Outcomes of Fecal Microbiota Transplantation in Patients With Inflammatory Bowel Diseases and Recurrent Clostridioides difficile Infection

Abstract

There has been an increase in the burden of Clostridioides difficile infection (CDI),1Cohen S.H. et al.Infect Control Hosp Epidemiol. 2010; 31: 431-455Crossref PubMed Scopus (2460) Google Scholar especially in high-risk populations such as patients with inflammatory bowel disease (IBD).2Ananthakrishnan A.N. Nat Rev Gastroenterol Hepatol. 2011; 8: 17-26Crossref PubMed Scopus (262) Google Scholar The prevalence of CDI in the IBD population is up to 8-fold higher than comparable controls, with increased rates of recurrence and CDI-associated mortality.3Razik R. et al.Am J Gastroenterol. 2016; 111: 1141-1146Crossref PubMed Scopus (74) Google Scholar In addition, CDI may induce an IBD flare, and worsen disease severity and clinical course.4Kelsen J.R. et al.Inflamm Bowel Dis. 2011; 17: 50-55Crossref PubMed Scopus (81) Google Scholar Fecal microbiota transplantation (FMT) is a guideline recommended therapy for recurrent CDI5McDonald L.C. et al.Clin Infect Dis. 2018; 66: 987-994Crossref PubMed Scopus (447) Google Scholar; however, supportive randomized trials excluded patients with IBD. In retrospective trials of patients with IBD, FMT failure rates had been reported to be approximately 25% to 30%.6Newman K.M. et al.Gut Microbes. 2017; : 1-7Google Scholar In addition, Khoruts and colleagues reported that patients with IBD and CDI were more likely to fail FMT,7Khoruts A. et al.Clin Gastroenterol Hepatol. 2016; 14: 1433-1438Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar leading to further uncertainty regarding the safety and efficacy of FMT in IBD patients with concurrent CDI. Accordingly, we conducted the first prospective study examining the efficacy of FMT among patients with IBD and CDI. We conducted an open-label, prospective, single-arm, multicenter cohort study at 4 tertiary care FMT referral centers (Brigham and Women’s Hospital, Indiana University, Brown University, and Mount Sinai Hospital; NCT03106844). Patients with a confirmed diagnosis of IBD and 2 or more confirmed CDI episodes within 12 months, including the most recent episode occurring within 3 months, were enrolled. In keeping with CDI clinical guidelines,5McDonald L.C. et al.Clin Infect Dis. 2018; 66: 987-994Crossref PubMed Scopus (447) Google Scholar polymerase chain reaction or glutamate dehydrogenase with toxin enzyme immunoassay were permitted for the qualifying CDI episode. Patients with a total or subtotal colectomy, isolated ileal or small bowel Crohn’s disease, those pregnant or breastfeeding, those treated with vancomycin or metronidazole for more than 60 days, or those who had undergone a prior FMT within 12 months were excluded. Baseline IBD and CDI data were collected. All patients underwent a single FMT via colonoscopy. Four robustly screened healthy donors were used (OpenBiome, Cambridge, MA).8Kassam Z. et al.N Engl J Med. 2019; 381: 2070-2072Crossref PubMed Scopus (63) Google Scholar Stool testing, including glutamate dehydrogenase, toxin enzyme immunoassay ,and polymerase chain reaction, was performed 1, 8, and 12 weeks post-FMT regardless of symptoms to assess for CDI and C. difficile colonization rates. All stool testing was performed at a central laboratory. The primary outcome was FMT failure through week 8, defined as diarrhea (3 or more loose stools daily for 3 or more days) and stool testing positive for C. difficile via 2-step testing using glutamate dehydrogenase and toxin enzyme immunoassay. Patients who met the criteria for failure underwent a second FMT. Secondary outcomes included C. difficile colonization defined as patients without diarrhea whose stool remained positive via polymerase chain reaction post-FMT. Fifty participants were enrolled (August 2017 to October 2019) among whom 15 had Crohn’s disease and 35 had ulcerative colitis (Table 1). The mean age of participants was 43 years (range 21–91) and the cohort was primarily female (58%). A total of 49 patients received treatment. One patient withdrew before treatment and was not replaced. Among the 49 participants, 1 patient was lost to follow-up after the week 1 visit and was treated as an FMT failure. Baseline CDI characteristics: 48% had 2 CDI episodes before entry, among whom 87.5% (21/24) were diagnosed via polymerase chain reaction at the qualifying episode; 38% had 3 confirmed episodes, among whom 78.9% (15/19) were diagnosed via polymerase chain reaction; and 14% had 4 prior CDI episodes among whom 71% were diagnosed via polymerase chain reaction (5/7).Table 1Enrolled Patient CharacteristicsVariableFemale, % (n)58 (29)Mean age43.0 (range 21–91)Crohn’s, % (n)30 (15)Colonic20.0 (3)Ileo-colonic66.7 (10)Unknown13.3 (2)UC, % (n)70 (35)Proctitis8.6 (3)Left-sided25.7 (9)Pancolitis60.0 (21)Unknown5.7 (2)Race, % (n)White94.0 (47)Black or African American4.0 (2)Asian2.0 (1)Mean baseline calprotectin (SD)1918.23 ± 2458.5Mean baseline CRP5.8 ± 10.1Mean daily BMs at baseline5.2 ± 4.0Mean baseline Bristol score5.5 ± 1.0Mean baseline partial Mayo score4.2 ± 2.1Mean baseline HBI score5.9 ± 3.5BM, bowel movement; CRP, C-reactive protein; HBI, Harvey-Bradshaw Index; UC, ulcerative colitis Open table in a new tab BM, bowel movement; CRP, C-reactive protein; HBI, Harvey-Bradshaw Index; UC, ulcerative colitis Overall, among 49 treated patients, 5 participants (10.2%) were FMT failures, 4 with confirmed diarrhea and a positive stool test via glutamate dehydrogenase and toxin enzyme immunoassay as well as the patient lost to follow-up. Among the failures, 3 patients had 3 prior CDI episodes, and 2 patients has 2 prior CDI episodes. Notably, the failures were all primary nonresponders with failure by week 1 post-FMT. All 4 underwent a second FMT from the same donor and achieved clinical cure through week 8. Two additional patients received a second FMT based on investigator discretion, but did not meet the criteria for FMT failure (toxin enzyme immunoassay and polymerase chain reaction negative, but ongoing symptoms). Importantly, 45 patients (91.8%) experienced C. difficile decolonization 1-week post-FMT and remained polymerase chain reaction negative. Overall the treatment was safe and well-tolerated. Two serious adverse events were reported, both were determined to not be treatment-related by the treating physician. Overall, these data suggest the efficacy and safety profile of FMT in IBD-CDI is more favorable than previously reported. In this cohort, only 5 patients (10.2%) experienced FMT failure, which is significantly lower than the previous failure rates reported in retrospective trials, with a mean ∼25%.6Newman K.M. et al.Gut Microbes. 2017; : 1-7Google Scholar This discordant result may be for several reasons. First, patients with IBD are prone to diarrhea and patients who remain colonized with ongoing polymerase chain reaction positive stools may be misdiagnosed as FMT failures. Second, we enrolled patients with their first recurrence (2 CDI episodes) in contrast to second recurrence (3 CDI episodes) or further, which is common clinical practice. Importantly, we found that most were decolonized post-FMT, which may have public health implications in avoiding spreading C. difficile. This study had several limitations. First, this trial was not controlled. We did not feel it was appropriate to compare clinical cure rates with standard of care alone given CDI guideline recommendations. In addition, a strong placebo effect seems unlikely in participants with prolonged and severe symptoms and an objective laboratory test used for the primary outcome. In addition, we estimated our sample size based on FMT failure rates from retrospective studies. We had a significantly lower rate of FMT failure, making subgroup analysis between failures and nonfailures difficult. We undertook the first prospective IBD-CDI trial to follow patients systematically post-FMT assessing for CDI eradication and decolonization. We were able to use a central laboratory and were able to perform robust testing on all stool samples for CDI (glutamate dehydrogenase, toxin enzyme immunoassay, and polymerase chain reaction). Overall, this study suggests FMT for the treatment of recurrent CDI in patients with IBD is safe and better tolerated than has been previously reported in retrospective studies, and results in a high rate of C. difficile decolonization. In addition, positioning FMT earlier in the treatment course for patients with IBD-CDI may improve FMT failure rates. The authors acknowledge OpenBiome for providing the FMT material used in this trial. In addition, the authors acknowledge Lynn Bry, Socheat Men, Mary Louise Delaney, and Andrea DuBois from the Brigham and Women’s Hospital pathology department and microbiology lab for coordinating the centralized stool testing efforts. The following were collaborators on this article: Jonathan Hurtado,1 Madeline Carrellas,1 Jenna Marcus,1 Julian R. Marchesi,2,3 Julie A.K. McDonald,2,4 Ylaine Gerardin,5 Michael Silverstein,5 Alexandros Pechlivanis,2,6 Grace F. Barker,2 Jesus Miguens Blanco,2 James L. Alexander,2 Kate I. Gallagher,2 Will Pettee,7 Emmalee Phelps,8 Sara Nemes,8 Sashidhar V. Sagi,8 Matthew Bohm8 1Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women’s Hospital, Boston, Massachusetts; 2Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK; 3School of Biosciences, Cardiff University, Cardiff, UK; 4MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK; 5Finch Therapeutics, Somerville, Massachusetts; 6Center for Interdisciplinary Research and Innovation, School of Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece; 7OpenBiome, Cambridge, Massachusetts; and 8Division of Gastroenterology, Indiana University School of Medicine, Indianapolis, Indiana. Jessica R. Allegretti, MD, MPH (Conceptualization: Lead; Funding acquisition: Lead; Investigation: Lead; Writing – original draft: Lead). Colleen R. Kelly, MD (Conceptualization: Supporting; Investigation: Supporting; Writing – review & editing: Supporting). Ari Grinspan, MD (Data curation: Supporting; Investigation: Supporting; Writing – review & editing: Equal). Benjamin H. Mullish, MD, PhD (Formal analysis: Equal; Methodology: Equal; Writing – review & editing: Equal). Zain Kassam, MD, MPH (Conceptualization: Supporting; Methodology: Equal; Writing – review & editing: Lead). Monika Fischer, MD, MSc (Conceptualization: Equal; Funding acquisition: Supporting; Investigation: Equal; Writing – review & editing: Equal).