Alimentary Pharmacology and Therapeutics
Systematic review: faecal microbiota transplantation therapy for digestive and nondigestive disorders in adults and children S. Shaa, J. Lianga, M. Chena, B. Xu, C. Liang, N. Wei & K. Wu
State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi Province, China.
Correspondence to: Dr Kaichun Wu, State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, the Fourth Military Medical University, 17 Changle Western Road, Xi’an, Shaanxi Province 710032, China. E-mail: [email protected] a
These authors contributed equally to this work.
Publication data Submitted 28 August 2013 First decision 27 September 2013 Resubmitted 19 February 2014 Accepted 20 February 2014 EV Pub Online 18 March 2014 This commissioned systematic review was subject to full peer-review and the authors received an honorarium from Wiley, on behalf of AP&T.
SUMMARY Background There has been growing interest in the use of faecal microbiota transplantation (FMT) for the treatment of gastrointestinal and nongastrointestinal diseases. Aim To review systematically the reported efficacy and safety of FMT in the management of gastrointestinal and nongastrointestinal disorders in adults and children. Methods The systematic review followed Cochrane and PRISMA recommendations. Available articles were identified using three electronic databases in addition to hand searching and contacting experts. Inclusion criteria were any reports of FMT therapy written in English. Results A total of 844 patients who had undergone FMT were identified from 67 published studies. The most common indications were refractory/relapsing Clostridium difficile infection (CDI) (76.3%) and inflammatory bowel disease (IBD) (13.2%). There has been only one placebo-controlled trial, a successful trial in 43 patients with recurrent CDI. Seven publications report FMT in paediatric patients with a total of 11 treated, 3 with chronic constipation and the remainder with recurrent CDI or ulcerative colitis (UC). 90.7% of patients with refractory/relapsing CDI were cured and 78.4% of patients with IBD were in remission after FMT. FMT therapy could also be effective in treatment of some nongastrointestinal disorders such as chronic fatigue syndrome. The only reported serious adverse event attributed to the therapy was a case of suspected peritonitis. Conclusions Although more controlled trials are needed, faecal microbiota transplantation therapy shows promise in both adults and children with gastrointestinal diseases such as CDI and IBD. Aliment Pharmacol Ther 2014; 39: 1003–1032
ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12699
1003
S. Sha et al. INTRODUCTION Humans have been proposed to be ‘meta-organisms’ consisting of 10-fold greater numbers of bacterial than human cells. It is calculated that the intestinal bacteria typically encode 100-fold more genes than are present in the human genome.1 The majority of microbes reside in the gut, where they have a profound influence on human physiology and nutrition, and are crucial for human health.2, 3 Alteration of the intestinal microbiota has been associated not only with digestive tract dysfunction, but also with diseases beyond the gut including diabetes and metabolic syndrome.4–10 Given the role of the gastrointestinal microbiota in driving these disorders, it follows that manipulation of the microbiota represents a promising therapeutic strategy for conditions where the microbiota is known to be altered. Faecal microbiota transplantation (FMT) therapy involves infusing intestinal microorganisms (present in a suspension of healthy donor stool) into the intestine of a sick patient to restore the balance of the normal intestinal microbiota. Brandt et al.11 noted that this idea was possibly first used in veterinary medicine by the Italian anatomist Fabricius Aquapendente in the 17th century. Zhang et al.12 reported even earlier literary evidence of FMT therapy during the Dong-jin dynasty in the 4th century in China. In the recent literature, it was first reported by doctors in Denver, who administered faeces by enema to their patients with fulminant, life-threatening pseudomembranous enterocolitis in 1958.13 Over the subsequent decades since then, leading experts from US, Canada and Australia have recently showed that FMT therapy is safe and effective for recurrent Clostridium difficile infection (CDI).14, 15 Recently, there has been a proliferation of reports of FMT as a therapy, not only in CDI but also for other diverse indications including inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS), metabolic syndrome, neurodevelopmental disorders, auto immune diseases, allergic diseases, pulmonary diseases, constipation and even colorectal carcinoma prevention.16, 17 FMT has been reported from many countries and the methods used, screening of donors and patient groups treated with this therapy have varied greatly. Several studies reviewed the use of FMT therapy in the management of IBD and other gastrointestinal disease in recent years,15, 18 but none of these has tried to compare the effectiveness of FMT therapy between adults and children. Because the intestinal microbiota alters with lifestyle, diet and age in different individuals,19 we review
1004
here the use of FMT therapy for diseases in adults and children since the first report from 1958.
METHODS Search strategy The systematic review was undertaken in line with the recommendations of the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions (http://handbook.cochrane.org/). This systematic review adheres to the relevant criteria of the PRISMA statement (Preferred Reporting Items for Systematic reviews and Meta-Analyses)20 and the meta-analysis of observational studies in Epidemiology (MOOSE) statement.21, 22 A comprehensive search strategy was developed by a research librarian to identify any potentially relevant studies on FMT therapy. The search terms were derived from the previously published study.18 The paediatric patients were defined as aged from 0 to 18 years. Electronic databases searched included the Cochrane Library, PubMed and EMBASE. The search also included international gastroenterology conference proceedings and the bibliographies of key reviews. In addition, hand searching of the reference lists of relevant reviews and included studies was undertaken to identify further relevant references. All studies reported in English were included because there is a lack of controlled trials in this area. The last search was run on 27 May 2013. Study selection Two investigators (S. S. and C. M.) independently assessed the title, abstract and key words of every record for eligible publications. Disagreements were resolved by consensus. The inclusion criteria were patients treated with FMT therapy. Primary studies were included if they (i) included patients of any age with FMT therapy, (ii) compared FMT with standard care or reported safety and efficacy/effectiveness outcomes of FMT in a series of patients without a control group, (iii) certain publication types (i.e. letters to the editor, abstracts and proceedings from scientific meetings) were also included, if a full set of data were available from the authors, (iv) were English full text studies published between 1958 and 2013. Studies were excluded if they (i) focused on the treatment using antibiotics or other probiotics, (ii) did not report original data of the FMT therapy procedure, (iii) reports describing the use of a cultured bacterial suspension rather than human faeces, (iv) were interviews and reviews.
Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
Systematic review: faecal microbiota transplantation therapy in adults and children Data extraction and synthesis Once eligibility was determined, the next step was retrieval of the full text of potentially relevant trials. Two reviewers (S. S. and C. M.) independently abstracted data from selected publications using a standardised pretested form. If they had different opinions, these were resolved by discussion with the third reviewer (L. J.). When multiple publications related to the same patient group,11, 23–35 the most complete data were analysed.11, 24, 26, 28, 30, 32, 35 Individual patient information was extracted from each study. The following information was retrieved: (i) characteristics of patients (including number of patients, age, gender and disease types); (ii) characteristics of intervention (including delivery method, route of instillation, relationship between the recipients and the donors); (iii) type of outcome measures (included duration of follow-up, change in frequency and severity of symptoms, resolution, treatment failure, relapse, death et al.); (iv) safety outcomes included any adverse events associated with the FMT procedure. Study time, country and study design were also abstracted. Data extracted from each study were synthesised using a narrative approach. RESULTS Description of included studies A total of 16 610 nonduplicated articles were identified in the search. The titles and abstracts were reviewed and only 98 were deemed potentially eligible. Following review of the full article, 67 fulfilled the inclusion criteria (Figure 1). The majority of reports were journal articles (52.2%); followed by abstracts (37.3%) and letters (10.4%). 62.7% (42/67) were case series, the others were case reports. Twenty eight of these were published since 2012, demonstrating the recently renewed interest in this area (Tables 1–4). Patient characteristics Worldwide, at least 844 cases of FMT have been reported from 10 countries (Tables 1–4). The most common indication is refractory/relapsing CDI (644/844, 76.3%) (Table 1), others including IBD (111/844, 13.2%) (94 UC, 14 CD and 3 UC/CD) (Table 2), CDI in IBD (21/844, 2.5%) (Table 3), chronic constipation (12/844, 1.4%) (Table 4), no clear diagnoses but with symptoms including IBS, diarrhoea, or abdominal pain (6/844, 0.7%) (Table 4), antibiotic-associated diarrhoea (AAD) (32/844, 3.8%) (Table 4) and metabolic syndrome (18/ 844, 2.1%) (Table 4). Taken together, 307/739 (41.5%) of Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
patients were male (eight studies did not report the gender ratio). Follow-up ranged from 1 day to 15 years after the transplantation. FMT has been described in patients as young as 16 months old to patients over 95 years of age. There have been seven publications on FMT for the treatment in children since 2001 and these included 11 patients aged between 16 months and 17 years. FMT was most frequently offered to patients with severe, intractable disease. In most cases, faecal microbiota replacement was used alone following the failure of other standard therapies or due to recurrence of the condition after withdrawal of conventional medications.
Outcomes treatment of CDI (C. difficile infection) in adults and children In agreement with a previous systematic review,36 we found FMT therapy to be a safe and effective procedure in adult patients with recurrent/refractory CDI, and the success rate of FMT in treating CDI is 90.8% (Table 5). Only one placebo-controlled trial was done for 43 patients with recurrent CDI.37 In this trial, duodenal infusion of healthy donor faeces cured 15 of 16 recurrent CDI patients (94%) (Cure was defined as an absence of diarrhoea or persistent diarrhoea that could be explained by other causes with three consecutive negative stool tests for C. difficile toxin, within 10 weeks after FMT), whereas vancomycin resolved CDI in only 3 of 13 patients (31%). FMT was shown to be more effective (P < 0.001) than the use of vancomycin for the treatment of CDI. At least 644 patients have received FMT for treatment of CDI, including six children.14, 38–42 It also proved a feasible selection for paediatric patients in this study. Five of the six children experienced a clinical resolution following the FMT, while only one had a clinical relapse.41 Outcomes treatment in IBD in adults and children We found reports of 111 patients receiving FMT therapy for IBD (Table 5). The overall success rate of IBD (including UC and CD) in adults is 77.8%. FMT may improve UC, with a success rate close to 90%, as measured by disappearance of symptoms or reduction in ulcerative colitis activity index (UCAI). To date, there has been report of three paediatric patients receiving FMT for treatment of UC and C. difficile infections with UC, by nasogastric (NG) tube or enema.42, 43 All of them demonstrated FMT as a feasible and well-tolerated therapy as it is usually given by duodenal endoscopic lavage during endoscopy or performed as an enema. There were no serious adverse events noted in those children. 1005
S. Sha et al. Literature search Databases: PubMed, EMBASE, and the Cochrane Library
Citations from backward search of reference lists from relevant papers
Search results combined (n = 16610) (duplicates excluded)
Articles screened on basis of title and abstract Limits: English-language articles only
16512 Citations rejected upon review of title/abstract Deemed potentially eligible (n = 98)
Excluded: Manuscript review and application of inclusion criteria When multiple publications reported on the same patients, the most recent and complete data were included 67 Citations of case series or case reports (35/67 journal articles; 25/67 abstracts 7/67 letters)
43 repoting FT for refractory/relapsing CDI (644 patients)
1 reporting FT in patients with AAD (32 patients)
12 reporting FT for IBD (111 patients)
3 reporting FT for chronic constipation (11 patients),1 reporting FT in patients IBS or abdominal pain (37 patients)
Did not report original data
7 reporting FMT for CDI in IBD (21 patients)
1 reporting FT Metabolic Syndrome (18 patients)
Figure 1 | Flow chart of studies of faecal microbiota transplantation therapy in adults and children.
FMT has so far proved disappointing in CD. In most patients, FMT therapy was not effective in achieving clinical remission or biologic/endoscopic benefit (Table 5). However, CDI in IBD patients has been improved by FMT therapy. Twenty-one patients have received FMT for treatment of CDI in patients with IBD, including a child.42 FMT therapy resolved C. difficile in 90.5% patients, as measured by negative stool sample enterotoxin and improved response to IBD medications. 1006
Outcomes treatment of other gastrointestinal diseases in adults and children One study reported that 30 of 32 patients with AAD (who had received antibiotic drugs before and hospitalised owing to diarrhoea from 3 to 20 stools daily, C. difficile toxin positive or negative) were cured by FMT.34 FMT also showed effective in treatment of IBS, although the number treated was small (the total number in this systematic review is 6), its successful rate was 100% in the studied.44, 45 In addition, Borody et al. successfully Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
Systematic review: faecal microbiota transplantation therapy in adults and children Table 1 | Summary of FMT for treating CDI Characteristics of studies
Author (Year) Eiseman13 (1958)
Type (country)
Characteristics of patients
Number (Male/ Female)
Journal article (US) Journal article (US)
4 (3/1)
Fenton77 (1974)
Characteristics of intervention
Faeces suspension/ volume Age infused median (route of Donor (range) FMT) Frequency relationship
1 (1/0)
56 (45– 68) 65
/(retention enemas) Two ounces of faeces and 10 ounces of yogurt in a quart of normal saline) (Cantor tube)
Journal article (Canada)
1 (0/1)
57
Schwan24 (1984)
Journal article (Sweden)
1 (0/1)
Tvede78 (1989)
Journal article (Denmark)
Borody44 (1989)
Letter (Australia)
Cutolo LC
76
(1959)
Characteristics of outcomes
1–3
Healthy adults
3/day for 7 days
Healthy humans
-/500 mL saline (enema)
1
/
67
450 mL mixture contain faeces and saline (retention enemas)
2 (over three consecutive days)
Husband
2 (1/1)
60 (59– 60)
50 g faeces suspended in 500 mL saline (Enema)
1–2
Husband daughter
1 (0/1)
35
Retention enemas (/)
/
/
Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
and
Outcome Severe diarrhoea ceased within 48 h The first formed stool was passed 36 h later, after 48 h the diarrhoea ceased. A response was obtained and both clinical and laboratory evidence revealed the elimination of the staphylococcus from the intestine Marked improvement occurred and continued to complete resolution of the clinical and sigmoidoscopic abnormalities within 4 days. Prompt and complete normalisation of the bowel function with disappearance of IBS symptoms. Stools of normal consistency, colour and smell have thereafter been passed daily or every other day. Weight gain 6 kg Patient 1: complete clinical recovery with eradication of C. difficile and its toxin after 1 infusion; Patient 2 had 2 infusions but did not respond (but did respond to a cultured bacterial mixture) The patient appear to be ‘cured’ by resolution of symptoms dramaticly.
Success rate 4/4 (100%) 1/1 (100%)
Adverse events None Died of upper GI haemorrhage (not related to the FMT therapy)
1/1 (100%)
None
1/1 (100%)
None
1/2 (50%)
None
1/1 (100%)
None
1007
S. Sha et al. Table 1 | (Continued) Characteristics of studies
Author (Year)
Type (country)
Characteristics of patients
Number (Male/ Female)
Faeces suspension/ volume infused Age (route of Donor median FMT) Frequency relationship (range)
Patterson-179 (1994)
Letter (Australia)
1 (0/1)
39
Patterson-279 (1994)
Letter (Australia)
6 (-/-)
56 (30– 80)
Persky80 (2000)
Journal article (US)
1 (0/1)
60
Faust81 (2002)
Abstract (Canada)
6 (1/5)
Aas63 (2003)
Journal article (US)
18 (5/13)
1008
Characteristics of intervention
Characteristics of outcomes
Outcome
Success rate
Adverse events
Single daily retention enemas for 3 days (400 mL consisting of 200 mL stool mixed with 200 mL saline (Rectal tube) Single daily retention enemas for 3 days (400 mL consisting of 200 mL stool mixed with 200 mL saline) (Rectal tube) (500 mL containing stool mixed in saline) (colonoscopy)
3
Husband
No recurrence of diarrhoea in 2 years
1/1 (100%)
None
3
Relative
All patients experienced rapid resolution of disabling persistent C. difficile infection without relapse
6/6 (100%)
None
1
Husband
1/1 (100%)
None
53 (37–74)
/(/)
1
Family members (spouse 4, brother 1, son 1)
6/6 (100%)
None
73 (51–88)
30 g faeces homogenised in 50–70 mL saline (Single 25 mL dose of stool suspension) (Nasogastric tube)
1
Family members or clinic staff
Immediate and complete resolution of diarrhoea with normal bowel movements that was maintained long term. Repeat C. difficile toxin assay negative All patients responded promptly and continued to be asymptomatic; 4/6 patients C. difficile toxin negative 15/18 patients asymptomatic for duration of followup. 13 patients were C. difficile negative (2 patients not tested); 2 died of unrelated illnesses; 1 treatment failure (C. difficile positive)
15/16 (94%) (who survived)
*
Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
Systematic review: faecal microbiota transplantation therapy in adults and children Table 1 | (Continued) Characteristics of studies
Author (Year)
Type (country)
Characteristics of patients
Number (Male/ Female)
Faeces suspension/ volume infused Age (route of Donor median FMT) Frequency relationship (range)
Broody (CD SYNDROMES)61 (2003)
Abstract (Australia)
24 (11/13)
19–59
Wettstein38 (2007)
Abstract (Australia)
16 (5/11)
11–87
You82 (2008)
Letter (US)
1 (1/0)
69
Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
Characteristics of intervention
200–300 g stool diluted in 200– 300 mL saline (The suspension was infused into the colon) (colonoscope and/or rectal enema and/or nasojejunal tube (Combination of colonoscopy and rectal enema was the most common (46%) delivery method)) 200–300 g/ 200–300 mL Saline with added psyllium [Colonoscopy (day 1) Enema (between 5, 10, or 24 days)] 45 g/300 mL normal saline (Retention enema)
Characteristics of outcomes
Outcome
Success rate
Adverse events
Daily for 1 (3/ 24, 13%), 5 (11/24, 46%) or 10 days (10/24, 42%)
Relatives or unrelated healthy individuals
Eradication of C. difficile was confirmed by negative Cd toxin and culture results in 20/24 patients (83%, P < 0.0001) post-treatment. 2/ 24 unsuccessful, 2/24 nonresponse, (including 1/24 recurrent)
20/24 (83%)
†
5–24
Relatives or unrelated healthy individuals
Eradication of C. difficile was confirmed by negative Cd toxin A or B and culture results in 15/16 patients (93.5%) 4 –6 weeks posttreatment
Resolution in 15/16
None
1
Daughter
The patient’s blood pressure stabilised, the leucocyte count normalised, and oliguria resolved and both vasopressors and continuous venovenous hemofiltration was discontinued. The patient’s bowel function returned, and abdominal distention decreased
1/1 (100%)
None
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S. Sha et al. Table 1 | (Continued) Characteristics of studies
Author (Year)
Type (country)
Characteristics of patients
Number (Male/ Female)
Faeces suspension/ volume infused Age (route of Donor median FMT) Frequency relationship (range)
Keller83 (2009)
Abstract (Netherlands)
11 (-/-)
/
Maccanochie84 (2009)
Journal article (UK)
15 (1/14)
81.5 (68– 95)
Rubin85 (2009)
Letter (US)
16 (-/-)
70–99
Arkkila, P. E.86 (2010)
Abstract (/)
37 (-/-)
69 (24– 90)
Silverman26 (2010)
Journal article (Canada)
7 (4/3)
65 (30– 88)
1010
Characteristics of intervention
Characteristics of outcomes
Outcome
Success rate
Adverse events
>100 g/300– 400 mL saline (infusion of suspension of donor faeces) (in jejunum (nasoduodenal tube) or in coecum and colon ascendens (via colonoscope)) 30 g faeces in 150 mL saline (30 mL of faecal fluid was administered) (Nasogastric tube) ~30 g or 2cm3/50– 70 mL saline (30–60 mL suspense) (Nasogastric tube) 20–30 mL mixed with 100–200 mL of water (colonoscopy)
1
/
Successfully treated 11 patients with multiple recurrences of CDI
11/11 (100%)
None
1 (14/15) or 2 (1/15)
Healthy related volunteers
Patients were symptom free. 2 no responses; 2 relapsed (1 responded to the 2nd FMT)
12/15 (80%)
None
1
Family member
14/16 ambulatory patients are able to return to normal diet and activities immediately after the procedure
14/16 (87.5%)
None
1–2
Related to the recipient
34/37 (92%)
None
50 mL faeces in 200 mL saline (250 mL of faecal fluid was administered) (Retention enema)
1
Family member
34/37 (92%) patients were cured patients had relapse after 5– 12 months after receiving new antibiotic treatment and they got successful faeces reinfusion thereafter. One noncured patient died after 1 month due to the toxic megacolon All of the patients were successfully cured
7/7 (100%)
None
Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
Systematic review: faecal microbiota transplantation therapy in adults and children Table 1 | (Continued) Characteristics of studies
Author (Year)
Type (country)
Characteristics of patients
Number (Male/ Female)
Faeces suspension/ volume infused Age (route of Donor median FMT) Frequency relationship (range)
Khoruts60 (2010)
Journal article (US)
1 (0/1)
61
Rohlke87 (2010)
Journal article (US)
19 (2/17)
49 (29– 82)
Yoon88 (2010)
Journal article (US)
12 (3/9)
66 (30– 86)
Garborg89 (2010)
Journal article (Norway)
40 (19/21)
75 (53–94)
Kelly90 (2010)
Abstract (US)
12 (1/11)
55.6 (19– 80)
Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
Characteristics of intervention
25 g/300 mL saline (250 mL of faecal fluid was administered) (colonoscope) -/350 mL saline (200– 300 mL of faecal fluid was administered) (colonoscopy)
Unknown volume faeces in 1000 mL saline (250– 400 mL of faecal fluid was administered) (colonoscopy) 50–100/250 saline (200 mL of faecal fluid was administered) [Gastroscopy (38) or colonoscopy (2)] 6–8 tablespoons of donor stool was added to 1 L of sterile water (740 mL (range 500– 960 mL) of faeces suspension was delivered) (colonoscope)
Characteristics of outcomes
Outcome
Success rate
Adverse events
1
Husband
At 1 month after bacteriotherapy, stool studies were culture negative for C. difficile
1/1 (100%)
‡
1 (majority) or 2 (1 patient)
Intimate domestic partners, family members and close friends.
19/19 (100%)
/
1
Family member or partner
All of the patients in this study maintained prolonged periods free of symptoms and are considered ‘cured’ after treatment with Faeces Flora Reconstitution Absence of diarrhoea, cramps, and fever. All patients experienced a durable clinical response to faeces transplantation
12/12 (100%)
None
1 (34/40) or 2 (6/40)
Close relatives or other household members
A total of 33/40 patients (4 patients responded to the 2nd FMT) were successfully treated
33/40 (83%)
None (5 unrelated deaths 3 weeks to 2 months post-FMT)
1
Partner or family member
Ten have remained symptom free. Two had diarrhoea after the procedure, but both were C. difficile negative. One responded to treatment with a fibre supplement and the other resumed vancomycin. None have had a documented recurrence of CDI to date
12/12 (100%)
None
1011
S. Sha et al. Table 1 | (Continued) Characteristics of studies
Author (Year)
Type (country)
Characteristics of patients
Number (Male/ Female)
Characteristics of intervention
Faeces suspension/ volume infused Age (route of Donor median FMT) Frequency relationship (range)
Mellow31 (2010)
Journal article (US)
13 (7/6)
67 (32–87)
-/300–600 mL saline (colonoscopy)
1
Healthy donors
Miller91 (2010)
Abstract (US)
2 (0/2)
42 (34– 50)
Fresh stool was liquefied and delivered (colonoscopy)
1
Sister/husband
Russell14 (2010)
Journal article (US)
1 (0/1)
2
30 g/50–75 mL saline (25 mL mL of faecal fluid was administered) (temporary nasogastric tube)
1
Father
Girotra92 (2011)
Abstract (US)
3 (0/3)
56.3 (31– 85)
/(colonoscopy and enteroscopy)
1
Healthy donors
Wilcox93 (2011)
Abstract (Portland)
13 (4/9)
69.4 (27– 93)
/(colonoscope into the patient’s caecum)
1
Family members or friends
1012
Characteristics of outcomes
Outcome A total of 12/13 patients were successfully treated with diarrhoea resolved. 3 patients have died (B strep pneumonia 1 month after FMT; superior mesenteric vein thrombosis 5 months after FMT; ovarian cancer 7 months after FB) One patient had an immediate improvement in symptoms and has been infection free for 9 months The abdominal symptoms and diarrhoea resolved and did not recur during 6 months of monitoring. The stool tested negative for C difficile toxin 2 weeks, 3 months, and 6 months after the procedure All three patients had complete resolution of symptoms within a few days after administration of faeces bacteriotherapy. complete resolution of symptoms FMT appears to be effective, tolerated well by patients, and without complications
Success rate
Adverse events
12/13 (%)
None (3 unrelated deaths 1– 7 months post-FMT)
2/2 (100%)
None
1/1 (100%)
None
3/3 (100%)
None
13/13 (100%)
None
Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
Systematic review: faecal microbiota transplantation therapy in adults and children Table 1 | (Continued) Characteristics of studies
Author (Year)
Type (country)
Characteristics of patients
Number (Male/ Female)
Characteristics of intervention
Faeces suspension/ volume infused Age (route of Donor median FMT) Frequency relationship (range)
Brandt11 (2012)
Journal article (US)
77 (21/56)
65 (22–87)
300–700 mL (colonoscopic)
1 or 2 (4 patients)
Spouse/ partner, 46; 1st degree relative, 19; friend, 9; other relative, 2; unknown, 1
Gallegos-Orozco94 (2012)
Journal article (US)
1 (1/0)
71
1
Brother
Garg39 (2012)
Abstract (US)
1 (1/0)
20-monthold
-/400 mL saline (400 mL) of faecal fluid was administered (colonoscopic) /(colonoscopy)
1
Mother
Hamilton30 (2012)
Journal article (US)
29 (9/20)
64.7 3.3
1 (37/43) or 2 (6/43)
Mothers, daughters, sons, wives, husbands and friends
Jorup-Ronstrom95 (2012)
Journal article (Sweden)
32 (12/20)
75 (27–94)
50 g/250 mL saline (220– 240 mL of faecal fluid was administered) (Colonoscopy (1 patient used upper push enteroscopy)) 30–60 mL (Enema and colonoscopy)
1–3
A healthy adult
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Characteristics of outcomes
Outcome
Success rate
Adverse events
diarrhoea resolved in 82% and improved in 17% of patients within an average of 5 days after FMT. The primary cure rate was 91%. Seven patients either failed to respond or experienced early CDI recurrence (≤90 days) The patient’s diarrhoea and abdominal pain resolved
70/77 (90.9%)
One patient was not treated and died in hospice care of unclear cause
1/1 (100%)
None
The patient has now remained symptom free with complete resolution of diarrhoea, haematochezia and had gained weight consistently for the past 3 months One other patients were treated with a second infusion, and all cleared the infection bringing the overall success rate to 100%.
1/1 (100%)
None
29/29 (100%)
§
26/32 (81.3%)
None
22 patients were cured and 10 patients failed to fully respond to treatment. Later in the study, the culture was given by colonoscopy in patients who failed after the simple enema procedure. 4 out of 5 healed. 6/32 relapse
1013
S. Sha et al. Table 1 | (Continued) Characteristics of studies
Author (Year)
Type (country)
Characteristics of patients
Number (Male/ Female)
Characteristics of intervention
Faeces suspension/ volume infused Age (route of Donor median FMT) Frequency relationship (range)
Kahn40 (2012)
Letter (US)
1 (1/0)
16-months
(140 mL of faecal fluid was administered) (colonoscopy)
1
Mother
Kurtz96 (2012)
Journal article (US)
1 (0/1)
78
/(colonoscopy)
1
Husband
Mellow97 (2012)
Abstract (US)
1 (1/0)
39
/(colonoscopy)
1
Wife
Neemann98 (2012)
Journal article (US)
1 (0/1)
21
30 mL/- in saline (suspension) (nasojejunal instillation)
1
Husband
1014
Characteristics of outcomes
Outcome Within 24 h the patient’s symptoms resolved completely. One week post-FMT, Clostridium difficile toxin PCR was negative and 2 months postFMT he remains asymptomatic The patient failed to respond to the stool transplant. Biopsies from a colonoscopy revealed concomitant cytomegalovirus (CMV) infection. The patient underwent an emergency total colectomy, and oral valganciclovir Over the next several days, diarrhoea resolved and stool for C. difftoxin A&B was negative on day seven post-FMT. Diarrhoea did not recur after 1 year The patient had no further diarrhoea or haematochezia. Her abdominal pain and distention had resolved completely, and she was eating a regular diet. Repeat C. difficile toxin and antigen EIA assays were negative at 3 and 11 days after faeces transfer, and the patient remained well at 2 months after treatment
Success rate
Adverse events
1/1 (100%)
None
0/1 (0%)
None
1/1 (100%)
None
1/1 (100%)
None
Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
Systematic review: faecal microbiota transplantation therapy in adults and children Table 1 | (Continued) Characteristics of studies
Author (Year)
Type (country)
Characteristics of patients
Number (Male/ Female)
Characteristics of intervention
Faeces suspension/ volume infused Age (route of Donor median FMT) Frequency relationship (range)
Kelly71 (2012)
Journal article (US)
26 (2/24)
59 (19–86)
6–8 tablespoons/ 1 L sterile water (or saline) (500– 960 mL was administered) (colonoscopy)
1
Intimate partner or adult family member
Kassam99 (2012)
Journal article (Canada)
27 (14/13)
69.4 (26– 87)
150 g/300 mL water (The supernatant component was administered rectally by enema) (retention enema)
1 (22/27) or 2 (5/27)
Two healthy volunteers
Matilla100 (2012)
Journal article (Finland)
70 (28/42)
73 (22– 90)
20–30 mL/100– 200 mL water (100 mL suspension) (colonoscopy)
1 (68/70) or 2 (2/70)
Close relatives, household members, or healthy volunteer
Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
Characteristics of outcomes
Outcome 24/26 patients have remained free of significant diarrhoea or CDI. One experienced loose stool and resumed vancomycin despite remaining C. difficile negative; she developed CDI recurrence 11 months postFMT after taking cephalexin. Another had diarrhoea 2 months post-FMT. Stool was not tested for C. difficile; she received 1 week of vancomycin and CDI did not recur after this 22 resolved within 24 h of transplant. 5 patients underwent a second FMT because of ongoing diarrhoea; 3 had symptom resolution and 2 continued to experience diarrhoea despite 2 FMTs During the first 12 weeks of followup evaluation the transplantation resulted in the resolution of symptoms in 66 patients. During the 1-year follow-up period, 4 patients with an initial favourable response had a relapse after receiving antibiotics for unrelated causes. 2 were treated successfully with another faeces transplantation and 2 with antibiotics for CDI
Success rate
Adverse events
24/26 (92.3%)
None
25/27 (93%)
None
66/70 (94.3%)
10 patients died of unrelated illnesses during the 1-year follow-up period
1015
S. Sha et al. Table 1 | (Continued) Characteristics of studies
Author (Year)
Type (country)
Characteristics of patients
Number (Male/ Female)
Characteristics of intervention
Faeces suspension/ volume infused Age (route of Donor median FMT) Frequency relationship (range)
Rubin41 (2013)
Journal article (US)
75 FMT courses (49/26) (74 patients)
63 (6–94) two paediatric patients (age 6 and 8)
~30 g (~3 cm3)/50– 70 mL saline (25 mL) (nasogastric tube, or gastroscope or through a PEG tube)
1 or 2 patient)
Trubiano101 (2013)
Journal article (Australia)
1 (0/1)
75
30 g/70 mL saline(30 mL suspension of donor faeces) (delivered into the jejunum through gastroscopy)
1
Husband
Van Nood37 (2013)
Journal article (Netherlands)
16 (8/8)
73 13
Faeces were diluted with 500 mL of sterile saline (0.9%) (nasoduodenal tube)
1(13/16) 2 (3/ 16)
Volunteers
(1
Healthy close household member
Characteristics of outcomes
Outcome Fifty-nine FMT courses resulted in clinical resolution of diarrhoea for a primary cure rate of 79%. diarrhoea relapsed following 16 FMT courses; in 9 of these cases diarrhoea subsequently resolved after a single course of vancomycin. (paediatric patients: one experienced a clinical resolution following the FMT, while the other had a clinical relapse) The C. difficilerelated symptoms were resolved. An abdominal computed tomography in the days before death showed no evidence of colitis, whereas stool cultures for C. difficile remained negative for culture and toxin on days 14, 20 and 30 after transplant The infusion of donor faeces was significantly more effective for the treatment of recurrent C. difficile infection than the use of vancomycin. 13 (81%) had resolution of C. difficile-associated diarrhoea after the first infusion. The 3 remaining patients received a second infusion with faeces from a different donor, with resolution in 2 patients
Success rate
Adverse events
59/75 (79.7%)
None
1/1 (100%)
¶
15/16 (94%)
Mild diarrhoea and abdominal cramping on the infusion day
FMT, faeces microbiota transplantation; CDI, Clostridium difficile infection; PEG, percutaneous endoscopic gastroscopy. * Two deaths: 1 after development of peritonitis (3 days post-FMT); 1 of pneumonia (14 days post-FMT). † Transient and included sore throat, flatulence, rectal discomfort, nausea, abdominal cramping, bloating, headache and abdominal pain. ‡ Developed constipation in the initial months after the procedure. § Approximately a third noted some irregularity of bowel movements and excessive flatulence, but resolved in clinic follow-up. ¶ The patient died because of ongoing renal failure and acute respiratory failure. 1016
Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
Systematic review: faecal microbiota transplantation therapy in adults and children treated at least 12 patients with chronic constipation in adults and children (Table 4).44–48
Outcomes treatment of nongastrointestinal diseases in adults and children Several reports described patients with autoimmune and neurologic disorders who showed improvement with FMT therapy (Table 4). One report described the co-development of myoclonus dystonia and chronic diarrhoea in a patient who was subsequently treated with FMT therapy, resulting in 90% improvement of her myoclonus dystonia symptoms, allowing her to resume employment and execute fine motor tasks.49 The onset of autism is often accompanied by gastrointestinal complaints and preceded by antibiotic use so it has been suggested that an altered microbiota might be involved in its pathogenesis.50 For example, autistic patients were found to have greater numbers and different types of Clostridial species when compared with controls.51 Improvement in autistic symptoms was reported in two children after FMT and in five children who received daily cultured Bacteroidetes and Clostridia for several weeks.52 Neurologic improvement has also been reported in one patient with Parkinson’s disease who received FMT for chronic constipation.53 Vrieze et al.54 reported the first application of FMT therapy in metabolic syndrome. In this study, they found FMT from lean donors significantly increased insulin sensitivity of 18 recipients with metabolic syndrome, which was most likely by increasing concentrations of butyrate-producing intestinal bacteria in the small and large intestine. These findings demonstrated FMT therapy for metabolic diseases warrants further investigation. FMT was also proved effect in patients with chronic fatigue syndrome (CFS). In patients with CFS followed up for up to 20 years, FMT has been reported to be effective with an initial success rate of 42/60 (70%) and sustained response in 35/60 (58%).55 It is suggested that the pathophysiology of CFS could be in part explained by enteric derived toxin-releasing bacteria capable of producing systemic effects.56 Outcomes FMT therapy for diseases in children We compared the characteristics with FMT therapy for diseases in adults and children (Table 5). Since the number of reports of FMT in children, we here review them all. The first case report of FMT in children was published in 2001 by Borody et al.47 In the three enrolled chronic constipation patients, two were aged 7 and
Systematic review: faecal microbiota transplantation therapy for digestive and nondigestive disorders in adults and children S. Shaa, J. Lianga, M. Chena, B. Xu, C. Liang, N. Wei & K. Wu
State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi Province, China.
Correspondence to: Dr Kaichun Wu, State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, the Fourth Military Medical University, 17 Changle Western Road, Xi’an, Shaanxi Province 710032, China. E-mail: [email protected] a
These authors contributed equally to this work.
Publication data Submitted 28 August 2013 First decision 27 September 2013 Resubmitted 19 February 2014 Accepted 20 February 2014 EV Pub Online 18 March 2014 This commissioned systematic review was subject to full peer-review and the authors received an honorarium from Wiley, on behalf of AP&T.
SUMMARY Background There has been growing interest in the use of faecal microbiota transplantation (FMT) for the treatment of gastrointestinal and nongastrointestinal diseases. Aim To review systematically the reported efficacy and safety of FMT in the management of gastrointestinal and nongastrointestinal disorders in adults and children. Methods The systematic review followed Cochrane and PRISMA recommendations. Available articles were identified using three electronic databases in addition to hand searching and contacting experts. Inclusion criteria were any reports of FMT therapy written in English. Results A total of 844 patients who had undergone FMT were identified from 67 published studies. The most common indications were refractory/relapsing Clostridium difficile infection (CDI) (76.3%) and inflammatory bowel disease (IBD) (13.2%). There has been only one placebo-controlled trial, a successful trial in 43 patients with recurrent CDI. Seven publications report FMT in paediatric patients with a total of 11 treated, 3 with chronic constipation and the remainder with recurrent CDI or ulcerative colitis (UC). 90.7% of patients with refractory/relapsing CDI were cured and 78.4% of patients with IBD were in remission after FMT. FMT therapy could also be effective in treatment of some nongastrointestinal disorders such as chronic fatigue syndrome. The only reported serious adverse event attributed to the therapy was a case of suspected peritonitis. Conclusions Although more controlled trials are needed, faecal microbiota transplantation therapy shows promise in both adults and children with gastrointestinal diseases such as CDI and IBD. Aliment Pharmacol Ther 2014; 39: 1003–1032
ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12699
1003
S. Sha et al. INTRODUCTION Humans have been proposed to be ‘meta-organisms’ consisting of 10-fold greater numbers of bacterial than human cells. It is calculated that the intestinal bacteria typically encode 100-fold more genes than are present in the human genome.1 The majority of microbes reside in the gut, where they have a profound influence on human physiology and nutrition, and are crucial for human health.2, 3 Alteration of the intestinal microbiota has been associated not only with digestive tract dysfunction, but also with diseases beyond the gut including diabetes and metabolic syndrome.4–10 Given the role of the gastrointestinal microbiota in driving these disorders, it follows that manipulation of the microbiota represents a promising therapeutic strategy for conditions where the microbiota is known to be altered. Faecal microbiota transplantation (FMT) therapy involves infusing intestinal microorganisms (present in a suspension of healthy donor stool) into the intestine of a sick patient to restore the balance of the normal intestinal microbiota. Brandt et al.11 noted that this idea was possibly first used in veterinary medicine by the Italian anatomist Fabricius Aquapendente in the 17th century. Zhang et al.12 reported even earlier literary evidence of FMT therapy during the Dong-jin dynasty in the 4th century in China. In the recent literature, it was first reported by doctors in Denver, who administered faeces by enema to their patients with fulminant, life-threatening pseudomembranous enterocolitis in 1958.13 Over the subsequent decades since then, leading experts from US, Canada and Australia have recently showed that FMT therapy is safe and effective for recurrent Clostridium difficile infection (CDI).14, 15 Recently, there has been a proliferation of reports of FMT as a therapy, not only in CDI but also for other diverse indications including inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS), metabolic syndrome, neurodevelopmental disorders, auto immune diseases, allergic diseases, pulmonary diseases, constipation and even colorectal carcinoma prevention.16, 17 FMT has been reported from many countries and the methods used, screening of donors and patient groups treated with this therapy have varied greatly. Several studies reviewed the use of FMT therapy in the management of IBD and other gastrointestinal disease in recent years,15, 18 but none of these has tried to compare the effectiveness of FMT therapy between adults and children. Because the intestinal microbiota alters with lifestyle, diet and age in different individuals,19 we review
1004
here the use of FMT therapy for diseases in adults and children since the first report from 1958.
METHODS Search strategy The systematic review was undertaken in line with the recommendations of the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions (http://handbook.cochrane.org/). This systematic review adheres to the relevant criteria of the PRISMA statement (Preferred Reporting Items for Systematic reviews and Meta-Analyses)20 and the meta-analysis of observational studies in Epidemiology (MOOSE) statement.21, 22 A comprehensive search strategy was developed by a research librarian to identify any potentially relevant studies on FMT therapy. The search terms were derived from the previously published study.18 The paediatric patients were defined as aged from 0 to 18 years. Electronic databases searched included the Cochrane Library, PubMed and EMBASE. The search also included international gastroenterology conference proceedings and the bibliographies of key reviews. In addition, hand searching of the reference lists of relevant reviews and included studies was undertaken to identify further relevant references. All studies reported in English were included because there is a lack of controlled trials in this area. The last search was run on 27 May 2013. Study selection Two investigators (S. S. and C. M.) independently assessed the title, abstract and key words of every record for eligible publications. Disagreements were resolved by consensus. The inclusion criteria were patients treated with FMT therapy. Primary studies were included if they (i) included patients of any age with FMT therapy, (ii) compared FMT with standard care or reported safety and efficacy/effectiveness outcomes of FMT in a series of patients without a control group, (iii) certain publication types (i.e. letters to the editor, abstracts and proceedings from scientific meetings) were also included, if a full set of data were available from the authors, (iv) were English full text studies published between 1958 and 2013. Studies were excluded if they (i) focused on the treatment using antibiotics or other probiotics, (ii) did not report original data of the FMT therapy procedure, (iii) reports describing the use of a cultured bacterial suspension rather than human faeces, (iv) were interviews and reviews.
Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
Systematic review: faecal microbiota transplantation therapy in adults and children Data extraction and synthesis Once eligibility was determined, the next step was retrieval of the full text of potentially relevant trials. Two reviewers (S. S. and C. M.) independently abstracted data from selected publications using a standardised pretested form. If they had different opinions, these were resolved by discussion with the third reviewer (L. J.). When multiple publications related to the same patient group,11, 23–35 the most complete data were analysed.11, 24, 26, 28, 30, 32, 35 Individual patient information was extracted from each study. The following information was retrieved: (i) characteristics of patients (including number of patients, age, gender and disease types); (ii) characteristics of intervention (including delivery method, route of instillation, relationship between the recipients and the donors); (iii) type of outcome measures (included duration of follow-up, change in frequency and severity of symptoms, resolution, treatment failure, relapse, death et al.); (iv) safety outcomes included any adverse events associated with the FMT procedure. Study time, country and study design were also abstracted. Data extracted from each study were synthesised using a narrative approach. RESULTS Description of included studies A total of 16 610 nonduplicated articles were identified in the search. The titles and abstracts were reviewed and only 98 were deemed potentially eligible. Following review of the full article, 67 fulfilled the inclusion criteria (Figure 1). The majority of reports were journal articles (52.2%); followed by abstracts (37.3%) and letters (10.4%). 62.7% (42/67) were case series, the others were case reports. Twenty eight of these were published since 2012, demonstrating the recently renewed interest in this area (Tables 1–4). Patient characteristics Worldwide, at least 844 cases of FMT have been reported from 10 countries (Tables 1–4). The most common indication is refractory/relapsing CDI (644/844, 76.3%) (Table 1), others including IBD (111/844, 13.2%) (94 UC, 14 CD and 3 UC/CD) (Table 2), CDI in IBD (21/844, 2.5%) (Table 3), chronic constipation (12/844, 1.4%) (Table 4), no clear diagnoses but with symptoms including IBS, diarrhoea, or abdominal pain (6/844, 0.7%) (Table 4), antibiotic-associated diarrhoea (AAD) (32/844, 3.8%) (Table 4) and metabolic syndrome (18/ 844, 2.1%) (Table 4). Taken together, 307/739 (41.5%) of Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
patients were male (eight studies did not report the gender ratio). Follow-up ranged from 1 day to 15 years after the transplantation. FMT has been described in patients as young as 16 months old to patients over 95 years of age. There have been seven publications on FMT for the treatment in children since 2001 and these included 11 patients aged between 16 months and 17 years. FMT was most frequently offered to patients with severe, intractable disease. In most cases, faecal microbiota replacement was used alone following the failure of other standard therapies or due to recurrence of the condition after withdrawal of conventional medications.
Outcomes treatment of CDI (C. difficile infection) in adults and children In agreement with a previous systematic review,36 we found FMT therapy to be a safe and effective procedure in adult patients with recurrent/refractory CDI, and the success rate of FMT in treating CDI is 90.8% (Table 5). Only one placebo-controlled trial was done for 43 patients with recurrent CDI.37 In this trial, duodenal infusion of healthy donor faeces cured 15 of 16 recurrent CDI patients (94%) (Cure was defined as an absence of diarrhoea or persistent diarrhoea that could be explained by other causes with three consecutive negative stool tests for C. difficile toxin, within 10 weeks after FMT), whereas vancomycin resolved CDI in only 3 of 13 patients (31%). FMT was shown to be more effective (P < 0.001) than the use of vancomycin for the treatment of CDI. At least 644 patients have received FMT for treatment of CDI, including six children.14, 38–42 It also proved a feasible selection for paediatric patients in this study. Five of the six children experienced a clinical resolution following the FMT, while only one had a clinical relapse.41 Outcomes treatment in IBD in adults and children We found reports of 111 patients receiving FMT therapy for IBD (Table 5). The overall success rate of IBD (including UC and CD) in adults is 77.8%. FMT may improve UC, with a success rate close to 90%, as measured by disappearance of symptoms or reduction in ulcerative colitis activity index (UCAI). To date, there has been report of three paediatric patients receiving FMT for treatment of UC and C. difficile infections with UC, by nasogastric (NG) tube or enema.42, 43 All of them demonstrated FMT as a feasible and well-tolerated therapy as it is usually given by duodenal endoscopic lavage during endoscopy or performed as an enema. There were no serious adverse events noted in those children. 1005
S. Sha et al. Literature search Databases: PubMed, EMBASE, and the Cochrane Library
Citations from backward search of reference lists from relevant papers
Search results combined (n = 16610) (duplicates excluded)
Articles screened on basis of title and abstract Limits: English-language articles only
16512 Citations rejected upon review of title/abstract Deemed potentially eligible (n = 98)
Excluded: Manuscript review and application of inclusion criteria When multiple publications reported on the same patients, the most recent and complete data were included 67 Citations of case series or case reports (35/67 journal articles; 25/67 abstracts 7/67 letters)
43 repoting FT for refractory/relapsing CDI (644 patients)
1 reporting FT in patients with AAD (32 patients)
12 reporting FT for IBD (111 patients)
3 reporting FT for chronic constipation (11 patients),1 reporting FT in patients IBS or abdominal pain (37 patients)
Did not report original data
7 reporting FMT for CDI in IBD (21 patients)
1 reporting FT Metabolic Syndrome (18 patients)
Figure 1 | Flow chart of studies of faecal microbiota transplantation therapy in adults and children.
FMT has so far proved disappointing in CD. In most patients, FMT therapy was not effective in achieving clinical remission or biologic/endoscopic benefit (Table 5). However, CDI in IBD patients has been improved by FMT therapy. Twenty-one patients have received FMT for treatment of CDI in patients with IBD, including a child.42 FMT therapy resolved C. difficile in 90.5% patients, as measured by negative stool sample enterotoxin and improved response to IBD medications. 1006
Outcomes treatment of other gastrointestinal diseases in adults and children One study reported that 30 of 32 patients with AAD (who had received antibiotic drugs before and hospitalised owing to diarrhoea from 3 to 20 stools daily, C. difficile toxin positive or negative) were cured by FMT.34 FMT also showed effective in treatment of IBS, although the number treated was small (the total number in this systematic review is 6), its successful rate was 100% in the studied.44, 45 In addition, Borody et al. successfully Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
Systematic review: faecal microbiota transplantation therapy in adults and children Table 1 | Summary of FMT for treating CDI Characteristics of studies
Author (Year) Eiseman13 (1958)
Type (country)
Characteristics of patients
Number (Male/ Female)
Journal article (US) Journal article (US)
4 (3/1)
Fenton77 (1974)
Characteristics of intervention
Faeces suspension/ volume Age infused median (route of Donor (range) FMT) Frequency relationship
1 (1/0)
56 (45– 68) 65
/(retention enemas) Two ounces of faeces and 10 ounces of yogurt in a quart of normal saline) (Cantor tube)
Journal article (Canada)
1 (0/1)
57
Schwan24 (1984)
Journal article (Sweden)
1 (0/1)
Tvede78 (1989)
Journal article (Denmark)
Borody44 (1989)
Letter (Australia)
Cutolo LC
76
(1959)
Characteristics of outcomes
1–3
Healthy adults
3/day for 7 days
Healthy humans
-/500 mL saline (enema)
1
/
67
450 mL mixture contain faeces and saline (retention enemas)
2 (over three consecutive days)
Husband
2 (1/1)
60 (59– 60)
50 g faeces suspended in 500 mL saline (Enema)
1–2
Husband daughter
1 (0/1)
35
Retention enemas (/)
/
/
Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
and
Outcome Severe diarrhoea ceased within 48 h The first formed stool was passed 36 h later, after 48 h the diarrhoea ceased. A response was obtained and both clinical and laboratory evidence revealed the elimination of the staphylococcus from the intestine Marked improvement occurred and continued to complete resolution of the clinical and sigmoidoscopic abnormalities within 4 days. Prompt and complete normalisation of the bowel function with disappearance of IBS symptoms. Stools of normal consistency, colour and smell have thereafter been passed daily or every other day. Weight gain 6 kg Patient 1: complete clinical recovery with eradication of C. difficile and its toxin after 1 infusion; Patient 2 had 2 infusions but did not respond (but did respond to a cultured bacterial mixture) The patient appear to be ‘cured’ by resolution of symptoms dramaticly.
Success rate 4/4 (100%) 1/1 (100%)
Adverse events None Died of upper GI haemorrhage (not related to the FMT therapy)
1/1 (100%)
None
1/1 (100%)
None
1/2 (50%)
None
1/1 (100%)
None
1007
S. Sha et al. Table 1 | (Continued) Characteristics of studies
Author (Year)
Type (country)
Characteristics of patients
Number (Male/ Female)
Faeces suspension/ volume infused Age (route of Donor median FMT) Frequency relationship (range)
Patterson-179 (1994)
Letter (Australia)
1 (0/1)
39
Patterson-279 (1994)
Letter (Australia)
6 (-/-)
56 (30– 80)
Persky80 (2000)
Journal article (US)
1 (0/1)
60
Faust81 (2002)
Abstract (Canada)
6 (1/5)
Aas63 (2003)
Journal article (US)
18 (5/13)
1008
Characteristics of intervention
Characteristics of outcomes
Outcome
Success rate
Adverse events
Single daily retention enemas for 3 days (400 mL consisting of 200 mL stool mixed with 200 mL saline (Rectal tube) Single daily retention enemas for 3 days (400 mL consisting of 200 mL stool mixed with 200 mL saline) (Rectal tube) (500 mL containing stool mixed in saline) (colonoscopy)
3
Husband
No recurrence of diarrhoea in 2 years
1/1 (100%)
None
3
Relative
All patients experienced rapid resolution of disabling persistent C. difficile infection without relapse
6/6 (100%)
None
1
Husband
1/1 (100%)
None
53 (37–74)
/(/)
1
Family members (spouse 4, brother 1, son 1)
6/6 (100%)
None
73 (51–88)
30 g faeces homogenised in 50–70 mL saline (Single 25 mL dose of stool suspension) (Nasogastric tube)
1
Family members or clinic staff
Immediate and complete resolution of diarrhoea with normal bowel movements that was maintained long term. Repeat C. difficile toxin assay negative All patients responded promptly and continued to be asymptomatic; 4/6 patients C. difficile toxin negative 15/18 patients asymptomatic for duration of followup. 13 patients were C. difficile negative (2 patients not tested); 2 died of unrelated illnesses; 1 treatment failure (C. difficile positive)
15/16 (94%) (who survived)
*
Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
Systematic review: faecal microbiota transplantation therapy in adults and children Table 1 | (Continued) Characteristics of studies
Author (Year)
Type (country)
Characteristics of patients
Number (Male/ Female)
Faeces suspension/ volume infused Age (route of Donor median FMT) Frequency relationship (range)
Broody (CD SYNDROMES)61 (2003)
Abstract (Australia)
24 (11/13)
19–59
Wettstein38 (2007)
Abstract (Australia)
16 (5/11)
11–87
You82 (2008)
Letter (US)
1 (1/0)
69
Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
Characteristics of intervention
200–300 g stool diluted in 200– 300 mL saline (The suspension was infused into the colon) (colonoscope and/or rectal enema and/or nasojejunal tube (Combination of colonoscopy and rectal enema was the most common (46%) delivery method)) 200–300 g/ 200–300 mL Saline with added psyllium [Colonoscopy (day 1) Enema (between 5, 10, or 24 days)] 45 g/300 mL normal saline (Retention enema)
Characteristics of outcomes
Outcome
Success rate
Adverse events
Daily for 1 (3/ 24, 13%), 5 (11/24, 46%) or 10 days (10/24, 42%)
Relatives or unrelated healthy individuals
Eradication of C. difficile was confirmed by negative Cd toxin and culture results in 20/24 patients (83%, P < 0.0001) post-treatment. 2/ 24 unsuccessful, 2/24 nonresponse, (including 1/24 recurrent)
20/24 (83%)
†
5–24
Relatives or unrelated healthy individuals
Eradication of C. difficile was confirmed by negative Cd toxin A or B and culture results in 15/16 patients (93.5%) 4 –6 weeks posttreatment
Resolution in 15/16
None
1
Daughter
The patient’s blood pressure stabilised, the leucocyte count normalised, and oliguria resolved and both vasopressors and continuous venovenous hemofiltration was discontinued. The patient’s bowel function returned, and abdominal distention decreased
1/1 (100%)
None
1009
S. Sha et al. Table 1 | (Continued) Characteristics of studies
Author (Year)
Type (country)
Characteristics of patients
Number (Male/ Female)
Faeces suspension/ volume infused Age (route of Donor median FMT) Frequency relationship (range)
Keller83 (2009)
Abstract (Netherlands)
11 (-/-)
/
Maccanochie84 (2009)
Journal article (UK)
15 (1/14)
81.5 (68– 95)
Rubin85 (2009)
Letter (US)
16 (-/-)
70–99
Arkkila, P. E.86 (2010)
Abstract (/)
37 (-/-)
69 (24– 90)
Silverman26 (2010)
Journal article (Canada)
7 (4/3)
65 (30– 88)
1010
Characteristics of intervention
Characteristics of outcomes
Outcome
Success rate
Adverse events
>100 g/300– 400 mL saline (infusion of suspension of donor faeces) (in jejunum (nasoduodenal tube) or in coecum and colon ascendens (via colonoscope)) 30 g faeces in 150 mL saline (30 mL of faecal fluid was administered) (Nasogastric tube) ~30 g or 2cm3/50– 70 mL saline (30–60 mL suspense) (Nasogastric tube) 20–30 mL mixed with 100–200 mL of water (colonoscopy)
1
/
Successfully treated 11 patients with multiple recurrences of CDI
11/11 (100%)
None
1 (14/15) or 2 (1/15)
Healthy related volunteers
Patients were symptom free. 2 no responses; 2 relapsed (1 responded to the 2nd FMT)
12/15 (80%)
None
1
Family member
14/16 ambulatory patients are able to return to normal diet and activities immediately after the procedure
14/16 (87.5%)
None
1–2
Related to the recipient
34/37 (92%)
None
50 mL faeces in 200 mL saline (250 mL of faecal fluid was administered) (Retention enema)
1
Family member
34/37 (92%) patients were cured patients had relapse after 5– 12 months after receiving new antibiotic treatment and they got successful faeces reinfusion thereafter. One noncured patient died after 1 month due to the toxic megacolon All of the patients were successfully cured
7/7 (100%)
None
Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
Systematic review: faecal microbiota transplantation therapy in adults and children Table 1 | (Continued) Characteristics of studies
Author (Year)
Type (country)
Characteristics of patients
Number (Male/ Female)
Faeces suspension/ volume infused Age (route of Donor median FMT) Frequency relationship (range)
Khoruts60 (2010)
Journal article (US)
1 (0/1)
61
Rohlke87 (2010)
Journal article (US)
19 (2/17)
49 (29– 82)
Yoon88 (2010)
Journal article (US)
12 (3/9)
66 (30– 86)
Garborg89 (2010)
Journal article (Norway)
40 (19/21)
75 (53–94)
Kelly90 (2010)
Abstract (US)
12 (1/11)
55.6 (19– 80)
Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
Characteristics of intervention
25 g/300 mL saline (250 mL of faecal fluid was administered) (colonoscope) -/350 mL saline (200– 300 mL of faecal fluid was administered) (colonoscopy)
Unknown volume faeces in 1000 mL saline (250– 400 mL of faecal fluid was administered) (colonoscopy) 50–100/250 saline (200 mL of faecal fluid was administered) [Gastroscopy (38) or colonoscopy (2)] 6–8 tablespoons of donor stool was added to 1 L of sterile water (740 mL (range 500– 960 mL) of faeces suspension was delivered) (colonoscope)
Characteristics of outcomes
Outcome
Success rate
Adverse events
1
Husband
At 1 month after bacteriotherapy, stool studies were culture negative for C. difficile
1/1 (100%)
‡
1 (majority) or 2 (1 patient)
Intimate domestic partners, family members and close friends.
19/19 (100%)
/
1
Family member or partner
All of the patients in this study maintained prolonged periods free of symptoms and are considered ‘cured’ after treatment with Faeces Flora Reconstitution Absence of diarrhoea, cramps, and fever. All patients experienced a durable clinical response to faeces transplantation
12/12 (100%)
None
1 (34/40) or 2 (6/40)
Close relatives or other household members
A total of 33/40 patients (4 patients responded to the 2nd FMT) were successfully treated
33/40 (83%)
None (5 unrelated deaths 3 weeks to 2 months post-FMT)
1
Partner or family member
Ten have remained symptom free. Two had diarrhoea after the procedure, but both were C. difficile negative. One responded to treatment with a fibre supplement and the other resumed vancomycin. None have had a documented recurrence of CDI to date
12/12 (100%)
None
1011
S. Sha et al. Table 1 | (Continued) Characteristics of studies
Author (Year)
Type (country)
Characteristics of patients
Number (Male/ Female)
Characteristics of intervention
Faeces suspension/ volume infused Age (route of Donor median FMT) Frequency relationship (range)
Mellow31 (2010)
Journal article (US)
13 (7/6)
67 (32–87)
-/300–600 mL saline (colonoscopy)
1
Healthy donors
Miller91 (2010)
Abstract (US)
2 (0/2)
42 (34– 50)
Fresh stool was liquefied and delivered (colonoscopy)
1
Sister/husband
Russell14 (2010)
Journal article (US)
1 (0/1)
2
30 g/50–75 mL saline (25 mL mL of faecal fluid was administered) (temporary nasogastric tube)
1
Father
Girotra92 (2011)
Abstract (US)
3 (0/3)
56.3 (31– 85)
/(colonoscopy and enteroscopy)
1
Healthy donors
Wilcox93 (2011)
Abstract (Portland)
13 (4/9)
69.4 (27– 93)
/(colonoscope into the patient’s caecum)
1
Family members or friends
1012
Characteristics of outcomes
Outcome A total of 12/13 patients were successfully treated with diarrhoea resolved. 3 patients have died (B strep pneumonia 1 month after FMT; superior mesenteric vein thrombosis 5 months after FMT; ovarian cancer 7 months after FB) One patient had an immediate improvement in symptoms and has been infection free for 9 months The abdominal symptoms and diarrhoea resolved and did not recur during 6 months of monitoring. The stool tested negative for C difficile toxin 2 weeks, 3 months, and 6 months after the procedure All three patients had complete resolution of symptoms within a few days after administration of faeces bacteriotherapy. complete resolution of symptoms FMT appears to be effective, tolerated well by patients, and without complications
Success rate
Adverse events
12/13 (%)
None (3 unrelated deaths 1– 7 months post-FMT)
2/2 (100%)
None
1/1 (100%)
None
3/3 (100%)
None
13/13 (100%)
None
Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
Systematic review: faecal microbiota transplantation therapy in adults and children Table 1 | (Continued) Characteristics of studies
Author (Year)
Type (country)
Characteristics of patients
Number (Male/ Female)
Characteristics of intervention
Faeces suspension/ volume infused Age (route of Donor median FMT) Frequency relationship (range)
Brandt11 (2012)
Journal article (US)
77 (21/56)
65 (22–87)
300–700 mL (colonoscopic)
1 or 2 (4 patients)
Spouse/ partner, 46; 1st degree relative, 19; friend, 9; other relative, 2; unknown, 1
Gallegos-Orozco94 (2012)
Journal article (US)
1 (1/0)
71
1
Brother
Garg39 (2012)
Abstract (US)
1 (1/0)
20-monthold
-/400 mL saline (400 mL) of faecal fluid was administered (colonoscopic) /(colonoscopy)
1
Mother
Hamilton30 (2012)
Journal article (US)
29 (9/20)
64.7 3.3
1 (37/43) or 2 (6/43)
Mothers, daughters, sons, wives, husbands and friends
Jorup-Ronstrom95 (2012)
Journal article (Sweden)
32 (12/20)
75 (27–94)
50 g/250 mL saline (220– 240 mL of faecal fluid was administered) (Colonoscopy (1 patient used upper push enteroscopy)) 30–60 mL (Enema and colonoscopy)
1–3
A healthy adult
Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
Characteristics of outcomes
Outcome
Success rate
Adverse events
diarrhoea resolved in 82% and improved in 17% of patients within an average of 5 days after FMT. The primary cure rate was 91%. Seven patients either failed to respond or experienced early CDI recurrence (≤90 days) The patient’s diarrhoea and abdominal pain resolved
70/77 (90.9%)
One patient was not treated and died in hospice care of unclear cause
1/1 (100%)
None
The patient has now remained symptom free with complete resolution of diarrhoea, haematochezia and had gained weight consistently for the past 3 months One other patients were treated with a second infusion, and all cleared the infection bringing the overall success rate to 100%.
1/1 (100%)
None
29/29 (100%)
§
26/32 (81.3%)
None
22 patients were cured and 10 patients failed to fully respond to treatment. Later in the study, the culture was given by colonoscopy in patients who failed after the simple enema procedure. 4 out of 5 healed. 6/32 relapse
1013
S. Sha et al. Table 1 | (Continued) Characteristics of studies
Author (Year)
Type (country)
Characteristics of patients
Number (Male/ Female)
Characteristics of intervention
Faeces suspension/ volume infused Age (route of Donor median FMT) Frequency relationship (range)
Kahn40 (2012)
Letter (US)
1 (1/0)
16-months
(140 mL of faecal fluid was administered) (colonoscopy)
1
Mother
Kurtz96 (2012)
Journal article (US)
1 (0/1)
78
/(colonoscopy)
1
Husband
Mellow97 (2012)
Abstract (US)
1 (1/0)
39
/(colonoscopy)
1
Wife
Neemann98 (2012)
Journal article (US)
1 (0/1)
21
30 mL/- in saline (suspension) (nasojejunal instillation)
1
Husband
1014
Characteristics of outcomes
Outcome Within 24 h the patient’s symptoms resolved completely. One week post-FMT, Clostridium difficile toxin PCR was negative and 2 months postFMT he remains asymptomatic The patient failed to respond to the stool transplant. Biopsies from a colonoscopy revealed concomitant cytomegalovirus (CMV) infection. The patient underwent an emergency total colectomy, and oral valganciclovir Over the next several days, diarrhoea resolved and stool for C. difftoxin A&B was negative on day seven post-FMT. Diarrhoea did not recur after 1 year The patient had no further diarrhoea or haematochezia. Her abdominal pain and distention had resolved completely, and she was eating a regular diet. Repeat C. difficile toxin and antigen EIA assays were negative at 3 and 11 days after faeces transfer, and the patient remained well at 2 months after treatment
Success rate
Adverse events
1/1 (100%)
None
0/1 (0%)
None
1/1 (100%)
None
1/1 (100%)
None
Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
Systematic review: faecal microbiota transplantation therapy in adults and children Table 1 | (Continued) Characteristics of studies
Author (Year)
Type (country)
Characteristics of patients
Number (Male/ Female)
Characteristics of intervention
Faeces suspension/ volume infused Age (route of Donor median FMT) Frequency relationship (range)
Kelly71 (2012)
Journal article (US)
26 (2/24)
59 (19–86)
6–8 tablespoons/ 1 L sterile water (or saline) (500– 960 mL was administered) (colonoscopy)
1
Intimate partner or adult family member
Kassam99 (2012)
Journal article (Canada)
27 (14/13)
69.4 (26– 87)
150 g/300 mL water (The supernatant component was administered rectally by enema) (retention enema)
1 (22/27) or 2 (5/27)
Two healthy volunteers
Matilla100 (2012)
Journal article (Finland)
70 (28/42)
73 (22– 90)
20–30 mL/100– 200 mL water (100 mL suspension) (colonoscopy)
1 (68/70) or 2 (2/70)
Close relatives, household members, or healthy volunteer
Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
Characteristics of outcomes
Outcome 24/26 patients have remained free of significant diarrhoea or CDI. One experienced loose stool and resumed vancomycin despite remaining C. difficile negative; she developed CDI recurrence 11 months postFMT after taking cephalexin. Another had diarrhoea 2 months post-FMT. Stool was not tested for C. difficile; she received 1 week of vancomycin and CDI did not recur after this 22 resolved within 24 h of transplant. 5 patients underwent a second FMT because of ongoing diarrhoea; 3 had symptom resolution and 2 continued to experience diarrhoea despite 2 FMTs During the first 12 weeks of followup evaluation the transplantation resulted in the resolution of symptoms in 66 patients. During the 1-year follow-up period, 4 patients with an initial favourable response had a relapse after receiving antibiotics for unrelated causes. 2 were treated successfully with another faeces transplantation and 2 with antibiotics for CDI
Success rate
Adverse events
24/26 (92.3%)
None
25/27 (93%)
None
66/70 (94.3%)
10 patients died of unrelated illnesses during the 1-year follow-up period
1015
S. Sha et al. Table 1 | (Continued) Characteristics of studies
Author (Year)
Type (country)
Characteristics of patients
Number (Male/ Female)
Characteristics of intervention
Faeces suspension/ volume infused Age (route of Donor median FMT) Frequency relationship (range)
Rubin41 (2013)
Journal article (US)
75 FMT courses (49/26) (74 patients)
63 (6–94) two paediatric patients (age 6 and 8)
~30 g (~3 cm3)/50– 70 mL saline (25 mL) (nasogastric tube, or gastroscope or through a PEG tube)
1 or 2 patient)
Trubiano101 (2013)
Journal article (Australia)
1 (0/1)
75
30 g/70 mL saline(30 mL suspension of donor faeces) (delivered into the jejunum through gastroscopy)
1
Husband
Van Nood37 (2013)
Journal article (Netherlands)
16 (8/8)
73 13
Faeces were diluted with 500 mL of sterile saline (0.9%) (nasoduodenal tube)
1(13/16) 2 (3/ 16)
Volunteers
(1
Healthy close household member
Characteristics of outcomes
Outcome Fifty-nine FMT courses resulted in clinical resolution of diarrhoea for a primary cure rate of 79%. diarrhoea relapsed following 16 FMT courses; in 9 of these cases diarrhoea subsequently resolved after a single course of vancomycin. (paediatric patients: one experienced a clinical resolution following the FMT, while the other had a clinical relapse) The C. difficilerelated symptoms were resolved. An abdominal computed tomography in the days before death showed no evidence of colitis, whereas stool cultures for C. difficile remained negative for culture and toxin on days 14, 20 and 30 after transplant The infusion of donor faeces was significantly more effective for the treatment of recurrent C. difficile infection than the use of vancomycin. 13 (81%) had resolution of C. difficile-associated diarrhoea after the first infusion. The 3 remaining patients received a second infusion with faeces from a different donor, with resolution in 2 patients
Success rate
Adverse events
59/75 (79.7%)
None
1/1 (100%)
¶
15/16 (94%)
Mild diarrhoea and abdominal cramping on the infusion day
FMT, faeces microbiota transplantation; CDI, Clostridium difficile infection; PEG, percutaneous endoscopic gastroscopy. * Two deaths: 1 after development of peritonitis (3 days post-FMT); 1 of pneumonia (14 days post-FMT). † Transient and included sore throat, flatulence, rectal discomfort, nausea, abdominal cramping, bloating, headache and abdominal pain. ‡ Developed constipation in the initial months after the procedure. § Approximately a third noted some irregularity of bowel movements and excessive flatulence, but resolved in clinic follow-up. ¶ The patient died because of ongoing renal failure and acute respiratory failure. 1016
Aliment Pharmacol Ther 2014; 39: 1003-1032 ª 2014 John Wiley & Sons Ltd
Systematic review: faecal microbiota transplantation therapy in adults and children treated at least 12 patients with chronic constipation in adults and children (Table 4).44–48
Outcomes treatment of nongastrointestinal diseases in adults and children Several reports described patients with autoimmune and neurologic disorders who showed improvement with FMT therapy (Table 4). One report described the co-development of myoclonus dystonia and chronic diarrhoea in a patient who was subsequently treated with FMT therapy, resulting in 90% improvement of her myoclonus dystonia symptoms, allowing her to resume employment and execute fine motor tasks.49 The onset of autism is often accompanied by gastrointestinal complaints and preceded by antibiotic use so it has been suggested that an altered microbiota might be involved in its pathogenesis.50 For example, autistic patients were found to have greater numbers and different types of Clostridial species when compared with controls.51 Improvement in autistic symptoms was reported in two children after FMT and in five children who received daily cultured Bacteroidetes and Clostridia for several weeks.52 Neurologic improvement has also been reported in one patient with Parkinson’s disease who received FMT for chronic constipation.53 Vrieze et al.54 reported the first application of FMT therapy in metabolic syndrome. In this study, they found FMT from lean donors significantly increased insulin sensitivity of 18 recipients with metabolic syndrome, which was most likely by increasing concentrations of butyrate-producing intestinal bacteria in the small and large intestine. These findings demonstrated FMT therapy for metabolic diseases warrants further investigation. FMT was also proved effect in patients with chronic fatigue syndrome (CFS). In patients with CFS followed up for up to 20 years, FMT has been reported to be effective with an initial success rate of 42/60 (70%) and sustained response in 35/60 (58%).55 It is suggested that the pathophysiology of CFS could be in part explained by enteric derived toxin-releasing bacteria capable of producing systemic effects.56 Outcomes FMT therapy for diseases in children We compared the characteristics with FMT therapy for diseases in adults and children (Table 5). Since the number of reports of FMT in children, we here review them all. The first case report of FMT in children was published in 2001 by Borody et al.47 In the three enrolled chronic constipation patients, two were aged 7 and
