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TITLEFive years of fecal microbiota transplantation - an update of the Israeli experienceAUTHOR(s)Sharon A Greenberg, Ilan Youngster, Nathaniel A Cohen, Dan M Livovsky, Jacob Strahilevitz, Eran Israeli, Ehud Melzer, Kalman Paz, Naomi Fliss-Isakov and Nitsan MaharshakCITATIONGreenberg SA, Youngster I, Cohen NA, Livovsky DM, Strahilevitz J, Israeli E, Melzer E, Paz K, Fliss-Isakov N, Maharshak N. Five years of fecal microbiota transplantation - an update of the Israeli experience. World J Gastroenterol 2018; 24(47): 5403-5414URLhttps://www.wjgnet.com/1007-9327/full/v24/i47/5403.htmDOIhttps://dx.doi.org/10.3748/wjg.v24.i47.5403OPEN ACCESSThis is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/CORE TIPFecal microbiota transplantation (FMT) emerged as a promising treatment for Clostridium difficile infection (CDI). Our aim was to summarize the national Israeli experience in FMT. One-hundred and eleven patients with CDI underwent FMT, 37 (35%) of which via oral capsules and 50 (45%) via colonoscopy. The overall success rate was 87.4%, with no difference between administration routes. Success was independently related to mild disease and an ambulatory setting. One-third of the patients were younger than 60 years. 14 of which (40%) also suffered from inflammatory bowel disease. FMT is an effective treatment for recurrent CDI. FMT via capsules was shown to be a successful alternative to endoscopy.KEY WORDSClostridium difficile infection, Capsules, Israel, and Fecal microbiota transplantationCOPYRIGHT The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.NAME OF JOURNALWorld Journal of GastroenterologyISSN1007-9327PUBLISHERBaishideng Publishing Group Inc, 7901 Stoneridge Drive, Suite 501, Pleasanton, CA 94588, USAWEBSITEHttp://www.wjgnet.comName of journal: World Journal of Gastroenterology
Manuscript NO: 40145
Manuscript type: ORIGINAL ARTICLE
Retrospective Cohort Study
Five years of fecal microbiota transplantation an update of the Israeli experience
Greenberg SA et al. FMT in Israel
Sharon A Greenberg, Ilan Youngster, Nathaniel A Cohen, Dan M Livovsky, Jacob Strahilevitz, Eran Israeli, Ehud Melzer, Kalman Paz, Naomi Fliss-Isakov, Nitsan Maharshak
Sharon A Greenberg, Nathaniel A Cohen, Naomi Fliss-Isakov, Nitsan Maharshak, Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6423906, Israel
Nitsan Maharshak, Bacteriotherapy Clinic, Tel Aviv Sourasky Medical Center, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6423906, Israel
Ilan Youngster, Assaf Harofe Medical Center, Zerifin 70300, Israel
Dan M Livovsky, Kalman Paz, Digestive Diseases Institute, Shaare Zedek Medical Center, Jerusalem 91031, Israel
Jacob Strahilevitz, Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University, Jerusalem 91120, Israel
Eran Israeli, Department of Gastroenterology and Liver Diseases, Hadassah-Hebrew University, Jerusalem 91120, Israel
Ehud Melzer, Gastrointestinal and Liver Diseases Institute, Kaplan Medical Center, Rehovot 76100, Israel
ORCID number: Sharon A Greenberg (0000-0001-7346-1746); Ilan Youngster (0000-0001-5233-1213); Nathaniel A Cohen (0000-0002-3997-4174); Dan M Livovsky (0000-0002-8212-9638); Jacob Strahilevitz (0000-0002-9192-7164); Eran Israeli (0000-0001-8679-4363); Ehud Melzer (0000-0002-3021-6684); Kalman Paz (0000-0001-5357-1593); Naomi Fliss-Isakov (0000-0003-4849-0291); Nitsan Maharshak (0000-0002-9324-0024).
Author contributions: All authors helped to perform the research; Greenberg SA contributed to collecting data, data analysis and writing the manuscript; Youngster I, Livovsky DM, Melzer E and Paz K contributed to performing procedures and data collection; Cohen NA contributed to data collection and writing the manuscript; Strahilevitz J contributed to data collection; Israeli E contributed to performing procedures; Fliss-Isakov N contributed to data analysis; Maharshak N contributed to drafting conception and design, performing procedures, writing the manuscript and data collection.
Institutional review board statement: This study was approved by the institutional review board of Tel Aviv Sourasky Medical Center.
Informed consent statement: Informed consent was obtained from the patients.
Conflict-of-interest statement: The authors have declared no conflicts of interest.
Data sharing statement: No additional data are available.
STROBE statement: The authors have checked the manuscript according to STROBE checklist.
Open-Access: This is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: HYPERLINK "http://creativecommons.org/licenses/by-nc/4.0/" http://creativecommons.org/licenses/by-nc/4.0/
Manuscriptsource: Unsolicitedmanuscript
Corresponding author to: Nitsan Maharshak, MD, Chief Doctor, Director, Doctor, Senior Lecturer, Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, 6 Weizmann St., Tel Aviv 6423906, Israel. HYPERLINK "mailto:nitsanm@tlvmc.gov.il" nitsanm@tlvmc.gov.il
Telephone: +972-3-6947305
Fax: +972-3-6974184
Received: August 10, 2018
Peer-review started: August 10, 2018
First decision: October 24, 2018
Revised: November 26, 2018
Accepted: December 6, 2018
Article in press:
Published online:
Abstract
AIM
To evaluate and describe the efficacy of fecal microbiota transplantation (FMT) for Clostridium difficile infection (CDI) in a national Israeli cohort.
METHODS
All patients who received FMT for recurrent (recurrence within 8 wk of the previous treatment) or refractory CDI from 2013 through 2017 in all the five medical centers in Israel currently performing FMT were included. Stool donors were screened according to the Israeli Ministry of Health guidelines. Clinical and laboratory data of patients were collected from patients medical files, and they included indications for FMT, risk factors for CDI and disease severity. Primary outcome was FMT success (at least 2 mo free of CDI-related diarrhea post-FMT). Secondary outcomes included initial response to FMT (cessation of diarrhea within 7 d) and recurrence at 6 mo.
RESULTS
There were 111 FMTs for CDI, with a median age of 70 years [interquartile range (IQR): 53-82], and 42% (47) males. Fifty patients (45%) were treated via the lower gastrointestinal (LGI, represented only by colonoscopy) route, 37 (33%) via capsules, and 24 (22%) via the upper gastrointestinal (UGI) route. The overall success rate was 87.4% (97 patients), with no significant difference between routes of administration (P = 0.338). In the univariant analysis, FMT success correlated with milder disease (P = 0.01), ambulatory setting (P < 0.05) and lower Charlson comorbidity score (P < 0.05). In the multivariant analysis, only severe CDI [odd ratio (OR) = 0.14, P < 0.05] and inpatient FMT (OR = 0.19, P < 0.05) were each independently inversely related to FMT success. There were 35 (32%) patients younger than 60 years of age, and 14 (40%) of them had a background of inflammatory bowel disease.
CONCLUSION
FMT is a safe and effective treatment for CDI, with capsules emerging as a successful and well-tolerated route. Severe CDI is less likely to respond to FMT.
Key words: Fecal microbiota transplantation; Clostridium difficile infection; Capsules; Israel
The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
Core tip: Fecal microbiota transplantation (FMT) emerged as a promising treatment for Clostridium difficile infection (CDI). Our aim was to summarize the national Israeli experience in FMT. One-hundred and eleven patients with CDI underwent FMT, 37 (35%) of which via oral capsules and 50 (45%) via colonoscopy. The overall success rate was 87.4%, with no difference between administration routes. Success was independently related to mild disease and an ambulatory setting. One-third of the patients were younger than 60 years. Fourteen patients (40%) also suffered from inflammatory bowel disease. FMT is an effective treatment for recurrent CDI. FMT via capsules was shown to be a successful alternative to endoscopy.
Greenberg SA, Youngster I, Cohen NA, Livovsky DM, Strahilevitz J, Israeli E, Melzer E, Paz K, Fliss-Isakov N, Maharshak N. Five years of fecal microbiota transplantation an update of the Israeli experience. World J Gastroenterol 2018; In press
Introduction
Background
The incidence of Clostridium difficile infection (CDI) is rising in parallel to the increased use of broad-spectrum antibiotics, with more than 500000 cases and 29000 related deaths annually in the United States alone ADDIN EN.CITE Lessa201577717Lessa, Fernanda CMu, YiBamberg, Wendy MBeldavs, Zintars GDumyati, Ghinwa KDunn, John RFarley, Monica MHolzbauer, Stacy MMeek, James IPhipps, Erin CBurden of Clostridium difficile infection in the United StatesNew England Journal of MedicineNew England Journal of Medicine825-834372920150028-47932571416010.1056/NEJMoa1408913[1]. The resistance to current treatment with metronidazole and vancomycin is also increasing, with recurrence rates of up to 20% after the first episode and 40%-65% after the second ADDIN EN.CITE ADDIN EN.CITE.DATA [2-4]. Fecal microbiota transplantation (FMT) has cure rates ranging between 85%-95%, and it has emerged as being a safe and promising treatment option that is widely accepted for recurrences and refractory or severe cases of CDI ADDIN EN.CITE ADDIN EN.CITE.DATA [5-10]. FMT is considered the most effective treatment for recurrent CDI ADDIN EN.CITE ADDIN EN.CITE.DATA [11,12] in both young and elderly patient populations ADDIN EN.CITE Friedman-Korn201812121217Friedman-Korn, TaliLivovsky, Dan MeirMaharshak, NitsanCohen, Nathaniel AvivPaz, KalmanShitrit, Ariella Bar-GilGoldin, EranKoslowsky, BenjaminFecal Transplantation for Treatment of Clostridium Difficile Infection in Elderly and Debilitated PatientsDigestive diseases and sciencesDigestive diseases and sciences1-620180163-211629134299 10.1007/s10620-017-4833-2[13]. FMT it is also a promising potential treatment for conditions other than CDI, such as inflammatory bowel diseases (IBD), irritable bowel syndrome, neuropsychiatric conditions, obesity, insulin resistance, and autoimmune diseases ADDIN EN.CITE Cohen201715151517Cohen, Nathaniel AvivMaharshak, NitsanNovel indications for fecal microbial transplantation: update and review of the literatureDigestive diseases and sciencesDigestive diseases and sciences1131-114562520170163-211628315032 10.1007/s10620-017-4535-9Brandt201316161617Brandt, Lawrence JAroniadis, Olga CAn overview of fecal microbiota transplantation: techniques, indications, and outcomesGastrointestinal endoscopyGastrointestinal endoscopy240-24978220130016-510723642791 10.1016/j.gie.2013.03.1329[14,15].
Current techniques for FMT administration vary considerably between institutions and can be performed via a nasogastric/nasojejunal tube, gastroscopy, oral capsules, enema, sigmoidoscopy or colonoscopy ADDIN EN.CITE ADDIN EN.CITE.DATA [6,15-18]. The procedure is considered safe and is mostly free of severe adverse events, although peri-procedural transient gastrointestinal (GI) symptoms may develop in some patients. The mortality cited in previous studies was attributed to the patients pre-morbid conditions, and generally occurred in elderly and critically ill patients ADDIN EN.CITE ADDIN EN.CITE.DATA [5,15-17,19].
Objective
We had earlier described the initial Israeli experience of 22 patients that were treated with FMT for CDI and experienced an overall cure rate above 89% ADDIN EN.CITE Cohen201644417Cohen, Nathaniel ALivovsky, Dan MYaakobovitch, ShirBen, M YehoyadaBen, R AmiAdler, AmosGuzner-Gur, HananGoldin, EranSanto, Moshe EHalpern, ZamirA Retrospective Comparison of Fecal Microbial Transplantation Methods for Recurrent Clostridium Difficile InfectionThe Israel Medical Association journal: IMAJThe Israel Medical Association journal: IMAJ594-599181020161565-108828471618https://www.ncbi.nlm.nih.gov/pubmed/28471618[20]. However, during the past 5 years, the procedure has been performed in additional Israeli centers that processed feces from a wide range of donors in a significantly larger number of patients with different disease conditions, and using all acceptable transplantation routes. Therefore, our aim was to examine whether FMT continued to demonstrate efficacy despite this wider range of donors and patients, to investigate FMT-dependent variables, and to examine the efficacy of individual FMT routes.
MATERIALS AND METHODS
Study design and settings
This multi-center retrospective study included all the patients who were treated with FMT for CDI in Israel between January 2013 and October 2017. The participating medical centers were the Tel Aviv Medical Center (TLVMC), Tel Aviv; Shaare Zedek Medical Center (SZMC) and Hadassah Medical Center (HMC), Jerusalem; Assaf Harofe Medical Center (AHMC), Zerifin; and Kaplan Medical Center (KMC), Rehovot. All the patients or their legal surrogates provided written informed consent. The study was approved by the ethics committees of each medical center. Patients were followed routinely at 48 h, 7 d, 2 mo, and 6 mo after the procedure for the assessment of side effects and treatment outcome.
Following the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) practice guidelines ADDIN EN.CITE Cohen201010101017Cohen, Stuart HGerding, Dale NJohnson, StuartKelly, Ciaran PLoo, Vivian GMcDonald, L CliffordPepin, JacquesWilcox, Mark HClinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA)Infection Control & Hospital EpidemiologyInfection Control & Hospital Epidemiology431-455315