Experimental Use of FMT for Ulcerative Colitis

In a recent randomized, double-blind study (SP Costello et al. JAMA. 2019;321(2):156-164. doi:10.1001/jama.2018.20046), the use of fecal microbiota transplantation (FMT) was effective in 32% in inducing remission in adult patients with ulcerative colitis (UC).

Key Finding:  In this randomized clinical trial that included 73 adults with mild to moderately active ulcerative colitis, the proportion achieving steroid-free remission at 8 weeks was 32% with donor FMT vs 9% with autologous FMT, a significant difference

Abstract:

Importance  High-intensity, aerobically prepared fecal microbiota transplantation (FMT) has demonstrated efficacy in treating active ulcerative colitis (UC). FMT protocols involving anaerobic stool processing methods may enhance microbial viability and allow efficacy with a lower treatment intensity.

Objective  To assess the efficacy of a short duration of FMT therapy to induce remission in UC using anaerobically prepared stool.

Design, Setting, and Participants  A total of 73 adults with mild to moderately active UC were enrolled in a multicenter, randomized, double-blind clinical trial in 3 Australian tertiary referral centers between June 2013 and June 2016, with 12-month follow-up until June 2017.

Interventions  Patients were randomized to receive either anaerobically prepared pooled donor FMT (n = 38) or autologous FMT (n = 35) via colonoscopy followed by 2 enemas over 7 days. Open-label therapy was offered to autologous FMT participants at 8 weeks and they were followed up for 12 months.

Main Outcomes and Measures  The primary outcome was steroid-free remission of UC, defined as a total Mayo score of ≤2 with an endoscopic Mayo score of 1 or less at week 8. Total Mayo score ranges from 0 to 12 (0 = no disease and 12 = most severe disease). Steroid-free remission of UC was reassessed at 12 months. Secondary clinical outcomes included adverse events.

Results  Among 73 patients who were randomized (mean age, 39 years; women, 33 [45%]), 69 (95%) completed the trial. The primary outcome was achieved in 12 of the 38 participants (32%) receiving pooled donor FMT compared with 3 of the 35 (9%) receiving autologous FMT (difference, 23% [95% CI, 4%-42%]; odds ratio, 5.0 [95% CI, 1.2-20.1]; P = .03). Five of the 12 participants (42%) who achieved the primary end point at week 8 following donor FMT maintained remission at 12 months. There were 3 serious adverse events in the donor FMT group and 2 in the autologous FMT group.

Conclusions and Relevance  In this preliminary study of adults with mild to moderate UC, 1-week treatment with anaerobically prepared donor FMT compared with autologous FMT resulted in a higher likelihood of remission at 8 weeks. Further research is needed to assess longer-term maintenance of remission and safety.

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Fecal Microbioata Transplantation for Recurrent Clostridium difficile — Position Paper

A recent position paper (ZH Davidovics et al. JPGN 2019; 68: 130-43) from NASPGHAN/ESPGHAN on Fecal Microbioata Transplantation (FMT) for Recurrent Clostridium difficile infection (CDI) provides a pretty good review. Though, I think a summary table of recommendations would have made this publication much more helpful.

Here is a full-text link: Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection and Other Conditions in Children: A Joint Position Paper

A couple key points/excerpts:

In general, we concur with current adult guidelines  when considering FMT for the treatment of rCDI in children and propose FMT be considered in children with one of the following:
1. rCDI (recurrence of symptoms within 8 weeks of treatment for CDI) (either a or b)
a. At least 3 episodes of mild to moderate CDI and failure of a 6- to 8-week taper with vancomycin with or without an alternative antibiotic (eg, rifaximin, nitazoxanide).
b. At least 2 episodes of severe CDI resulting in hospitalization and associated with significant morbidity.

2. Moderate CDI not responding to standard therapy (including vancomycin) for at least 1 week. We recommend caution, however, in such cases, with repeated testing for etiologies other than CDI such as IBD.

3. Severe CDI or fulminant C difficile colitis with no response to standard therapy after 48 hours.

My take:  I think the IDSA 2017 guidelines are more useful: Clostridium difficile Guidelines (2017 IDSA/SHEA)

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Fecal Microbiota Transplantation: How important is the BMI of the stool donor?

Currently fecal microbiota transplantation (FMT) “best practices” exclude obese stool donors based on a report of germ-free mice gaining weight after FMT from mice with obesity and based on a case report of an individual with 34 pound weight gain after FMT.

A recent report (M Fischer et al. Clin Gastroenterol Hepatol 2018; 16: 1351-3) suggests that the the BMI of the stool donor does not affect recipient weight after a single FMT procedure for C difficile infection.

This analysis included 173 patients with a mean age of 57 years.  One group of 103 were from a randomized control trial; in this group, 66 (64%) received FMT from a normal weight (BMI 18-24.9) donor and 37 (36%) received FMT from an overweight (BMI 25-29.9) donor. Among an additional 70 individuals from an observational cohort, 25 received FMT from normal weight donor, 30 received FMT from overweight donor, and 15 received FMT from an obese donor.

Key finding:

  • There was no significant difference in BMI among the FMT recipients up to 48 weeks after a single FMT.  Based on data from Figure 1, patients who received FMT from normal weight donor had slightly higher mean weight gain at 48 weeks afterwards (not statistically-significant)

The authors caution that a prospective study is required to confirm these findings and in the interim, they recommend exclusion of obese/overweight FMT donors.

My take: There are plenty of willing stool donors –so who knows if this will ever be examined adequately.  This study challenges the idea that FMT from an obese donor will result in recipient obesity, presumably via changes in the microbiome.

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Cost Effective Fecal Transplantation

A recent retrospective study (DE Brumbaugh et al. J Pediatr 2018; 194: 123-7) examined the effectiveness of intragastric fecal microbiota transplantation (FMT) for recurrent Clostridium difficile infection (CDI) in 42 children (47 FMTs).

Key findings:

  • 94% (16/17) success in otherwise healthy children
  • 75%  (9/12) success in medically complex children
  • 54% (7/13) success in inflammatory bowel disease.
  • Figure 2 describes cost: nasogastric FMT cost for hospital/professional charges was $1139 compared to $4998 for nasoduodenal FMT and $7767 for colonoscopy FMT

To understand the results better, one needs to look at their methods.  The authors defined CDI based on a positive fecal polymerase chain reaction (PCR) test.  All patients undergoing FMT had to have had >2 episodes of CDI.

The authors discuss the issue that asymptomatic Clostridium difficile carriage is common in IBD (“6 times that in healthy controls”) and the fact that true CDI can be difficult to ascertain as the relative contribution of IBD activity can be difficult to separate from CDI.  Interestingly, the authors did not comment on their use of PCR testing to establish infection.

As noted in a previous blog post (Overdiagnosis of Clostridium difficile with PCR assays), immunoassay testing for toxin is likely helpful in equivocal cases.  In an influential JAMA Intern Med study (JAMA Intern Med. 2015;175(11):1792-1801.  doi:10.1001/jamainternmed.2015.4114), virtually all CDI-related complications and deaths occurred in patients with positive toxin immunoassay test results. Patients with a positive molecular test result and a negative toxin immunoassay test result had outcomes that were comparable to patients without C difficile by either method.

Other useful points in this study:

  • The authors note that craniofacial anatomy may preclude NG placement in some patients (in some orogastric insertion could be an alternative)
  • Patients at high risk for GERD/aspiration along with general anesthesia patients are “not good candidates for FMT”
  • “If there is concern for undiagnosed IBD or other GI pathology, FMT via colonoscopy may be preferable” as FMT could be diagnostic and therapeutic.

My take: This study confirms the utility of intragastric FMT for recurrent CDI as a cost-effective option.  More careful examination of CDI in patients with IBD could result in determining which patients are most likely to benefit from FMT

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What Happens Four Years After Fecal Microbiota Transplantation?

A recent study (J Jalanka et al. AP&T 2018; 47: 371-9-thanks to Ben Gold for this reference) provide long-term data of fecal microbiota transplantation (FMT).

In this study of 84 adult patients who were treated for C difficile infection, 45 who had received FMT and 39 treated with antibiotics, the authors determined the frequency of adverse sequelae at 3.8 years using a retrospective questionnaire.

Key findings:

  • There were no difference in the development of severe diseases between FMT recipients and control patients (eg. IBD, cancer, autoimmune diseases, allergy, and neurological diseases)
  • There were no differences in weight gain
  • FMT patients reported faster improvements in bowel habits and reported that their mental health improved after treatment
  • FMT patients had fewer symptoms of functional gastrointestinal disorders than the control (antibiotic) patients

The authors note that FMT is frequently recommended based on three recurrences of C difficile infection and that their study would support using FMT earlier as a treatment option.

My take: Though a small study, these data suggest that FMT is effective and without long-term consequences.

Oral Capsules for Fecal Microbiota Transplantation

A recent study (D Kao et al.JAMA. 2017;318(20):1985-1993. doi:10.1001/jama.2017.17077showed that oral stool capsules are as effective as stool delivered via colonoscopy for recurrent C difficile infection (RCDI).  Thanks to Ben Gold for this reference.

Findings  In this noninferiority randomized clinical trial that included 116 adults with RCDI, the proportion without recurrence over 12 weeks was 96.2% after a single treatment in a group treated with oral capsules and in a group treated via colonoscopy, meeting the noninferiority margin of 15%.

My take: This study adds to the literature that oral delivery is effective in fecal microbiota transplantation and that capsules could be a convenient way to deliver.

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Thinking Clearly About Fecal Microbiota Transplantation & Hepatic Encephalopathy

An intriguing open-label randomized clinical trial (JS Bajaj et al. Hepatology 2017; 66: 1727-38) showed that fecal microbiota transplantation (FMT) was helpful in hepatic encephalopathy.

Background: It is well-recognized that changing bacteria flora can be beneficial in patients with hepatic encephalopathy (HE) associated with cirrhosis.  This has been shown with prior treatments with both lactulose and rifaximin.  It is clear that FMT can improve microbial dysbiosis, particularly in patients with Clostridium difficile.  In this study, the authors randomized 20 patients to either standard of care (SOC) or to SOC & FMT (single enema) with a 5-month follow-up. SOC patients received lactulose and rifaximin.

Key findings:

  • No FMT patients and 5 SOC patients developed further HE
  • Cognition improve in the FMT, but not the SOC, group
  • FMT was associated with increased microbial diversity

Since this was a small study, a bigger trial with longer follow-up is needed.

My take: This intriguing study suggests that FMT, or similar more selected modification of bacterial flora, could be helpful in reducing hepatic encephalopathy among patients with cirrhosis.

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