Immunocompromised (IC) patients are at increased risk of developing Clostridium difficile infection (CDI) . A fecal microbiota transplant (FMT) is effective therapy for recurrent CDIs in 85% to 90% of adult and pediatric patients [2, 3]. However, IC patients might be at increased risk of adverse events after FMT, and its efficacy might be reduced in IC patients. The short-term safety of FMT in IC adults  and adult hematopoietic stem cell transplant (HSCT) recipients has been determined , but the use of FMT in children who have undergone HSCT has not been reported. We performed a retrospective chart review of 3 IC children who underwent FMT for treatment of recurrent CDIs after HSCT at Seattle Children’s Hospital between January 2010 and August 2016. According to hospital routine, their stools were analyzed for C difficile antigen and toxin by enzyme immunoassay (EIA); samples that were antigen positive but toxin negative were reflexively analyzed via polymerase chain reaction assay to detect C difficile toxin. Our local practice is to offer an FMT with either donor stool from a family member or OpenBiome (Somerville, Massachusetts) anonymous-donor stool because of cost savings and ease of use. FMTs were often performed via gastric tube for convenience, but colonoscopy was performed instead if there was concern about another underlying disease that could predispose the patient to CDI. We also increased the use of colonoscopy over time after more recent studies suggested a slightly better efficacy of FMT delivered via colonoscopy over that delivered via gastric tube. The product was the same when delivered by colonoscopy, but the volume was increased to 240 mL in that circumstance. In all cases, recurrence was defined as a positive result on repeat C difficile testing performed in the setting of either recurrence or continuation of diarrheal symptoms. Alternative etiologies for symptom recurrence were not always sought. The protocol of this study was approved by the Seattle Children’s Hospital institutional review board. CASES Three children developed recurrent CDIs after HSCT and were offered FMT therapy. Two of these patients experienced CDI recurrences after FMT, including 1 who experienced multiple relapses that required 6 FMTs. The median age at first FMT was 6.6 years, and the median follow-up time was 34 weeks; all 3 patients tolerated the procedure without adverse events or invasive infection. Case 1 A 12-year-old girl received 2 HSCTs to treat acute myelogenous leukemia, the second of which was from a mismatched unrelated donor cord (Table 1); 2 years 9 months after the HSCT, she developed her first CDI. She received most of her nutrition from formula via a gastric tube. She was treated initially with metronidazole but subsequently developed 14 documented CDI recurrences, during which she received courses of metronidazole, oral vancomycin, oral vancomycin with a prolonged taper, and fidaxomicin. Immunosuppression at the time of the first FMT included 1 mg of tacrolimus and 0.5 mg/kg of body weight prednisolone daily. She underwent another FMT 9 months after her first CDI but ultimately required 6 FMTs and experienced various degrees of short-lived relief from her diarrheal symptoms (range, 0–35 months). FMTs 1, 2, and 3 used filtered family-donor stool that was blenderized and infused through her gastric tube. FMT 4 used filtered family-donor stool that was blenderized and infused via colonoscopy, and FMTs 5 and 6 used OpenBiome anonymous-donor stool, screened according to protocol , and infused via her gastric tube. A volume of 30 to 60 mL was infused during each FMT. Her last FMT was unsuccessful; she experienced recurrence of symptoms, and EIA results for C difficile stool antigen and toxin were positive after 2 months. Her absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) during each FMT are provided in Table 1. She continued on immunosuppressive therapy with tacrolimus and prednisolone for skin and mild upper gastrointestinal graft-versus-host disease (GVHD) throughout each FMT treatment. She was taking meropenem before her first episode of CDI, but she was not taking broad-spectrum antibiotics at the time of any of the recurrences. She tolerated each FMT without infection or an adverse event. Table 1. Characteristics of Patients Before and After Fecal Microbiota Transplantation Patient No. Age (y) Underlying Diagnosis Type of HSCT Time to First CDI (mo) FMT No. FMT Source Immunosuppression at FMT ANC (/mL) ALC (/mL) Outcome 1 12 AML Mismatched unrelated cord 33 1 Family Tacrolimus, prednisolone 2472 1344 Relapse after 2 mo 2 Family Tacrolimus, prednisolone 2214 800 Relapse after 2 mo 3 Family Tacrolimus, prednisolone 3097 1288 Relapse after 1 mo 4 Family Tacrolimus, prednisolone 6306 2084 Relapse after 6 mo 5 OpenBiome Tacrolimus, prednisolone 5070 910 Relapse after 2 mo 6 OpenBiome Tacrolimus, prednisolone 2505 515 Relapse after 1 mo 2 8 DiGeorge syndrome Mismatched unrelated cord 29 1 OpenBiome Prednisone 5954 859 Resolution 3 2 Hurler syndrome Mismatched unrelated cord (second HSCT) 1 1 OpenBiome Cyclosporine, beclomethasone 3234 3095 Relapse after 2 mo Patient No. Age (y) Underlying Diagnosis Type of HSCT Time to First CDI (mo) FMT No. FMT Source Immunosuppression at FMT ANC (/mL) ALC (/mL) Outcome 1 12 AML Mismatched unrelated cord 33 1 Family Tacrolimus, prednisolone 2472 1344 Relapse after 2 mo 2 Family Tacrolimus, prednisolone 2214 800 Relapse after 2 mo 3 Family Tacrolimus, prednisolone 3097 1288 Relapse after 1 mo 4 Family Tacrolimus, prednisolone 6306 2084 Relapse after 6 mo 5 OpenBiome Tacrolimus, prednisolone 5070 910 Relapse after 2 mo 6 OpenBiome Tacrolimus, prednisolone 2505 515 Relapse after 1 mo 2 8 DiGeorge syndrome Mismatched unrelated cord 29 1 OpenBiome Prednisone 5954 859 Resolution 3 2 Hurler syndrome Mismatched unrelated cord (second HSCT) 1 1 OpenBiome Cyclosporine, beclomethasone 3234 3095 Relapse after 2 mo Abbreviations: ALC, absolute lymphocyte count; AML, acute myelogenous leukemia; ANC, absolute neutrophil count; CDI, Clostridium difficile infection; FMT, fecal microbiota transplantation; HSCT, hematopoietic stem cell transplantation. View Large Case 2 An 8-year-old boy received a mismatched unrelated donor cord HSCT in infancy to treat DiGeorge syndrome. His first CDI was 29 months after this HSCT. Antimicrobial agents given to the patient at the time included ceftriaxone treatment for bacteremia and trimethoprim-sulfamethoxazole (TMP/SMX) and penicillin prophylaxis. He received all his nutrition as formula feeds. He experienced 13 CDI recurrences, during which he received courses of metronidazole and oral vancomycin and prolonged courses of vancomycin with a taper, with and without a rifaximin tail for 2 weeks after completion of the oral vancomycin. His first relapse was preceded by a single dose of ceftazidime, but he did not otherwise receive broad-spectrum antibiotics before his CDIs. He underwent FMT 31 months after his first CDI; his ANC was 5954/mL, and his ALC was 859/mL. At the time of the FMT, he was being given immunosuppressive therapy, including prednisone (alternating 0.12 mg/kg with 0.2 mg/kg every other day) for extensive chronic gastrointestinal, oral, and ocular GVHD. He also received antimicrobial prophylaxis, which included TMP/SMX and penicillin. The FMT used 30 mL of OpenBiome anonymous-donor stool, which was screened according to protocol and infused via a gastrojejunal tube. He tolerated the FMT with minimal nausea and retching and no adverse events. The FMT was successful; his symptoms resolved, and the results of repeat C difficile stool antigen and toxin testing by EIA were negative. He had no recurrence of CDI at follow-up 1 year 10 months after the FMT. Case 3 A 2-year-old boy received 2 HSCTs to treat Hurler syndrome, the second of which was from a mismatched unrelated cord. His first CDI episode occurred 1 month after the second transplant. He experienced at least 4 CDI episodes and received multiple antibiotic courses, including metronidazole and standard-dose oral vancomycin. At the time of the first FMT, 6 months after his initial CDI, he required cyclosporine and oral beclomethasone immunosuppression for gut GVHD. He also continued TMP/SMX and valacyclovir prophylaxis. All of his nutrition was given as formula-based gastric tube feeds. He underwent an FMT with an ANC of 3234/mL and ALC of 3095/mL. The FMT used 30 mL of OpenBiome anonymous-donor stool, which was screened according to protocol and infused via his gastric tube. After the FMT, he experienced vomiting without fever. This symptom resolved, and he experienced brief relief from symptomatic enteritis, but results of symptomatic stool antigen and toxin testing by EIA were positive after his CDI recurred within 2 months. He did not receive broad-spectrum antibiotics before this recurrence; however, he was given prophylactic TMP/SMX. A repeat FMT was not offered because this patient was entered into a study for the treatment of CDI and was no longer eligible for an FMT. DISCUSSION Our 3 IC patients who had undergone an HSCT experienced recurrent CDIs and were given 8 FMT treatments at our institution. Each of these patients had previous exposure to broad-spectrum antibiotics, was on immunosuppressive therapy and prophylactic antibiotics at the time of their first CDI, and had experienced multiple relapses of CDI before the FMT was attempted. The 2 main considerations for FMT in this population are its safety and efficacy. The procedure was well tolerated in all 3 patients; the only adverse effects reported were nausea and 1 episode of emesis, which resolved without intervention. No safety issues were revealed during follow-up with these 3 patients. One patient did experience successful clearance of C difficile after his FMT. It is unfortunate that symptomatic CDI recurred in 2 of the 3 patients, 1 of whom underwent several attempts at FMT, although admittedly, follow-up stool evaluations were often limited, and persistent C difficile shedding is not uncommon, so it is possible that symptom recurrence was attributable to other causes. Several factors might contribute to the lack of FMT efficacy in this population, including chemotherapeutics, frequent antimicrobial therapy, and formula-based diet, which can decrease the natural diversity of gut microbiota and allow C difficile to proliferate. Formula-based diets have been shown to decrease gut microbial biodiversity . This reduction in microbial biodiversity might contribute to C difficile colonization and CDI. Although the FMTs seemed safe and well tolerated, larger studies of FMT safety and efficacy are needed in this pediatric population of IC HSCT recipients. Additional therapeutics and ways to modulate C difficile risk factors, such as diet and antibiotic use, will be important to affect CDI outcomes in these patients. Note Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Kelly CR, Ihunnah C, Fischer Met al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol 2014; 109: 1065– 71. Google Scholar CrossRef Search ADS PubMed 2. van Nood E, Dijkgraaf MG, Keller JJ. Duodenal infusion of feces for recurrent Clostridium difficile. N Engl J Med 2013; 368: 2145. Google Scholar CrossRef Search ADS PubMed 3. Kronman MP, Nielson HJ, Adler ALet al. Fecal microbiota transplantation via nasogastric tube for recurrent Clostridium difficile infection in pediatric patients. J Pediatr Gastroenterol Nutr 2015; 60: 23– 6. Google Scholar CrossRef Search ADS PubMed 4. Webb BJ, Brunner A, Ford CDet al. Fecal microbiota transplantation for recurrent Clostridium difficile infection in hematopoietic stem cell transplant recipients. Transpl Infect Dis 2016; 18: 628– 33. Google Scholar CrossRef Search ADS PubMed 5. Bakken JS, Borody T, Brandt LJet al. ; Fecal Microbiota Transplantation Workgroup. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol 2011; 9: 1044– 9. Google Scholar CrossRef Search ADS PubMed © The Author(s) 2017. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: email@example.com.
Journal of the Pediatric Infectious Diseases Society – Oxford University Press
Published: Mar 1, 2018
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