Michael Docktor, MD Boston Children’s Hospital August 16, 2014

Michael Docktor, MD Boston Children’s Hospital August 16, 2014
FMT in Pediatric IBD Michael Docktor, MD Boston Children’s Hospital August 16, 2014

Disclosures I have no relevant disclosures or financial obligations

Outline Brief background Anecdotal experience at Boston Children’s
Oh and by the way, they have IBD Pediatric FMT in ulcerative colitis Pediatric FMT in Crohn’s disease Future directions

Factors affecting the stability and complexity of the gut microbiome in health and disease. Key characteristics of the microbiome, including stability, resilience, and complexity, are influenced over time from infancy to adulthood and into old age. In the healthy gut, these characteristics contribute to important physiological processes such as protection against pathogens, training of the immune system, and digestion of food to supply energy and nutrients including vitamins and SCFAs. Many factors are indicated to affect the microbiome throughout microbiome development and even established assembly, including genetics, diet, and medication, among others (marked in the gray boxes at the top of the figure). Some of these factors can introduce perturbations affecting the complexity and stability of the microbiome, potentially introducing microbial dysbiosis. Features of an imbalanced microbiome include, for example, an increase in gram-negative bacteria linked to an environment of oxidative stress and inflammation and metabolite production. Kostic, et al. Gastro. 2014; 146(5):

Our experience: FMT for IBD “Innovative Therapy”
7 patients with recalcitrant IBD Ages yrs. (average 15 yrs.), 3 M / 4 F 4 UC, 2 CD, 1 IC Related donor FMT via colonoscopy and f/u home enemas All seven were recommended escalation of therapy 85% (6/7) recommended Tacrolimus +/- surgical colectomy All 6 were steroid dependent at time of FMT 15% (1/7) recommended addition of a biologic Under the guidance of the BCH Innovative Therapy Toolkit, we have now completed seven, related-donor FMTs in pediatric patients with IBD at Boston Children’s Hospital. Our patients ranged in age from years (average 15 years) and included 3 males and 4 females. Diagnoses included 5 UC, 1 CD of the colon and 1 patient with indeterminate colitis. All patients were recalcitrant to standard medical therapy and were recommended an escalation of their therapy, (6/7) surgical colectomy, (1/7) the addition of a biologic. Six out of seven patients were on either an immunomodulator, biologic or both. These same 6 patients were all steroid dependent at the time of FMT. Four of six patients have since discontinued steroids entirely, (2/6) are actively weaning (<50% of initial dose) and all have remained clinically stable. All patients (7/7) report both subjective and objective improvement (as calculated by PUCAI), some as long as 15 months post-FMT. There were no adverse events of any type reported. Docktor M, et al. Unpublished data

Our experience: FMT for IBD “Innovative Therapy”
85% (6/7) stabilized and were weaned from steroids 57% (4/7) improved but remained stable on previous therapy 28% (2/7) discontinued steroids, biologic and 6-MP 1 in deep clinical remission on 5-ASA & Vancomycin 2+ years 1 with mild activity, de-escalated to 5-ASA 15% (1/7) continued to slowly worsen, Tac  surgical colectomy 9 months later No adverse events reported, all procedures and f/u well tolerated up to 2.5 years out. Under the guidance of the BCH Innovative Therapy Toolkit, we have now completed seven, related-donor FMTs in pediatric patients with IBD at Boston Children’s Hospital. Our patients ranged in age from years (average 15 years) and included 3 males and 4 females. Diagnoses included 5 UC, 1 CD of the colon and 1 patient with indeterminate colitis. All patients were recalcitrant to standard medical therapy and were recommended an escalation of their therapy, (6/7) surgical colectomy, (1/7) the addition of a biologic. Six out of seven patients were on either an immunomodulator, biologic or both. These same 6 patients were all steroid dependent at the time of FMT. Four of six patients have since discontinued steroids entirely, (2/6) are actively weaning (<50% of initial dose) and all have remained clinically stable. All patients (7/7) report both subjective and objective improvement (as calculated by PUCAI), some as long as 15 months post-FMT. There were no adverse events of any type reported. Docktor M, et al. Unpublished data

Microbial analysis of FMT
Docktor M, et al. Unpublished data

10 children with RCDI (1-19 years)
Open label single, related FMT via NG tube (2) or colonoscope (8) 3/10 patients had concomitant IBD Overall success rate 90% for curing RCDI 7/7 (100%) among non-IBD patients 2/3 (66%) among IBD patients Ten children at our institution received single-infusion fecal microbiome transplant (FMT) using healthy, related screened donor stool to treat recurrent Clostridium difficile infection (RCDI) via nasogastric tube (2 patients) or colonoscopic delivery. Nine of the 10 (90%) children had resolution of their symptoms after a single-infusion FMT with follow-up of 1 month to 4 years. No concerning related adverse events were recognized during short- or long- term follow-up. Three of these children had concomitant inflammatory bowel disease and 2 of these 3 (66%) patients cleared RCDI with no clinical change in their underlying inflammatory bowel disease clinical activity as assessed by Physician’s Global Assessment. All of the patients who had clinical improvement of gastrointestinal symptoms of RCDI while treated with antibiotics had lasting return of baseline health after FMT. Russell GH, et al. JPGN. 2014; 58(5):

Russell GH, et al. JPGN. 2014; 58(5): 588-592.
Ten children at our institution received single-infusion fecal microbiome transplant (FMT) using healthy, related screened donor stool to treat recurrent Clostridium difficile infection (RCDI) via nasogastric tube (2 patients) or colonoscopic delivery. Nine of the 10 (90%) children had resolution of their symptoms after a single-infusion FMT with follow-up of 1 month to 4 years. No concerning related adverse events were recognized during short- or long- term follow-up. Three of these children had concomitant inflammatory bowel disease and 2 of these 3 (66%) patients cleared RCDI with no clinical change in their underlying inflammatory bowel disease clinical activity as assessed by Physician’s Global Assessment. All of the patients who had clinical improvement of gastrointestinal symptoms of RCDI while treated with antibiotics had lasting return of baseline health after FMT. Russell GH, et al. JPGN. 2014; 58(5):

Redeveloped CDI after re-admission 2 months
11 y/o M with CD Counted as failure Redeveloped CDI after re-admission 2 months Russell GH, et al. JPGN. 2014; 58(5):

Admitted for severe, acute colitis
19 y/o F with UC Admitted for severe, acute colitis 100% better for 5 days then severe bloody diarrhea Never redeveloped CDI Potential fulminant UC flare secondary to FMT? Russell GH, et al. JPGN. 2014; 58(5):

Fecal Microbiota Transplantation in Children with Recurrent Clostridium difficile Infection Anne Pierog, MD, Ali Mencin, MD, and Norelle Rizkalla Reilly, MD Columbia University Medical Center, Division of Pediatric Gastroenterology, Hepatology and Nutrition 6 patients with RCDI Ages 4-21 yrs., 4 M / 2 F 1 CD, 1 IC Related donor FMT via colonoscopy 100% cure rate for C. diff 12 y/o M with CD Initial clinical 1 week Acute 2 weeks post FMT Clinical “remission” with optimized 12 weeks Follow up: both IBD patients cured of CDI, required escalation of IBD therapy Patient 4 had visual evidence of uncontrolled Crohn’s disease (ulcerations, purulence, diseased ileocecal valve) at the time of FMT. While reporting diminished diarrhea and abdominal pain one week post-FMT, he presented 2 weeks following his procedure with an acute abdomen and was diagnosed with appendicitis by CT scan. After appendectomy, pathologic examination showed acute appendicitis with multifocal granulomas. His IBD therapy was subsequently optimized, his C. difficile toxin remained negative after 9 weeks post-FMT, his weight percentiles increased from the 35th to the 52nd percentile, and he had no reported gastrointestinal symptoms at 12 weeks post-FMT. Patient 2 went on to adult GI at Columbia and last I looked before fellowship graduation, she had remained free of CDI. I believe she was started on biologics due to poor disease control by our adult colleague and this was a step up. Patient 4 also remained C.diff free as of June 30 but his Crohn's had been very hard to treat. After the FMT, he went on a steroid course and his parents were very nervous about doing double therapy- his primary GI had proposed MTX plus Humira. They had gone for a second opinion at CHOP and finally agreed to that right before I left. Feel free to call me directly if you have any other questions. My cell is And I can get you more current information from the folks at Columbia if you need it. Pierog A, et al. Peds Infec Dis Journ. Accepted for publication.

FMT for PEDIATRIC Ulcerative Colitis

Safety and tolerability of FMT via enema in 9 children w/ UC
7 – 21 years, mild-moderate disease (PUCAI 15-65) Daily enemas x 5 days 78% (7/9) showed clinical response within 1 week 67% (6/9) maintained clinical response at 1 month 33% (3/9) achieved clinical remission at 1 week FMT via enema was feasible and tolerable in children with limited side effects. Ten children, 7 to 21 years of age, with mild-to-moderate UC (pediatric UC activity index [PUCAI] between 15 and 65) received freshly prepared fecal enemas daily for 5 days. Data on tolerability, adverse events, and disease activity were collected during FMT and weekly for 4 weeks after FMT. Clinical response was defined as decrease in PUCAI by >15, and decrease in PUCAI to <10 was considered clinical remission. RESULTS: No serious adverse events were noted. Mild (cramping, fullness, flatulence, bloating, diarrhea, and blood in stool) to moderate (fever) adverse events were self-limiting. One subject could not retain fecal enemas. Average tolerated enema volume by remaining 9 subjects was 165 mL/day. After FMT, 7 of the 9 (78%) subjects showed clinical response within 1 week, 6 of the 9 (67%) subjects maintained clinical response at 1 month, and 3 of the 9 (33%) subjects achieved clinical remission at 1 week after FMT. Median PUCAI significantly improved after FMT (P = 0.03) compared with the baseline. CONCLUSIONS: Fecal enemas were feasible and tolerated by children with UC. Adverse events were acceptable, self-limiting, and manageable by subjects. FMT indicated efficacy in the treatment of UC. Kunde and colleagues recently published their safety and tolerability study of FMT enemas in children with UC showing it was safe and well tolerated.(9) Seven of nine (78%) of subjects showed clinical response within 1 week, six out of the nine (67%) of subjects maintained clinical response at 1 month, and three out of the nine (33%) subjects achieved clinical remission at 1 week after FMT. Kunde S, et al. JPGN 2013 Jun;56(6):

Kunde S, et al. JPGN 2013 Jun;56(6):597-601
FIGURE 2 . Clinical response to fecal microbial transplantation (FMT). Fecal enemas were provided in the second week of the study. Clinical disease activity was determined using pediatric ulcerative colitis activity index. Changes in disease activity can be seen after FMT (weeks 3-6). Subject no. 7 was not included in this….. AB Background and Objective: Colonic dysbiosis contributes to the development of colonic inflammation in ulcerative colitis (UC). Fecal microbial transplantation (FMT) is being proposed as a novel treatment for UC because it can eliminate dysbiosis; however, no prospective data exist. We initiated a pilot study to evaluate feasibility and safety of FMT in children with UC. Methods: Ten children, 7 to 21 years of age, with mild-to-moderate UC (pediatric UC activity index [PUCAI] between 15 and 65) received freshly prepared fecal enemas daily for 5 days. Data on tolerability, adverse events, and disease activity were collected during FMT and weekly for 4 weeks after FMT. Clinical response was defined as decrease in PUCAI by >15, and decrease in PUCAI to <10 was considered clinical remission. Results: No serious adverse events were noted. Mild (cramping, fullness, flatulence, bloating, diarrhea, and blood in stool) to moderate (fever) adverse events were self-limiting. One subject could not retain fecal enemas. Average tolerated enema volume by remaining 9 subjects was 165 mL/day. After FMT, 7 of the 9 (78%) subjects showed clinical response within 1 week, 6 of the 9 (67%) subjects maintained clinical response at 1 month, and 3 of the 9 (33%) subjects achieved clinical remission at 1 week after FMT. Median PUCAI significantly improved after FMT (P = 0.03) compared with the baseline. Conclusions: Fecal enemas were feasible and tolerated by children with UC. Adverse events were acceptable, self-limiting, and manageable by subjects. FMT indicated efficacy in the treatment of UC. Copyright 2013 by ESPGHAN and NASPGHAN Kunde S, et al. JPGN 2013 Jun;56(6):

Open label single FMT via NG tube Four male patients, 14.5 ± 1.7 years
Fecal Microbial Transplant via Nasogastric tube for active Pediatric Ulcerative Colitis David L. Suskind1 M.D., Namita Singh2 M.D., Heather Nielson, Ghassan Wahbeh1 M.D., Open label single FMT via NG tube Four male patients, 14.5 ± 1.7 years Pretreatment with Rifaximin TID x 3 days Follow 2, 6, 12 weeks Mild symptoms including vomiting and bloating 2/4 developed C.diff within 4 months (1 recurrence) No change in PUCAI, CRP, albumin, HCT Overall safe but not efficacious Suskind D, et al. JPGN. Accepted for publication.

FMT for PEDIATRIC CrohN’s DISEASE

Nine pediatric patients
Fecal Microbial Transplant Effect on Clinical Outcomes and Fecal Microbiome in Active Crohn’s disease David L. Suskind MD1, Mitchell J. Brittnacher PhD2, Ghassan Wahbeh MD1, Michele L. Shaffer PhD1, Hillary S. Hayden2, Namita Singh MD3, Christopher J. Damman MD4, Kyle R. Hager, Heather Nielson, Samuel I. Miller MD2,4,5,6 Nine pediatric patients Mild to moderate Crohn’s (PCDAI of 10-29) 12-19 years Open label NGT delivery of related donor FMT Studied Clinical response (PCDAI, CRP, calprotectin) Engraftment & % similarity to donor Microbial changes Fecal microbiome pre-similarity to donor ranged from 13 to 69% (mean± SD, 41.7 ± 16.1). The individual with the highest pre-FMT similarity to donor, approximately 69%, had little clinical response and was one of two patients that did not reach clinical remission at 2 week follow up. The individual with the greatest dissimilarity in stool microbiome had the greatest clinical improvement . On evaluation of specific individual’s microbial similarity to donor prior to transplant, two patients stand apart from the overall group. Patient 1 microbiome was the least similar to donor parental microbiome, with an initial similarity to donor of 13%. His clinical course was also one of the best with a decrease in PCDAI from 27.5 to 7.5 and a decrease in CRP from 3.1 mg/dL to 1.1 mg/dL. In contrast, patient 18 had the most similarity to donor with an initial similarity of 69%. This patient’s clinical course did not appear to be significantly altered: clinical remission with FMT was not achieved and additional medical therapy was required by the end of the study . The patient’s PCDAI went from 27.5 to 22.5 with CRP decreasing from 2.6 mg/dL to 1.5 mg/dL. Interestingly, two patients had significant clinical deterioration over the course of the study. The longitudinal analysis of fecal metagenomes during this period allowed us to observe a dramatic increase in the relative abundance of Escheria coli during a clinical disease flare. This data is highly correlative with a bloom of E. coli in response to inflammation or an expansion of E. coli could contribute to disease outcome. Therefore an examination of the relative abundance of E. coli in stool samples before and after FMT would suggest that a relative increase in the amount of E. coli in stool samples is associated with increased inflammation. For patient 18 who was a non-responder to FMT there was an increase from baseline after FMT. For those who responded initially but then had an increase in disease activity, E. coli abundance appears associated with increased calprotectin and thus worsening inflammation. Cite this Cite this Suskind DL, et al. Seattle Children’s Hospital. Data in submission for print.

Fecal Microbial Transplant Effect on Clinical Outcomes and Fecal Microbiome in Active Crohn’s disease David L. Suskind MD1, Mitchell J. Brittnacher PhD2, Ghassan Wahbeh MD1, Michele L. Shaffer PhD1, Hillary S. Hayden2, Namita Singh MD3, Christopher J. Damman MD4, Kyle R. Hager, Heather Nielson, Samuel I. Miller MD2,4,5,6 Objective: Crohn's disease (CD) is a chronic idiopathic inflammatory intestinal disorder associated with fecal dysbiosis. Fecal Microbial Transplant (FMT) is a potential therapeutic option for individuals with CD based on the hypothesis that changing the fecal dysbiosis could promote less intestinal inflammation. Design: Nine patients, ages years, with mild to moderate symptoms defined by Pediatric Crohn’s disease activity index (PCDAI of 10-29) were enrolled into a prospective open label study of FMT in CD (FDA IND 14942). Patients received FMT by nasogastric tube with follow up evaluations at 2, 6, and 12 weeks. PCDAI, C-reactive protein (CRP), and fecal calprotectin were evaluated at each study visit. Results: All reported adverse events (AE) were graded as mild except for one individual who reported moderate abdominal pain after FMT. All AE were self limiting. Metagenomic evaluation of stool microbiome indicated evidence of FMT engraftment in seven out of nine patients. The mean PCDAI score improved with patients having a baseline of 19.7 ± 7.2, with improvement at 2 weeks to 6.4 ± 6.6, and at 6 weeks to 8.6 ± 4.9. The mean CRP level at baseline was 2.4 ± 1.2 mg/dL, at 2 weeks 1.5 ± 0.6 mg/dL, and at 6 weeks 1.9 ± 1.2 mg/dL. No or modest improvement were seen in the patients who did not engraft or whose microbiome was most similar to their donor. Conclusion: This is the first study to demonstrate that FMT for CD is both well tolerated and may be efficacious in CD. Suskind DL, et al. Seattle Children’s Hospital. Data in submission for print.

7/9 (78%) Had PCDAI fall < 10 @ 2 weeks
Fecal Microbial Transplant Effect on Clinical Outcomes and Fecal Microbiome in Active Crohn’s disease David L. Suskind MD1, Mitchell J. Brittnacher PhD2, Ghassan Wahbeh MD1, Michele L. Shaffer PhD1, Hillary S. Hayden2, Namita Singh MD3, Christopher J. Damman MD4, Kyle R. Hager, Heather Nielson, Samuel I. Miller MD2,4,5,6 7/9 (78%) Had PCDAI fall < 2 weeks 2 required escalation of Rx 5/7 (71%) Remained < 12 weeks No or modest improvement in patients without engraftment More divergent = better engraftment and response Objective: Crohn's disease (CD) is a chronic idiopathic inflammatory intestinal disorder associated with fecal dysbiosis. Fecal Microbial Transplant (FMT) is a potential therapeutic option for individuals with CD based on the hypothesis that changing the fecal dysbiosis could promote less intestinal inflammation. Design: Nine patients, ages years, with mild to moderate symptoms defined by Pediatric Crohn’s disease activity index (PCDAI of 10-29) were enrolled into a prospective open label study of FMT in CD (FDA IND 14942). Patients received FMT by nasogastric tube with follow up evaluations at 2, 6, and 12 weeks. PCDAI, C-reactive protein (CRP), and fecal calprotectin were evaluated at each study visit. Results: All reported adverse events (AE) were graded as mild except for one individual who reported moderate abdominal pain after FMT. All AE were self limiting. Metagenomic evaluation of stool microbiome indicated evidence of FMT engraftment in seven out of nine patients. The mean PCDAI score improved with patients having a baseline of 19.7 ± 7.2, with improvement at 2 weeks to 6.4 ± 6.6, and at 6 weeks to 8.6 ± 4.9. The mean CRP level at baseline was 2.4 ± 1.2 mg/dL, at 2 weeks 1.5 ± 0.6 mg/dL, and at 6 weeks 1.9 ± 1.2 mg/dL. No or modest improvement were seen in the patients who did not engraft or whose microbiome was most similar to their donor. Conclusion: This is the first study to demonstrate that FMT for CD is both well tolerated and may be efficacious in CD. Suskind DL, et al. Seattle Children’s Hospital. Data in submission for print.

Fecal Microbial Transplant Effect on Clinical Outcomes and Fecal Microbiome in Active Crohn’s disease David L. Suskind MD1, Mitchell J. Brittnacher PhD2, Ghassan Wahbeh MD1, Michele L. Shaffer PhD1, Hillary S. Hayden2, Namita Singh MD3, Christopher J. Damman MD4, Kyle R. Hager, Heather Nielson, Samuel I. Miller MD2,4,5,6 Recipient Similarity to donor % Time relative to FMT (days) Suskind DL, et al. Seattle Children’s Hospital. Data in submission for print.

Fecal Microbial Transplant Effect on Clinical Outcomes and Fecal Microbiome in Active Crohn’s disease David L. Suskind MD1, Mitchell J. Brittnacher PhD2, Ghassan Wahbeh MD1, Michele L. Shaffer PhD1, Hillary S. Hayden2, Namita Singh MD3, Christopher J. Damman MD4, Kyle R. Hager, Heather Nielson, Samuel I. Miller MD2,4,5,6 Engraftment score (% ) Fecal microbiome pre-similarity to donor ranged from 13 to 69% (mean± SD, 41.7 ± 16.1). The individual with the highest pre-FMT similarity to donor, approximately 69%, had little clinical response and was one of two patients that did not reach clinical remission at 2 week follow up. The individual with the greatest dissimilarity in stool microbiome had the greatest clinical improvement . On evaluation of specific individual’s microbial similarity to donor prior to transplant, two patients stand apart from the overall group. Patient 1 microbiome was the least similar to donor parental microbiome, with an initial similarity to donor of 13%. His clinical course was also one of the best with a decrease in PCDAI from 27.5 to 7.5 and a decrease in CRP from 3.1 mg/dL to 1.1 mg/dL. In contrast, patient 18 had the most similarity to donor with an initial similarity of 69%. This patient’s clinical course did not appear to be significantly altered: clinical remission with FMT was not achieved and additional medical therapy was required by the end of the study . The patient’s PCDAI went from 27.5 to 22.5 with CRP decreasing from 2.6 mg/dL to 1.5 mg/dL. Interestingly, two patients had significant clinical deterioration over the course of the study. The longitudinal analysis of fecal metagenomes during this period allowed us to observe a dramatic increase in the relative abundance of Escheria coli during a clinical disease flare. This data is highly correlative with a bloom of E. coli in response to inflammation or an expansion of E. coli could contribute to disease outcome. Therefore an examination of the relative abundance of E. coli in stool samples before and after FMT would suggest that a relative increase in the amount of E. coli in stool samples is associated with increased inflammation. For patient 18 who was a non-responder to FMT there was an increase from baseline after FMT. For those who responded initially but then had an increase in disease activity, E. coli abundance appears associated with increased calprotectin and thus worsening inflammation. Cite this Time relative to FMT (days) Suskind DL, et al. Seattle Children’s Hospital. Data in submission for print.

Fecal microbial transplantation in a one-year-old girl with early onset colitis - caution advised Vandenplas Y, Veereman G, van der Werff ten Bosch J, A. Goossens, Pierard D, Samsom JN, Escher JC LB is a 10 month old baby girl from Belgium who presented at 10 mos of age with 6-8 bloody diarrheal stools a day with normal infectious work-up and no response to amino acid formulas and dietary restriction. She was evaluated endoscopically and had severe pancolitis. Mesalamine at 60 mg/kg/day induced remission for 2 months before initial symptoms resumed and Azathioprine at 2 mg/kg/day and Steroids were initiated without significant change. VSL, IV antibiotics, and Infliximab at 5 mg/kg induction treatment, rapamune all without effect and bloody diarrhea continued . Thorough immune deficiency w/u including IL-10 exon sequencing was completed. She was transfusion dependent every 3-4 weeks and was maintained on TPN via indwelling central line. Colectomy was recommend. FMT 1st through colonosocopy and then via ND tube performed 7 times. 1st four infusions were from a healthy age mathched niece. Each FMT seemed to improve symptoms and induce remission for about 7-14 days. Last 3 FMT were from older brother. After 1st fraternal FMT, a anaphylaxis like episode occurred with profuse sweating, tachycardia, high fever, and listlessness but resolved in 24 hours with ensuant improvement for 1 months when a 2nd FMT 6 weeks later caused a lesser similar systemic reaction but induced remission for 2 months. A 3rd fraternal FMT was performed without any systemic reaction and 6 months of remission ensued with colonoscopic and clinical remission. Vandenplas Y, et al. JPGN /MPG

Vandenplas Y, et al. JPGN. 10.1097/MPG.0000000000000281.
LB is a 10 month old baby girl from Belgium who presented at 10 mos of age with 6-8 bloody diarrheal stools a day with normal infectious work-up and no response to amino acid formulas and dietary restriction. She was evaluated endoscopically and had severe pancolitis. Mesalamine at 60 mg/kg/day induced remission for 2 months before initial symptoms resumed and Azathioprine at 2 mg/kg/day and Steroids were initiated without significant change. VSL, IV antibiotics, and Infliximab at 5 mg/kg induction treatment, rapamune all without effect and bloody diarrhea continued . Thorough immune deficiency w/u including IL-10 exon sequencing was completed. She was transfusion dependent every 3-4 weeks and was maintained on TPN via indwelling central line. Colectomy was recommend. FMT 1st through colonosocopy and then via ND tube performed 7 times. 1st four infusions were from a healthy age mathched niece. Each FMT seemed to improve symptoms and induce remission for about 7-14 days. Last 3 FMT were from older brother. After 1st fraternal FMT, a anaphylaxis like episode occurred with profuse sweating, tachycardia, high fever, and listlessness but resolved in 24 hours with ensuant improvement for 1 months when a 2nd FMT 6 weeks later caused a lesser similar systemic reaction but induced remission for 2 months. A 3rd fraternal FMT was performed without any systemic reaction and 6 months of remission ensued with colonoscopic and clinical remission. Vandenplas Y, et al. JPGN /MPG

Every 2 weeks FMT From healthy age matched niece
7- 14 days of remission LB is a 10 month old baby girl from Belgium who presented at 10 mos of age with 6-8 bloody diarrheal stools a day with normal infectious work-up and no response to amino acid formulas and dietary restriction. She was evaluated endoscopically and had severe pancolitis. Mesalamine at 60 mg/kg/day induced remission for 2 months before initial symptoms resumed and Azathioprine at 2 mg/kg/day and Steroids were initiated without significant change. VSL, IV antibiotics, and Infliximab at 5 mg/kg induction treatment, rapamune all without effect and bloody diarrhea continued . Thorough immune deficiency w/u including IL-10 exon sequencing was completed. She was transfusion dependent every 3-4 weeks and was maintained on TPN via indwelling central line. Colectomy was recommend. FMT 1st through colonosocopy and then via ND tube performed 7 times. 1st four infusions were from a healthy age mathched niece. Each FMT seemed to improve symptoms and induce remission for about 7-14 days. Last 3 FMT were from older brother. After 1st fraternal FMT, a anaphylaxis like episode occurred with profuse sweating, tachycardia, high fever, and listlessness but resolved in 24 hours with ensuant improvement for 1 months when a 2nd FMT 6 weeks later caused a lesser similar systemic reaction but induced remission for 2 months. A 3rd fraternal FMT was performed without any systemic reaction and 6 months of remission ensued with colonoscopic and clinical remission. Vandenplas Y, et al. JPGN /MPG

From older brother LB is a 10 month old baby girl from Belgium who presented at 10 mos of age with 6-8 bloody diarrheal stools a day with normal infectious work-up and no response to amino acid formulas and dietary restriction. She was evaluated endoscopically and had severe pancolitis. Mesalamine at 60 mg/kg/day induced remission for 2 months before initial symptoms resumed and Azathioprine at 2 mg/kg/day and Steroids were initiated without significant change. VSL, IV antibiotics, and Infliximab at 5 mg/kg induction treatment, rapamune all without effect and bloody diarrhea continued . Thorough immune deficiency w/u including IL-10 exon sequencing was completed. She was transfusion dependent every 3-4 weeks and was maintained on TPN via indwelling central line. Colectomy was recommend. FMT 1st through colonosocopy and then via ND tube performed 7 times. 1st four infusions were from a healthy age mathched niece. Each FMT seemed to improve symptoms and induce remission for about 7-14 days. Last 3 FMT were from older brother. After 1st fraternal FMT, a anaphylaxis like episode occurred with profuse sweating, tachycardia, high fever, and listlessness but resolved in 24 hours with ensuant improvement for 1 months when a 2nd FMT 6 weeks later caused a lesser similar systemic reaction but induced remission for 2 months. A 3rd fraternal FMT was performed without any systemic reaction and 6 months of remission ensued with colonoscopic and clinical remission. Vandenplas Y, et al. JPGN /MPG

From older brother FMT Vandenplas Y, et al. JPGN /MPG

FMT Remission 1 month From older brother

FMT Remission 1 month From older brother Remission 2 month 2 months

FMT Remission 1 month From older brother Remission 2 month
2 months Remission 2 month LB is a 10 month old baby girl from Belgium who presented at 10 mos of age with 6-8 bloody diarrheal stools a day with normal infectious work-up and no response to amino acid formulas and dietary restriction. She was evaluated endoscopically and had severe pancolitis. Mesalamine at 60 mg/kg/day induced remission for 2 months before initial symptoms resumed and Azathioprine at 2 mg/kg/day and Steroids were initiated without significant change. VSL, IV antibiotics, and Infliximab at 5 mg/kg induction treatment, rapamune all without effect and bloody diarrhea continued . Thorough immune deficiency w/u including IL-10 exon sequencing was completed. She was transfusion dependent every 3-4 weeks and was maintained on TPN via indwelling central line. Colectomy was recommend. FMT 1st through colonosocopy and then via ND tube performed 7 times. 1st four infusions were from a healthy age mathched niece. Each FMT seemed to improve symptoms and induce remission for about 7-14 days. Last 3 FMT were from older brother. After 1st fraternal FMT, a anaphylaxis like episode occurred with profuse sweating, tachycardia, high fever, and listlessness but resolved in 24 hours with ensuant improvement for 1 months when a 2nd FMT 6 weeks later caused a lesser similar systemic reaction but induced remission for 2 months. A 3rd fraternal FMT was performed without any systemic reaction and 6 months of remission ensued with colonoscopic and clinical remission. 2 months Remission 6 month

Clinical Trials NCT – DBPCT using FMT to treat chronic active UC (Padaramothy, New South Wales) NCT – FMT to treat active UC associated post-IPAA pouchitis (Shaffer, Emory) NCT FMT effect on the IBD microbiome (Moss, Beth Israel) NCT – FMT as a transition off immunosuppression with stable UC (Kellermeyer, Baylor)

Summary FMT appears safe and well tolerated in children independent of route Efficacious for RCDI Mixed response in IBD Best route ? Pre-FMT antibiotics ? Donor matching ? Durability / maintenance ?

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Michael Docktor, MD Boston Children’s Hospital August 16, 2014

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