SOCIETY PAPER Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection and Other Conditions in Children: A Joint Position Paper From the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition 01/02/2019 on BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3IJrtBKuSsQVsKRVaZGM1l4E1BpMVhD9eXUWmKDp4zSM= by https://journals.lww.com/jpgn from Downloaded Downloaded ÃZev H. Davidovics, ySonia Michail, zMaribeth R. Nicholson, §Larry K. Kociolek, jjNikhil Pai, ô # Ãà yy zz from Richard Hansen, Tobias Schwerd, Aldo Maspons, Raanan Shamir, Hania Szajewska, §§ jjjj ôô## ÃÃà yyy https://journals.lww.com/jpgn Nikhil Thapar, Tim de Meij, Alexis Mosca, Yvan Vandenplas, Stacy A. Kahn, and zzzRichard Kellermayer, and the FMT Special Interest Group of the North American Society of Pediatric Gastroenterology Hepatology, Nutrition, the European Society for Pediatric Gastroenterology Hepatology, Nutrition by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3IJrtBKuSsQVsKRVaZGM1l4E1BpMVhD9eXUWmKDp4zSM= ABSTRACT ey observations that the gut microbiome may play a role in Fecal microbiota transplantation (FMT) is becoming part of the treatment health and disease provide a strong basis for developing algorithms against recurrent Clostridium difficile infection (rCDI) both in strategiesK aimed at gut microbiota normalization. Among others, adult and pediatric gastroenterology practice. With our increasing recogni- these strategies include fecal microbiota transplantation (FMT). tion of the critical role the microbiome plays in human health and disease, Despite its increasing application, agreement as to how to define FMT is also being considered as a potential therapy for other disorders, FMT legally or scientifically is lacking. In 2017, a group of experts including inflammatory bowel disease (Crohn disease, ulcerative colitis), proposed a definition for microbiota transplantation, which, in graft versus host disease, neuropsychiatric diseases, and metabolic syn- addition to fecal, includes vaginal, skin, oral, and nasal microbiota drome. Controlled trials with FMT for rCDI have not been performed in transplantation. Based on considerations that are beyond the scope children, and numerous clinical and regulatory considerations have to be of this document, microbiota transplantation was defined as ‘‘a considered when using this untraditional therapy. This report is intended to transfer of biologic material containing a minimally manipulated provide guidance for FMT in the treatment of rCDI in pediatric patients. community of microorganisms from a human donor to a human Key Words: child, Clostridium difficile, fecal, fecal transplantation, recipient (including autologous use) with the intent of affecting the microbiome, microbiota, pediatric microbiota of the recipient’’ (1). In the case of FMT, fecal material is used. Throughout this manuscript, the term FMT is used. Other (JPGN 2019;68: 130–143) Received April 4, 2018; accepted October 3, 2018. From the ÃDepartment of Pediatric Gastroenterology, Digestive Diseases, Hospital (APHP), Paris, France, the ÃÃÃKidZ Health Castle, Universitair Hepatology, and Nutrition, Connecticut Children’s Medical Center, Ziekenuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium, the University of Connecticut School of Medicine, Farmington, CT, the yyyDivision of Gastroetenterology and Nutrition, Inflammatory Bowel yChildren’s Hospital Los Angeles, University of Southern California, Los Disease Center, Boston Children’s Hospital, Harvard Medical School, Angeles, CA, the zD. Brent Polk Division of Gastroenterology, Hepatol- Boston, MA, and the zzzSection of Pediatric Gastroenterology and ogy, and Nutrition, Vanderbilt University Medical Center, Nashville, TN, Nutrition, Texas Children’s Hospital, Baylor College of Medicine, Chil- the §Ann and Robert H. Lurie Children’s Hospital of Chicago, North- dren’s Nutrition and Research Center, Houston, TX. on western University Feinberg School of Medicine, Chicago, IL, the Address correspondence and reprint requests to Richard Kellermayer, MD, 01/02/2019 jjDivision of Pediatric Gastroenterology and Nutrition, McMaster Chil- PhD, Section of Pediatric Gastroenterology, Hepatology and Nutrition, dren’s Hospital, McMaster University, Hamilton, Ontario, Canada, the Baylor College of Medicine, 6621 Fannin St, CC1010.00, Houston, TX ôDepartment of Paediatric Gastroenterology, Royal Hospital for Chil- 77030-2399 (e-mail: [email protected]). dren, Glasgow, Scotland, the #Department of Pediatrics, Dr. von Hauner This article has been developed as a Journal CME Activity by NASPGHAN. Children’s Hospital, University Hospital, LMU Munich, Munich, Visit http://www.naspghan.org/content/59/en/Continuing-Medical-Educa- Germany, the ÃÃVeMiDoc, LLC, El Paso, TX, the yyInstitute for Gastro- tion-CME to view instructions, documentation, and the complete necessary enterology, Nutrition and Liver Disease, Schneider Children’s Medical steps to receive CME credit for reading this article. Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, Supplemental digital content is available for this article. Direct URL citations the zzDepartment of Paediatrics, The Medical University of Warsaw, appear in the printed text, and links to the digital files are provided in the Warsaw, Poland, the §§Department of Paediatric Gastroenterology, Great HTML text of this article on the journal’s Web site (www.jpgn.org). Ormond Street Hospital NHS Foundation Trust, London, United Kingdom, The authors report no conflicts of interest. the jjjjDepartment of Paediatric Gastroenterology, VU University Copyright # 2018 by European Society for Pediatric Gastroenterology, Medical Center, Amsterdam, The Netherlands, the ôôDivision of Hepatology, and Nutrition and North American Society for Pediatric Pediatric Gastroenterology and Nutrition, Robert Debre´ Hospital Gastroenterology, Hepatology, and Nutrition (APHP), the ##French Group of Fecal Transplantation, St Antoine DOI: 10.1097/MPG.0000000000002205 130 JPGN Volume 68, Number 1, January 2019 Copyright © ESPGHAN and NASPGHAN. All rights reserved. JPGN Volume 68, Number 1, January 2019 FMT for rCDI and Other Conditions terms such as ‘‘fecal microbiota transplant,’’ ‘‘stool transplantation and 2006 (7). More recent studies from Europe, however, showed or transfer,’’ ‘‘microbial reconstitution therapy (MRT),’’ or ‘‘intes- stable incidence rates of pediatric CDI in hospitalized patients over tinal microbiota transplant’’ (IMT) are, however, used interchange- 6 years (8). Although classically identified as a healthcare-associ- ably throughout the literature. ated infection, the rate of community-associated CDI has also FMT is increasingly being used in the management of increased in pediatric patients with 70% to 80% of pediatric cases recurrent Clostridium difficile infection (rCDI) in adults, with cure of CDI identified as community associated (9,10). In fact, in rates approaching 90% (2). Although recurrent or severe CDI is contrast to adults who have a predominance of healthcare-associ- increasingly problematic in children, data on the use of FMT in ated infections, community-associated CDI is 3-fold more common children are scarce. We also recognize that the nomenclature for than healthcare-associated CDI in children (11). C difficile is in the process of being modified to Clostridioides difficile (3) but we use the old name of the bacterium in this work because it is still its designation in Bergey’s Manual of Systematic Risk Factors for Pediatric C difficile Infection Bacteriology. and C difficile Infection in Special Populations This position paper was developed through the collaborative The risk factors for pediatric rCDI are slightly different than efforts of NASPGHAN and ESPGHAN. The NASPGHAN Clinical in adults and include prior antibiotic use, recent surgery, malig- Care and Quality Committee approved the outline of this manu- nancy, solid organ transplantation, presence of a tracheostomy or script, and the NASPGHAN and ESPGHAN Society Councils gastrostomy tube, acid suppression, and concomitant use of non- approved the list of authors. In addition to pediatric gastroenterol- CDI antibiotics during CDI treatment (12–16). In a large pediatric ogy and infectious disease experts, it included members with an database including more than 4000 pediatric patients with a diag- interest in gut microbiota and its applications. The purpose of this nosis of CDI, at least 2 of 3 had 1 complex chronic condition (17). position paper is to summarize current evidence and challenges Adults and children with inflammatory bowel disease (IBD), for related to the management of pediatric CDI with a focus on FMT as example, have rates of CDI that far exceed those seen in the general a treatment modality. To identify relevant data, searches of population (18,19). A statewide database of hospital discharges PubMed/MEDLINE databases were performed using terms such from 2009 to 2012 demonstrated a prevalence of CDI in children as C difficile, children, pediatric, recurrent fecal transplant, refrac- with IBD to be 46 per 1000 versus 4.1 per 1000 in children without tory fecal transplant, microbiota, microbiome, and microbial. A IBD (P < 0.001) (20). In addition, 25% of pediatric CDI cases occur further aim of this report is to summarize current evidence on FMT in children with cancer (21). Cancer has also been demonstrated