Fecal Microbiota Transplantation: Information for the Pediatrician

The past 2 decades have led to an explosion of interest and research into the gastrointestinal microbial environment, which consists of 500 to 1000 bacterial species in addition to viruses, archaea, fungi, bacteriophages, and other unicellular organisms.¹  The number of bacterial cells in the body is similar to the number of human cells, approximately 3 × 10¹³ (30 trillion), with the greatest abundance of bacteria residing in the colon.²  The composition of the gut microbiome is unique in each individual. Most of the colonization occurs in the first few years of life, but subsequently the microbiota remains relatively stable and distinct to each person into adulthood, even if transient changes occur with diet and medications.³  The gut microbiota has far-reaching impact on health and disease, playing an important role in metabolism, protecting the intestinal barrier, and maintaining immune homeostasis.¹  Disturbances in the composition of microbial communities have been associated with a broad array of autoimmune, metabolic, cardiovascular, and gastrointestinal disorders, and there are multiple reviews available on these topics.^4–6 

Fecal microbiota transplantation (FMT) is typically defined as the transfer of stool from a “healthy” donor to another individual with the intent of restoring the recipient’s imbalanced microbiome to a “healthy” one, thereby ameliorating or curing a specific disease.⁷  FMT is not itself a new concept. Documentation by the Chinese medical practitioner, Ge Hong, in the fourth century describes the use of human fecal suspensions called “yellow soup” for the treatment of diarrheal diseases.⁸  The first reported use of FMT in modern medical literature, from 1958, describes 4 adults with severe pseudomembranous enterocolitis who were cured after receiving fecal retention enemas.⁹  Since that initial case series, there have been thousands of patients reported in the medical literature who have been cured of Clostridioides difficile (formerly Clostridium difficile) infection (CDI) after FMT, and this success has led to increasing accounts in the media and greater public interest in this procedure. This clinical report highlights the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology and Nutrition joint position paper with the purpose of summarizing current evidence and providing expert opinion regarding the use of FMT in the management of CDI.¹⁰ 

The purpose of this clinical report is to present a broad overview of FMT to enable pediatricians to identify those patients who might benefit from timely referral for recurrent CDI and may be considered candidates for this procedure. Clinicians should also be aware of other forms of microbial therapies on the horizon. It should be noted that in the United States, fecal microbiota is classified as both a biological agent and drug and, therefore, subject to regulation by the US Food and Drug Administration (FDA). FMT has not been given market approval for a specific clinical indication and is still considered investigational. There have been no controlled trials of FMT in the pediatric population. However, in 2013 the FDA announced that it would exercise “enforcement discretion” for FMTs being performed for the treatment of CDI.¹¹  This means that if a health care provider believes that it is clinically indicated, FMT can be administered to patients with CDI without the need for an investigational new drug application (IND). However, an investigational new drug application is required when FMT is used for research purposes or to treat conditions other than CDI. Even though health insurance plans do not, as a matter of course, cover treatments without FDA approval, providers with specialty expertise can work with payers in certain circumstances when such treatments appear promising.

C difficile is a spore-forming Gram-positive anaerobe that is a major cause of hospital-associated diarrhea and is the most common infectious cause of antibiotic-associated diarrhea.¹²  It is a serious public health challenge with an estimated annual national burden of more than 476 000 cases and an increasing incidence since 2000 that has only recently begun to stabilize in the hospital setting but continues to rise in the community.¹³  In hospitalized children with symptomatic CDI, two-thirds have complex chronic conditions such as malignancy, hematologic, immunologic, cardiovascular, neuromuscular, gastrointestinal, and respiratory conditions.¹⁴  Children with inflammatory bowel disease, which includes Crohn’s disease and ulcerative colitis, have rates of CDI that far exceed those seen in the general population.¹⁵ 

Symptomatic CDI is typically defined as 3 or more liquid stools in a 24-hour period with C difficile toxins identified in the diarrheal stool specimen. Clinical manifestations can vary from mild diarrhea and abdominal discomfort to severe bloody diarrhea with pseudomembranous colitis to toxic megacolon and peritonitis, which, fortunately, are extremely rare in children. Although most patients will have resolution of symptoms, C difficile spore production can make the organism difficult to eradicate, and up to 30% of patients treated for CDI experience a recurrence after discontinuation of C difficile-directed antibiotic therapy. In those with a recurrence, the rates of further occurrences can be as high as 65%.¹⁶  Risk factors for recurrent CDI in children include prior use of antibiotics and acid suppression medications, recent surgery, malignancy, solid organ transplantation, and presence of tracheostomy or gastrostomy tube.^17–19 

After the initial case series reported in 1958, global experience with FMT for treating CDI developed in the adult population based on case reports and case series that included hundreds of patients.²⁰  Then in 2013, the first adult open-label randomized controlled trial comparing FMT delivered via nasoduodenal tube with vancomycin therapy showed superiority of short-course oral vancomycin followed by FMT over vancomycin alone in the treatment of recurrent CDI (81% vs 31%, P = .008).²¹  The pediatric experience began in 2010 with the case report of a 2-year-old child with CDI refractory to multiple courses of antibiotics and probiotics. FMT delivered via nasogastric tube led to symptom resolution and stool testing negative for C difficile toxin 6 months after the procedure. Two years later, a 16-month-old received the first successful pediatric FMT delivered via colonoscopy.^22,23  Subsequently, numerous adult studies, including large observational studies, randomized controlled trials, and registries have now established that FMT is 80% to 90% effective in curing CDI in adults and has a significant advantage over vancomycin and fidaxomicin.^21,24–26  Although controlled trials are not available in pediatric patients, a large multicenter cohort of 372 children reported CDI eradication rates of 81% after a single FMT and 86.6% after 1 or 2 FMTs.²⁷  These positive outcomes have led to the inclusion of FMT in therapeutic algorithms and guidelines throughout the life span, including the clinical practice guidelines for CDI by the Infectious Diseases Society of America and Society for Healthcare Epidemiology of America.²⁸  In most cases, cure of CDI—typically defined as resolution of symptoms without recurrence within 2 to 3 months after the procedure, can be achieved with only 1 FMT, although some patients may require a second FMT or further treatment with antibiotic therapy.

Indications for consideration of FMT in pediatric patients with CDI have been recommended by the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology and Nutrition.¹⁰  These include a history of recurrent CDI within 8 weeks of receiving treatment, moderate CDI not responsive to standard treatment, or severe or fulminant CDI not responsive to therapy, which is, fortunately, rare in pediatric CDI. It is recommended that a pediatrician consider referring a patient at the time of the first (or second) CDI recurrence to a center with specialists, such as pediatric infectious disease or gastroenterology providers who are experienced with the FMT procedure.

Given that antibiotic use has been identified as the most common associated risk factor for CDI, disruption of the health intestinal microbiota, also called “intestinal dysbiosis,” appears to be at the core of disease pathogenesis.^29,30  Although the mechanisms by which FMT resolves CDI remain unclear, the procedure has been shown to (1) result in durable restoration of normal gut microbial environment as manifested by increased relative abundance of Bacteroidetes (phylum containing multiple symbiotic, beneficial bacterial species) and decreased abundance of Proteobacteria (phylum including many pathogenic bacteria); (2) increase bacterial diversity; (3) result in a microbiome composition more similar to the donor profile; and (4) restore normal fecal bile acid composition.^31–33 

A detailed discussion regarding the FMT procedure itself is beyond the scope of this report but can be found in multiple publications both for adults and children.^10,34  Patients should be referred to centers that have experience with this procedure and are familiar with best practices, including the handling of the fecal suspension, delivery modalities, informed consent, and patient follow-up. Although national guidelines have been developed to standardize FMT, including donor screening and selection, this is a procedure that still contains variability across institutions.¹⁰ 

The process of FMT involves the selection and screening of an appropriate “healthy” donor and then the administration of the fecal material into the recipient’s gastrointestinal tract. Donor screening requires a rigorous process to evaluate risk of infectious diseases and a history of disorders potentially associated with perturbation of gut microbiota, such as chronic gastrointestinal diseases, autoimmune disorders, and obesity. Recommendations from various medical groups and experts employ a combination of screening questionnaires to exclude high-risk donors, donor blood, and stool tests to evaluate for enteric pathogens and serologic evidence of infections.³⁴ 

Donors can be known or unknown to the recipient. Typically, donors are requested to complete an extensive questionnaire similar to that administered for blood donation, undergo health evaluation by their primary care provider, and submit blood and stool samples to evaluate for transmittable infections. With the increasing need to screen for more infectious agents, the ability for individual clinicians to maintain a robust screening process and keep up with regulatory and safety concerns has become more difficult. This has led to an emergence of both institutional and third-party stool banks, typically operating under the regulatory authority of the FDA in the United States, to facilitate a more cost-effective, standardized, and traceable process in the collection, storage, and distribution of feces from screened undirected healthy donors. Using banked stool also reduces the likelihood of confidentiality concerns for the donor because they are not directly known to the recipient. Typically healthy, younger individuals (<40 years) with normal BMI are preferred as potential donors, and it is not uncommon for the vast majority of potential donors to be excluded from stool donation after screening medical evaluation.³⁵ 

If FMT is being performed with an identified donor known to the recipient, the processing of the fresh fecal material, such as homogenizing with saline and filtration, is often performed immediately before administration. If donor feces are to be banked, after processing, it is divided into aliquots, preferably with a cryoprotectant, and stored at −80°C. Fecal material for FMT can be delivered via oral capsules; nasogastric, nasoduodenal, gastrostomy, or jejunostomy tube; enema; or colonoscopy. For children and adults, most FMTs in the United States are performed by gastroenterologists who acquire material from donor stool banks and administer the transplant via colonoscopy, but in some institutions, infectious disease specialists also perform FMT.²⁶  Safety of intragastric administration has been reported in children.³⁶ 

FMT is vulnerable to a misperception that it can be performed safely as a “do-it-yourself” at-home procedure.³⁷  Lack of access to a provider who performs FMT, perceived delay in being able to obtain an FMT, associated cost, or a growing preference to managing conditions with little medical evidence have led to individuals performing FMTs at home either on themselves or their children using information from the internet or social media. In these do-it-yourself cases, recipients typically receive stool from a donor who is known to them. A clear risk in performing FMT in this manner is that the donor is not rigorously screened for chronic conditions and communicable diseases as is currently performed in clinical settings. There is also potential risk of damaging the colon or rectum while administering the enema. FMT also presents particular ethical issues that impact children, who are a vulnerable group because parents or guardians give consent on behalf of the child.³⁷  It is not uncommon for parents to believe that FMT is “safe” because they view it as more “natural” than medications.³⁸ 

Safety remains one of the greatest concerns with this procedure. Patients receiving FMT need to be monitored for procedure-related adverse reactions, including transmission of significant infections (eg, viral hepatitis or resistant organisms), hospitalizations, life-threatening events, and death. It is important to highlight that the FDA policy of enforcement discretion and the wide adoption of FMT in clinical practice has occurred without standard investigatory pathways being undertaken, such as larger randomized controlled trials that provide safety data before a product comes to market. Encouragingly, infectious short-term adverse reactions have been quite rare—in the range of 1% to 2%—even for immunocompromised adults.^25,39,40  However, serious infections have been highlighted by an FDA report in 2020 of 2 adult cases, including 1 fatality, of extended-spectrum β-lactamase-producing Escherichia coli infections that were suspected of being transmitted via donor stool that had not been screened for the organism.⁴¹  The need for appropriate donor screening was further highlighted after the announcement in March 2020 by the World Health Organization designating coronavirus disease 2019 as a pandemic.⁴²  In the same month, the FDA provided an alert that informed of the potential risk of FMT transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and recommended that any FMT products manufactured from stool donated on or after December 1, 2019 should not be used clinically until additional tests and criteria were met, including donor screening for SARS-CoV-2 diagnosis and testing to detect the presence of SARS-CoV-2 virus or RNA in the donor stool.⁴³  This led to Openbiome (Cambridge, MA), a nonprofit stool bank, discontinuing the provision of FMT material except in emergency cases from July 2020 until May 2021 while the company worked to develop and validate a test for SARS-CoV-2 in stool. However, providers were still able to obtain fecal material for emergency cases from a stock the company had collected before December 1, 2019.

Other short-term adverse events have been reported and may vary by route of FMT delivery. These include aspiration pneumonia when FMT is delivered via nasogastric or nasoduodenal and perforation when administered via colonoscopy.^27,39  The potential for other long-term consequences of FMT remains unknown. Although new conditions have been reported after FMT, no cause and effect has been proven.⁴⁴  The intestinal microbial community’s impact on human health and disease is significant, and although at this time we do not have clear knowledge as to whether transferring the microbiome from one individual to another will lead to long-term adverse effects, this concern may be more than theoretical, because transferring the microbiome in laboratory animals can increase the risk for certain chronic and/or autoimmune diseases associated with a particular microbiome.⁴⁵  The FDA requires that before FMT, informed consent be obtained and include a statement highlighting that the procedure remains investigational and that there are unknown future risks associated with FMT, including increased risk of developing a disease phenotype (eg, obesity) or a chronic disorder (eg, an autoimmune condition) that may be associated with intestinal microbiome changes.

The increasingly rapid acquisition of information about the human gut microbiome, the clinical success of FMT for CDI, and the explosion of interest on these topics in the media have led many patients to seek FMT for a variety of indications other than treatment of CDI, despite limited data to suggest efficacy in other conditions. As such, it is important for the pediatric medical community to understand the current state of research in FMT. Similar to the intestinal dysbiosis associated with CDI, there is mounting evidence that alterations in microbial composition may result in disturbances in metabolic processing or localized inflammation and may also play a significant role in multiple disease conditions, such as Crohn disease, ulcerative colitis, obesity, metabolic syndrome, autism spectrum disorder, and reduction of intestinal multidrug-resistant bacteria.^46–52  However, most of these conditions are more complicated than CDI, and the high efficacy of FMT for CDI has not been replicated in other chronic conditions for which results have been modest at best, even with repeated FMTs and variable across patients. Therefore, at this time, there are insufficient data to recommend FMT as treatment of any of these indications in clinical practice, and currently FMT use for conditions other than CDI should be limited to the research setting.

With the significant rise of FMT for CDI since 2013, came the emergence of nonprofit stool banks such Openbiome, which started in 2012 and subsequently became the principal supplier within the United States for most institutions and practices offering FMT, including those that had initially offered FMT by screening donors and processing the stools themselves. Obtaining material from a stool bank was advantageous to FMT providers, because as time went on, the expected screening process became more rigorous and laborious for individual clinical providers. The safety concerns involved with FMT, the realization that the demand for fecal material could outstrip supply, the decreased accessibility of FMT to many patients because of geographic location and the coronavirus disease 2019 pandemic, and the inherent variability of human feces led to pursuit of other options.⁵³  Inspired by the success of FMT for CDI, the race to find pharmacologic alternatives to FMT have led to the development of well-defined mixtures of selected microorganisms designed according to their proposed roles in the microbiota against CDI. Currently, several microbial therapeutics are in various stages of clinical trials in adults for CDI. The hope for the products, once approved, is that they will work similarly or better than FMT and will be simple to administer, reproducible, and cost-effective. Additionally, the development of standardized, laboratory-derived microbiota therapeutics has enabled research in a variety of conditions other than CDI.^54,55 

Although the anticipated benefit of these commercial microbiota therapeutics is appealing, they will likely come with their own set of challenges for children. Initial approval of any of these is likely to be for use in adults only, because these agents have not yet been studied in pediatric populations and there are no safety or efficacy data to inform therapy decisions in children. Although they could be prescribed for children for off-label use, accessibility will be difficult for pediatric patients because of lack of insurance coverage and lack of clear guidance on dosing. Inappropriate prescribing may also occur as patients may demand, and providers may prescribe, such products for conditions for which patients are unlikely to benefit. As with FMT, ensuring that these therapies are of reasonable cost and are covered by both public and commercial insurance will be key to increase availability to patients and reduce disparities in access to care. It is also important to advocate that clinical trials for microbial therapeutic products include pediatric populations.

1. There are no prospective pediatric clinical trials using FMT to treat CDI.

2. Studies support the use of FMT in pediatric patients with moderate to severe or recurrent CDI.

3. FMT is not recommended for the clinical treatment of any other medical conditions at this time.

4. Do-it-yourself, at-home FMT should not be performed in children for safety reasons.

5. It is recommended that FMT be performed in a center with experience in the procedure.

6. There is a lack of regulatory standards for fecal preparations for FMT.

7. The long-term effects of FMT are unknown.

8. The field of microbial therapies is anticipated to quickly advance and potentially bring commercial products for the treatment of CDI.

Maria M. Oliva-Hemker, MD, FAAP

Stacy A. Kahn, MD, FAAP

William Steinbach, MD, FAAP

Mitchell B. Cohen, MD, FAAP, Chairperson

David Brumbaugh, MD, FAAP

Conrad Cole, MD, FAAP

Jennifer L. Dotson, MD, FAAP

Sanjiv Harpavat, MD, PhD, FAAP

Jenifer R. Lightdale, MD, FAAP, Immediate Past Chairperson

Daniel Mallon, MD, FAAP

Maria M. Oliva-Hemker, MD, FAAP

Debra L. Burrowes, MHA

Yvonne A. Maldonado, MD, FAAP, Chairperson

Sean T. O’Leary, MD, MPH, FAAP, Vice Chairperson

Monica I. Ardura, DO, MSCS, FAAP

Ritu Banerjee, MD, PhD, FAAP

Kristina A. Bryant, MD, FAAP

James D. Campbell, MD, MS, FAAP

Mary T. Caserta, MD, FAAP

Chandy C. John, MD, MS, FAAP

Jeffrey S. Gerber, MD, PhD, FAAP

Athena P. Kourtis, MD, PhD, MPH, FAAP

Adam J. Ratner, MD, MPH, FAAP

José R. Romero, MD, FAAP

Samir S. Shah, MD, MSCE, FAAP

Kenneth M. Zangwill, MD, FAAP

William J. Steinbach, MD, FAAP

David W. Kimberlin, MD, FAAP – Red Book Editor

Elizabeth D. Barnett, MD, FAAP – Red Book Associate Editor

Ruth Lynfield, MD, FAAP – Red Book Associate Editor

Mark H. Sawyer, MD, FAAP – Red Book Associate Editor

Henry H. Bernstein, DO, MHCM, FAAP – Red Book Online Associate Editor

Amanda C. Cohn, MD, FAAP – Centers for Disease Control and Prevention

Karen M. Farizo, MD – US Food and Drug Administration

Lisa M. Kafer, MD, FAAP – Committee on Practice Ambulatory Medicine

David Kim, MD – HHS Office of Infectious Disease and HIV/AIDS Policy

Eduardo López Medina, MD, MSc – Sociedad Latinoamericana de Infectologia Pediatrica

Denee Moore, MD, FAAFP – American Academy of Family Physicians

Lakshmi Panagiotakopoulos, MD, MPH, FAAP – Centers for Disease Control and Prevention

Laura Sauvé, MD, FCPS – Canadian Paediatric Society

Neil S. Silverman, MD – American College of Obstetricians and Gynecologists

Jeffrey R. Starke, MD, FAAP – American Thoracic Society

Kay M. Tomashek, MD, MPH, DTM – National Institutes of Health

Jennifer M. Frantz, MPH

CDI

Clostridioides difficile infection

FDA

US Food and Drug Administration

FMT

fecal microbiota transplantation