22-10-2016, 11:48 AM
Fecal Transplant for Recurrent Clostridium difficileInfection in Children With and Without Inflammatory Bowel Disease
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ABSTRACT
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 longterm
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.
After initial Clostridium difficile infection (CDI), up to onethird
of adult patients and one-fifth of children will experience
a symptomatic recurrent CDI (RCDI) with discontinuation
of antibiotic therapy (1,2). Fifty percent to 65% of patients
with RCDI experience multiple recurrences (3). Few established
evidence-based therapies are available to the practitioner taking
care of children with RCDI. Accepted antibiotic therapies such as
metronidazole and vancomycin further perturb the gut flora that
may protect against colonization with C difficile, resulting in
reduced gut microbial diversity, depletion of Bacteroidetes and
Firmicutes, and increased prominence of Proteobacteria that may
predispose patients to recurrent infection (4).
Fecal microbiome transplant (FMT) is emerging as an
effective therapy for the treatment of RCDI. Eiseman et al (5) first
described FMT as curative in 4 adults with pseudomembranous colitis in 1958. Retrospective review of >300 published cases
of FMT for the treatment of adults with RCDI shows a success
rate of approximately 90% (6–12). A recent prospective doubleblind
randomized placebo-controlled trial showed superiority
of FMT to vancomycin to treat RCDI with a success rate of
93% without any short-term safety concerns (13). We report our
single-center experience using FMT to treat RCDI in children.
METHODS
Retrospective review of the medical record was completed
to describe our patient population with RCDI treated with singleinfusion
FMT from 2009 to 2013 at the MassGeneral Hospital
for Children. Eleven patients underwent single-infusion FMT for
RCDI. One family whose child received FMT for RCDI and for
whom RCDI cleared successfully by this method specifically
declined to include their child in any research efforts at the time
of his care and is not described fully herein. Three of 10 patients
reported had concomitant IBD. All of the patients had at least
3 recurrences of a diarrheal process of at least 2 to 3 daily loose,
watery, and/or bloody stools with evidence of C difficile on laboratory
testing that resolved or improved with CDI treatment. All of the
patients continued antibiotics until 36 to 48 hours before FMT.
Donors (who were all parents) completed a donor health screening
questionnaire, were screened for sexually transmitted diseases, and
had their stools tested for known pathogens based on previously
published screening protocols (14). Thirty to forty grams of fresh
donor stool was blended with 250 mL of sterile and preservativefree
normal saline and filtered with sterile gauze to decrease
particulate matter. The mixture was delivered into the stomach
via nasogastric tube or into the cecum via colonoscope following
previously published protocols (14). When appropriate, IBD disease
activity was measured by Physician’s Global Assessment (15).
During the time reviewed in this case series, the Partners
Healthcare institutional review board had approved FMT for the
treatment of RCDI following established protocols with written
informed consent. Once the US Food and Drug Administration
established the suggestion for an Investigational New Drug (IND)
Application for the use of FMT to treat RCDI in children, we
complied with those requirements (expanded access IND 15199–
03). Institutional review board approval (2013 P001294) was
obtained to complete this retrospective case series.
Patient 4
This 15-year-old boy had underlying diarrhea and chronic
abdominal pain that led to a hospitalization for diagnostic laparoscopy,
where it was believed he contracted an initial nosocomial
CDI assessed by polymerase chain reaction (PCR) DNA amplification
assay. His symptoms reportedly improved with antibiotic
administration, but his baseline intermittent diarrhea and chronic
abdominal pain never changed. He had several more episodes
of worsening of baseline diarrhea and pain that was associated
with persistent positive PCR testing that improved with antibiotics,
but did not improve his baseline symptoms. His baseline chronic
abdominal pain did not improve after FMT. Two months after FMT,
his local care team at another institution documented the absence of
CDI by enzyme immunoassay (EIA) for C difficile toxins, but has
not reassessed for the presence of CDI thereafter. He continues to
have chronic abdominal pain and diarrhea that are believed to be
functional and he is being treated locally by a multidisciplinary
pain clinic.
Patient 6
This 5-year-old boy with a history of constipation was
considered appropriate for FMT because he had reported
improvement of baseline diarrhea when treated with antibiotics
for presumed RCDI based on PCR testing. The colonoscopy showed
a tortuous and capacious colon consistent with constipation but
was otherwise normal. Following FMT, we initiated aggressive
treatment for chronic constipation and functional fecal retention and
he had resolution of symptoms.
Patient 8
This patient was a 5-year-old boy with failure to thrive and a
chronic diarrheal process that was responsive to vancomycin.
His diarrheal symptoms began after developing a presumed infectious
colitis while travelling in India. He was endoscopically
evaluated previously and was believed to have IBD-undetermined
but had 3 diarrheal episodes with RCDI detected by PCR assay. On
2 additional occasions, he had bloody and mucoid diarrhea episodes
without the documentation of CDI that improved empirically with
vancomycin treatment. Near the time of FMT, he had diarrhea and
CDI presence was assessed at an outside hospital by PCR assay.
At the time of FMT delivery, colonoscopy showed moderately
active ileocolitis and a granuloma in the left colon. Although his
bloody diarrhea never resolved, he remained EIA toxin free for
4 months following FMT. Within 1 month of FMT, he initiated
immunosuppressants for his Crohn disease with better control
of symptoms.
Patient 9
This 11-year-old boy with moderately active granulomatous
Crohn ileocolitis diagnosed at age 5 years had recurrent IBD
symptoms consistently responsive to vancomycin therapy with
2 documented CDIs by EIA. He was unable to taper or discontinue
vancomycin without prompt resumption of diarrhea and abdominal
pain. He was intolerant to 6-mercaptopurine and was maintained in
remission, by parents’ report, by 5-aminosalicylates and vancomycin.
At the time of FMT delivery, colonoscopy showed obvious
signs of ileocolitis and a stricture in the sigmoid colon. Eight weeks after FMT, while hospitalized for the symptoms of Crohn disease,
he developed CDI by EIA toxin identification that was successfully
treated with vancomycin. He ultimately required systemic corticosteroids
as a bridge to methotrexate therapy for Crohn disease.
Patient 10
This patient was a 19-year-old girl with ulcerative colitis
treated with adalimumab who developed RCDI after developing a
methicillin-resistant Staphylococcus aureus cellulitis requiring
multiple antibiotic courses. During vancomycin taper, she developed
acute severe colitis requiring hospitalization with CDI that was
refractory to vancomycin and nitazoxanide therapy. She had
12 bloody stools and was anemic and hypoalbuminemic. Colonoscopy
showed diffuse and severe pancolitis without pseudomembranes.
After FMT, diarrhea completely resolved for 5 days
and her stools tested negative for the presence ofC difficile toxin. Six
days after FMT, she redeveloped acute severe colitis symptoms
without return of CDI. She was unresponsive to high-dose steroids
for 5 days and she underwent colectomy.