Fecal Microbiota Transplantation (FMT) in Pediatrics Karastathi Christina June 2015 Cliniques Universitaires Saint Luc, UCL

Contents: Human Gut : Role & Symbiosis Dysbiosis & Associated Diseases FMT: a new challenge History of FMT Procedure of FMT: Donor selection , screening &preparing FMT Indications : Adults- Children Reactions of the public The future of FMT

Human Microbiota Microbiota: 100 trillion microbes- symbiosis Koala Birth Cohort Study -Effect of : Mode of Birth Gestational Age First Foods Hospitalisation Antibiotics Immunosuppression Coreen L et al, The human Microbiome &its potential importance to Pediatrics, Pediatrics 2012, 129;950

Human Microbiota: Who?

Firmicutes: Production IL-10, TGFb, IgA TH1 cell differentation Inhibition of Ag induced T cell activation Suppression of the TNF Bacteridetes: SCFAs 1) stimulation of G protein coupled receptors(Gpr 41)- gut epithelium 2) Promotion of Toll like receptor 2 immune responses 3) Induction of regulatory T cells Fecal samples from infants with NEC & patients with type 2 diabetes, compared to healthy controls (Koren O, Unravelling the effects of the environment & host genotype on the gut microbiome, Microbiol 2011;9(4):281)

M e c h a n i s m s

Therapeutic Challenge: Fecal Microbiota Transplantation

History : A 1,700-year-old method 4th century China- Li Shizhen: human fecal suspension by mouth « yellow soup » for food poisoning, severe diarrhea Fecal transplantation in veterinary medicine since the 17th century: Coprophagia Transfaunation- Hieronymus Fabricius « I have heard of animals which lose the capacity to ruminate, which ,when one puts their mouth a portion of materials of another healthy animal, they start chewing and recover former health »

History: Humans First decription of the procedure First description of the procedure First decription of the procedure

Donor Selection -1: 1st choice :Family donor but : Stool banks : not of the same environment /Donor of the environment , not of the family (Joossens M, Dysbiosis of the FMT in patients with Crohn’s Disease and their unaffected relatives) success rates for related and nonrelated donors: 89,5% vs 90,7% (Kassam et al, FMT for CDO, Am J Gastr 2013;108;500-508) Stool banks : OpenBiome- 2012, Massachussets General Hospital, University Hospital Atlanta….

Donor Selection -2 Age 18-65 IMC<30 Ref

Donor Screening

Mode of administration: phenotype & comorbidities of disease: Upper Gi tract: NGS tube / Nasojejunal tube Gastroscopy !!! Risk of inhalation !! One case of pneumoperitoneum& septic shock by NJT (Solari et al,Tempered enthousiasm for FMT, Clin Inf Dis, 2014) Lower Gi Tract: Left colon via enema/ colonoscopy Terminal ileum via colonoscopy !!! Colonoscopy Vs NGS/NJT : 91,4 Vs 82,3% (Kassam et al, FMT for CDO, Am J Gastr 2013;108;500-508)

Procedure -1: Donor preparation: Gentle Osmotic laxative the night before procedure. No potential allergenic foods to which recipient may be allergic for 5 days prior to the procedure. Instructions to notify the practitioner if any symptoms of infection (fevers, diarrhea, vomiting) which occur between screening and time of donation Recipient preparation: Bowel prep regardless of route of FMT. (! severity of the patient's illness! ) Loperamide (if giving FMT via enema or colonoscopy) is optional If FMT is to be delivered by NGT : PPI 12h before and the morning of the procedure

Procedure -2: FMT preparation A transplant within 6 hours Universal precautions: Those involved with mixing and/or handling the fecal transfusion material should wear a fluid-resistant gown, gloves, and mask with goggles or eye shield. Choice of diluents: may differ among practitioners :preservative-free normal saline for intravenous injection. Stool are homogenized in a conventional household blender, adding more diluent as necessary, until it reaches a liquid slurry consistency. Filter the material by number of methods (e.g., gauze pads, urine stone strainers). The finished stool slurry should be used immediately. The ideal volume for instillation has not been established.: smaller volumes (e.g., 25-50 mL) should be used for delivery from above; larger volumes (e.g., 250-500 mL) should be used for delivery from below.

Possible Indications of FMT: Recurrent CDI IBDs Chronic constipation Metabolic disorders Autoimmune disorders Neurodevelopmental disorders

Possible Indications (1) : CDI Traditional medical school fact: Clostridium difficile pseudomembranous colitis is a Clindamycin aftermath and highly treatable with metronidazole Increased need for ICU stay and prolonged antibiotic courses to clear infection, High colectomy rates (10%), High case mortality: 7500/year (10-fold increase since 1999) CDI in children : 2.2(1991)23.5 (2009) /100.000 Recurrence CDI: 12-24% Guidelines??? Poutanen SM et al. CMAJ. July 6,2004;171(1)

Duodenal infusion of donor feces after vancomycin for 4 days and bowel lavage therapy for 14 days Vancomycin therapy for 14 days plus bowel lavage on day 4-5

Possible Indications (2) : IBDs

4 children: 3 females ,10-17 y Severe UC (PUCAI) 50ml FMT via gastroscopy Donors not related 5infusions 1st week & one the 2nd week

Study: A phase I/II , Double Blinded, Placebo control, Single Center Ages : 5-30 y with active CD (colonoscopic & histology) Patients selected by strict criteria: 60 Ttment: Placebo/FMT (frozen), encapsulated, oral treatment for 8 w Plan: After 8w, opel label & option to stop or FMT treatment Follow up: 6months after the last dose of FMT Aims:  Safety of FMT  Clinical response  Maintenance therapy needed?

Belgian experience: CDI: UC: 2 y boy CDI recurrent Resolution persisting 1y after FMT ( UCL, Equipe de Gastroenterologie Ped) UC: 18months girl Early onset UC – failure cortico & Aza 7 infusions NGS & Colono 6months later : histology: no active disease (Vandeplas et al, FMT in a one-year –old girl with early onset colitis-caution advised, J Ped Gastro 2014)

Possible Other Indications (3) : Chronic Constipation: 45 patients - 1 colono & FMT enema infusions : 2 children Results: 40/45 clinical response ( bloating, defecation, abdominal pain) 18/30 normal defecation without laatove 9-months later (Andrews et al, Bacteriotherapy for chronic constipation- long term follow –up,Gastroenterology 1995;108;A563) Multiple sclerosis: 3 wheell chair patients , treated with FMT for constipation : 3 walked with support 2 regained autonomous urinary function No pediatric data (Borody et al, FMT in MS, Am J Gastroente 2011, 106, S352) Obesity IPT : 1 case of IPT in UC: amélioration of PLT (Borody et al, Reversal IPT with FMT , Am J Gastroente 2011, 106, S352)

Future of FMT Definition – THE debate Synthetic Microbiota ?? «  Re POOPulate » Rebiotix -2013- FDA – phase 3 ongoing (Petrof EO, RePOOPulating the gut, Microbiome 2013) Pills – Clin Trials ongoing (NCT01914731: FMT for relapsing CDI in adults & children using a frozen encapsulated inocolum)

Complementary References: Ciarán P. Kelly, M.D., and J. Thomas LaMont, M.D. Clostridium difficile — More Difficult Than Ever ,N Engl J Med 2008;359:1932-40. George Russell, MD, et al ,Fecal Bacteriotherapy for Relapsing Clostridium difficile Infection in a Child: A Proposed Treatment Protocol ,Pediatrics 2010;126: e239–e242 Mathew J.et al,High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria, Gut Microbes 4:2, 125–135; March/April 2013 Vrieze A, Transfer of Intestinal Microbiota From Lean Donors Increases Insulin Sensitivity in Individuals With Metabolic Syndrome, Gastroenterology 2012;143:913–916 Loek Smits et al, Therapeutic Potential of Fecal Microbiota Transplantation, Gastroenterology 2013;145:946–953 Clostridium difficile Infection in Infants and Children , oi:10.1542/peds.2012-2992 Richard Kellermayer ,Prospects and challenges for intestinal microbiome therapy in pediatric gastrointestinal disorders, World J Gastrointest Pathophysiol 2013 November 15; 4(4): 91-93 Ruben J. Colman1, David T. Rubin, Fecal microbiota transplantation as therapy for inflammatory bowel disease: A systematic review and meta-analysis , Journal of Crohn's and Colitis (2014) 8, 1569–1581 Brandt, L. Intestinal Microbiota and the Role of Fecal Microbiota Transplant in the Treatment of C. difficile Infection. AJG. 2013 Bakken, J. Treating Clostridium difficile Infection with Fecal Microbiota Transplantation (the Fecal Microbiota Transplantation Workgroup). CGH. 2011 Brandt, L. An overview of fecal microbiota transplantation. Gastrointest. Endosc. 2013

Thank you for your attention !!!