-FMT intestinal microbiota in CDI patients with IBD could contribute to a better understanding of the underlying mechanism of IBD flares in this population. Our meta-analysis had some limitations. First, although results of the funnel plot and Egger’s test did not show any sign of publication bias, the number of cohort studies we included was relatively small. Consequently, more randomised controlled trials should be implemented to avoid reporting and publication biases. Second, the meaningful variables data were inadequate [e.g. patients selected, FMT delivery, donor screening] and methodological quality of the included studies was moderate overall. These deficits restricted our study’s power to be conclusive. Third, most of the studies we analysed did not include Asian patients, limiting the relevance of our meta-analysis in Asian and other countries. Future trials in various patient populations could confirm the effect of FMT in CDI patients with IBD in different ethnic groups. 5. Conclusion In conclusion, our meta-analysis of cohort studies demonstrates that FMT is a highly effective therapy for CDI in patients with IBD. However, the studies we included had limitations, including moderate methodological quality. Further, after FMT, some studies identified a high CDI recurrence rate and adverse events including IBD flare. Therefore, well-designed randomised controlled trials and well-conducted microbiological studies are needed to verify the efficacy and safety of FMT in patients with IBD. Funding This work was supported by National Natural Science Foundation of China [NSFC] [no. 81573978] and also by Jiangsu Provincial Special Program of Medical Science [no. BL2014100]. Conflict of Interest None. Author Contributions The experiment was conceived and designed by Y-GC and TC. TC and QZ independently screened literature, extracted data, performed the statistical analysis, and drafted the paper. DZ, FJ, JW, J-Z, and XZ checked this work again and critically revised the paper. All authors read and approved the final paper. 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Journal of Crohn's and ColitisOxford University Press

Published: Mar 8, 2018

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