In 2013, Mayo Clinic researchers reported the results of a population-based epidemiological study of Clostridium difficile infection (CDI) in children. Their findings, published in Clinical Infectious Diseases, showed a marked increase in cases between 1991 and 2009. Among the study's cohort, the incidence rose from 2.2 per 100,000 person-years in the period from 1991 to 1997 to 23.4 per 100,000 person-years between 2004 and 2009.
Other studies also point to increased frequency and severity of CDI, especially among community-dwelling adults and children. Recurrences are also more common. Twenty percent of children in the Mayo Clinic study experienced repeat bouts of CDI. Recent data suggest the overall recurrence rate is higher — about 25 percent — with an incidence as high as 60 percent after multiple episodes.
In the last few years, fecal microbiota transplantation (FMT) has become a safe and accepted treatment for recurrent CDI, with most centers reporting a greater than 90 percent cure rate. Based on study data and successful programs at Mayo Clinic and elsewhere, Mark G. Bartlett, M.D., a pediatric gastroenterologist at Mayo Clinic's campus in Rochester, Minnesota, initiated a pediatric fecal microbiota transplant program there in 2013.
"At that time, just a few places were doing fecal transplants in children, but we felt we were ready. Mayo Clinic's campus in Arizona had an adult program for several years with a 100 percent cure rate, and we have a successful adult program here that paved the way for us," he says.
Since then, Mayo Clinic's pediatric FMT program has treated more than 100 children with a greater than 90 percent success rate and no adverse events.
"We have an expectation that most children will be cured with one treatment, but we've had to repeat treatments in three or four patients who were on immunosuppressive therapy after undergoing kidney or heart transplantation or were complex cases with inflammatory bowel disease," Dr. Bartlett says. "Most kids are extremely happy to be free of symptoms, even if it doesn't last forever."
In the current protocols, children receiving a fecal transplant must provide their own donor stool, usually from a parent or close relative — an expensive and logistically unwieldy process. Screening costs for each case are high, and donors must be physically present immediately prior to transplant. So Dr. Bartlett and colleagues are conducting a randomized controlled study comparing the effectiveness of fresh familial stool to frozen specimens from anonymous screened donors.
"We hope to show that a small number of healthy donors can provide stool that can be frozen and banked and then thawed for use in many patients, with the same greater than 90 percent success rate," he says.
The study's secondary outcomes include evaluation of the inflammatory response and intestinal microbiome in patients ages 1 to 3 years using the inflammatory markers fecal lactoferrin, calprotectin and alpha-1-antitrypsin. The investigators will also perform 16s rRNA sequencing in patients before and four weeks after transplant and measure quality of life pre- and post-transplant using the validated Child Health Questionnaire.
Dr. Bartlett's group is interested in investigating the idea of superdonors, a concept that originated with a 2015 study published in Gastroenterology evaluating FMT as a therapeutic intervention for patients with active ulcerative colitis. Of 70 patients in the study, nine who received FMT achieved remission. Seven of those patients received stool from a single donor, raising the possibility that fecal material from some donors may be more effective than stool from others.
In another study, published in 2016 in Science, UK researchers disputed the idea of a universal donor, arguing instead that compatibility between donor and recipient microbial strains was responsible for successful transplant outcomes.
Dr. Bartlett is hopeful his research will help move the science in the direction of superdonors and help refine FMT techniques so that more children will have access to this important therapy. He is also interested in analyzing the effect of diet on donor microbiomes to determine whether certain diet-influenced microbiomes lead to more successful FMT outcomes.
The current phase I study aims to enroll 40 patients ages 1 to 18 with recurrent CDI. To date, 31 have been enrolled, with full enrollment expected by June 2017. Contact information for referring physicians for this clinical trial is included at the end of this article.
"We don't have the microbiome data yet, but the vast majority of study participants are in complete remission, with no adverse outcomes, and preliminary reports indicate that quality of life has improved significantly. What's more, we have observed no differences in the fresh versus frozen stool groups," Dr. Bartlett says. "We are one of the more prolific programs in the United States, and we are cooperating and sharing protocols with our colleagues at other sites. We have good patient compliance and follow-through, and I think we will get excellent results."
For more information
Khanna S, et al. The epidemiology of Clostridium difficile infection in children: A population-based study. Clinical Infectious Diseases. 2013;56:1401.
Razik R. Recurrence of Clostridium difficile infection in patients with inflammatory bowel disease: The RECIDIVISM study. The American Journal of Gastroenterology. In press.
Moayyedi P, et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology. 2015;149:102.
Li SS, et al. Durable coexistence of donor and recipient strains after fecal microbiota transplantation. Science. 2016;352:586.
Clinical trials: Fresh versus frozen stool for fecal transplant in children. Mayo Clinic.