See “Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection in Pediatric Patients: Encouragement Wrapped in Caution” by Lynch on page 1.
Fecal microbiota transplantation (FMT) has been shown to be an effective and safe therapy for adults with recurrent Clostridium difficile colitis. Although the mechanism by which FMT results in C difficile eradication has not been completely elucidated, studies show that FMT is associated with the resolution of diarrhea, clearance of C difficile, and return of a more healthy fecal microbiota (1–6). A systematic review identified that FMT results in the disease resolution in 92% of cases overall (5).
A recent study in adults demonstrated that FMT delivery by colonoscopy and nasogastric (NG) tube appears equally efficacious (7). Given similar efficacy of FMT for C difficile via different routes of administration and the considerable cost difference between NG and colonoscopic administration, the question of safety and tolerability of FMT via NG administration arises.
Although a proposed treatment protocol exists for the use of FMT to treat recurrent C difficile colitis in children, few cases and case series describing the use of FMT in children have been described, and those that have been published have focused on colonoscopic administration of FMT (8–11). We report the results of 10 patients with recurrent C difficile infection treated with FMT via NG tube at a single institution using a uniform protocol.
Informed consent was obtained from the parent/guardian of each patient. This retrospective case series was approved by the institutional review board of the Seattle Children's Hospital (SCH).
This series includes 10 consecutive children who received FMT at SCH between August 2011 and May 2014 for the treatment of recurrent C difficile infection using the same protocol, defined as 3 or more recurrences of C difficile diarrhea with failed treatment, including vancomycin taper. During the study period, C difficile infection was identified at SCH using 2-step testing, first with enzyme immunoassay for C difficile antigen and toxins A&B, and then with C difficile toxin A&B polymerase chain reaction in cases of antigen-positive but toxin-negative specimens. This recommended two-step testing scheme maximizes sensitivity and specificity (12). Some patients referred by their primary care providers had initial C difficile testing using their local protocol. Retrospective chart review was performed to describe the demographics and clinical characteristics of the population. No patients with recurrent C difficile infection managed at SCH during this period were denied the opportunity for FMT.
Donor Screening and Preparation
We considered recipients’ adult family members, household members, or adult family friends as potentially acceptable donors. The American Association of Blood Banks Donor History questionnaire was used to evaluate study subject donors (Table 1) (13). Donor laboratory studies were guided by those suggested by Bakken et al (14) and included hepatitis A virus immunoglobulin (Ig)G and IgM, hepatitis B virus serum antigen and antibody and core antibody, hepatitis C virus IgG, human immunodeficiency virus 1 and human immunodeficiency virus 2 IgG, rapid plasma reagin, Epstein-Barr virus, and cytomegalovirus IgG and IgM, as well as stool testing for C difficile, bacterial culture, and ova and parasites. Donors were not allowed to have had antibiotics within 3 months before FMT. Directed stool donors were instructed to avoid foods to which the recipient may be allergic for 5 days before the procedure. In addition, all of the donors were instructed to notify the study investigators of any symptoms of infection, such as fevers, diarrhea, or vomiting, occurring between screening and time of donation.
Fecal Microbiota Transplantation
Recipients received premedication before FMT, including vancomycin/fidaxomicin, for at least 7 days before transplant, with the last dose given 24 hours before the procedure. Recipients also received 8.5 to 17 g of polyethylene glycol in 8 oz of water 3 times per day for 2 days before FMT, and omeprazole (1 mg/kg orally) on the day before and morning of procedure. For the FMT, an NG tube was placed and its location confirmed by x-ray. Alternatively, a nasoduodenal or nasojejunal tube was placed in patients with a baseline high risk of emesis; if patients already had a nasoduodenal or nasojejunal tube in place for feeding, that tube was used to administer the FMT. Approximately 30 g of donor stool was mixed with 100 mL of normal saline and blenderized until a homogenous texture was achieved. The stool suspension was then filtered using 4 × 4 gauze. Infusion of 30 to 60 mL was slowly administered via NG tube for a 3-minute period. The tube was flushed with 15 mL of normal saline for 1 minute. After 15 minutes, the tube was removed. Subjects were discharged home after 30 minutes of observation.
Study subject recipients were called 2 days after transplantation. Patients from Washington State followed up in the gastroenterology clinic after FMT; patients from out of state had follow-up by telephone to collect possible adverse events, including fever, abdominal pain, abdominal distension, nausea, vomiting, and flatulence, and those that could have been the result of the NG or nasojejunal tube placement, including epistaxis and sore throat.
We report standard descriptive statistics, such as mean, median, range, and interquartile range (IQR) as appropriate. STATA 12.1 (StataCorp, College Station, TX) was used for all analyses.
During the study period, 10 patients underwent FMT for recurrent C difficile infection; donors included 9 parents (90%) and 1 sibling (10%). The median duration of follow-up after FMT was 44 days (IQR 21–172; range 13–700). Follow-up consisted of a combination of clinic visits, follow-up telephone calls, and repeat C difficile testing.
Among these 10 patients, the median age was 5.4 years (IQR 2.7–10.6 years; Table 2) and 60% were girls. All of the subjects had 3 or more recurrences of C difficile before FMT, and 40% of the patients had received immunosuppressive medications (30% with present receipt). The median duration between the identification of the first C difficile infection and performing the FMT was 250 days (IQR 190–364; range 90–541).
Overall, the FMT was well tolerated. Patient 5 experienced vomiting in the outpatient clinic directly following the procedure but this resolved quickly. This patient had a nasojejunal tube placed for the FMT because of history of vomiting when upset, gastroesophageal reflux, and a strong gag reflex. In addition, this patient experienced mucoid stools for 2 days following the procedure. Otherwise, no additional adverse events were noted.
All of the patients developed initial resolution of symptoms, and 9 (90%) of the patients remained asymptomatic during follow-up. Patient 4 developed diarrhea 2 months after FMT and tested positive for C difficile. The patient had received a course of cephalexin 6 days before this recurrence. The patient was treated with oral vancomycin and underwent a second FMT via nasojejunal tube 3 months after this C difficile recurrence (5 months after initial FMT). Data from the patient's second FMT are not shown. The patient again experienced recurrent C difficile infection 3 months after the second FMT.
The results of this retrospective study of FMT via NG tube showed it to be safe and well tolerated in pediatric recurrent C difficile colitis. Our experience with FMT for recurrent C difficile infection mirrors the adult experience: FMT was safe and effective in curing recurrent C difficile infection in 90% of our subjects, a rate similar to that seen among adult study subjects who received FMT via the gastric or jejunal route. Questions regarding FMT remain, such as the long-term safety of using adult microbiota for pediatric FMT, and whether pre-FMT preparation with antibiotics and laxatives has an independent effect on either C difficile infection or FMT efficacy. Future studies will help elucidate both whether universal donors and frozen donated stool can streamline the FMT process by removing the necessity for donor screening for each new patient, and whether microbiota replacement can be accomplished using an oral pill, the FMT delivery method most preferred by patients in a recent attitude survey (15).
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