How Do You Discuss the Risks and Benefits of Fecal Microbiota Transplantation?
Majdi Osman, MD, MPH and Pratik Panchal, MD, MPH
Fecal microbiota transplantation (FMT) remains an investigational therapy; however, there has been significant media coverage that is likely to shape your patient’s perceptions of FMT prior to counseling the patient for the procedure.1 The widespread awareness of FMT may not have necessarily translated into a fully informed understanding of the risks, benefits, and alternatives. Sources of inaccurate information are widely available online, and patients may have preconceived ideas on the risks associated with FMT, as well as the potential benefits.2 This lack of awareness around the risks, compounded by challenges in access, can manifest in patients seeking out do-it-yourself (DIY) treatments that present an increased hazard due to inadequate donor screening and handling of material.3 Patients may also believe that FMT could offer cures for seemingly intractable diseases beyond Clostridioides difficile infection (CDI) despite no current evidence or guideline recommendations supporting routine use other than for prevention of recurrent CDI.
Clear communication of the risks of FMT is crucial prior to treatment. The case reports of extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli bacteremia following FMT highlights the importance of ensuring that risks are adequately understood.4 Potential risks may also require some clarification with your patient to ensure the nuances are fully appreciated and to enable the patient to make an informed decision. For example, a single case report of new-onset obesity post-FMT from an overweight donor garnered significant media attention in 2015.5 However, although weight change could be a potential risk of FMT, a more thorough analysis of 173 patients who received FMT using material from donors who were overweight, obese, and normal-weight revealed no significant weight changes post-FMT compared with their pre-CDI weight, regardless of donor weight.6 Therefore, it is critical that when patients are initially counseled, they fully understand both the existing evidence on the risks and the potential risks that have yet to be reported.
This chapter provides you with the key points to cover when discussing FMT with your patients to support them in being fully informed ahead of undergoing treatment. This chapter will also provide advice on pre- and post-FMT care, as well as setting expectations around FMT in the context of CDI.
Given the paucity of long-term safety data for FMT, it is critical to conduct and document a thorough informed consent discussion with the patient. This discussion should cover the risks and benefits of FMT material and the delivery modality, as well as any alternative treatment options, including no treatment. In addition, patients must be made aware that FMT is considered an investigational therapy, in keeping with guidance from regulatory agencies. Template informed consents are available from the Infectious Diseases Society of America7; however, you should make sure that the form is adapted to clearly communicate the appropriate information for your patient population and that it complies with your institution’s policies. Complications related to the method of administration should be discussed separately, and patients should be given standard informed consent prior to these procedures.
In the rapidly evolving science on the microbiome, any discussion on the risks of FMT faces the challenge of navigating the nuances in clear language suitable for your patient. Approaching the discussion with your patient to understand his or her ideas, concerns, and expectations of FMT should be the initial starting point for the informed consent process.
The patient should be informed of common, mild side effects and potentially serious or life-threatening adverse events. Reactions potentially related to FMT include transient diarrhea, abdominal cramps/discomfort and nausea, fever, bloating, belching, vomiting, borborygmus, constipation, and excess flatulence.8 These symptoms are usually self-limiting and of short duration. They may also be attributable to the delivery modality (eg, colonoscopy or upper endoscopy; Practical Pearl 7-1). There remains a paucity of prospective long-term follow-up data. Accordingly, the American Gastroenterological Association (AGA) has initiated a prospective FMT registry that will follow patients for up to 10 years. The following potential short- and long-term serious adverse events should be communicated to the patient.
Although material should have been screened for common enteric pathogens and antibiotic-resistant bacteria, there is a risk of transmission of known and unknown infectious organisms contained in the donor stool. Post-FMT bacteremia, sepsis, and fatal events may occur. Cases reported in the literature include bacteremia, cytomegalovirus (CMV) colitis, pyrexia of unknown origin, influenza B transmission, and non-CDI diarrhea (eg, norovirus).8–10
Immunocompromised patients should receive further counseling pre-FMT given the potential increased risk of bacteremia in this population. A multicenter retrospective study of immuno compromised patients receiving FMT to treat CDI did not report any infectious adverse events in this high-risk cohort.11 However, the case report of ESBL E. coli bacteremia post-FMT in 2 immunocompromised patients highlights the risk.4 Of note, in this case, the donor used to provide the treatments associated with these cases, administered by a hospital-based stool bank, was not screened for ESBL. Nevertheless, patients should be counseled on the risk of colonization, translocation, and infection.
Practical Pearl 7-1
What Are the Common Symptoms Your Patients May Experience Post–Fecal Microbiota Transplantation?
|Transient Gastrointestinal Symptoms|
24 Hours Following FMT
|% Occurrence in the Literature|
|During the 8-Week Follow-Up Period|
|Infection Transmission Related to Fecal Microbiota Transplantation|
Sources: DeFilipp et al,4 Lee et al,34 Osman et al,35 and Wang et al.8
Patients who are immunosuppressed and at particularly high risk of CMV or Epstein-Barr virus (EBV) infection should be counseled about the potential for additional risk of viral infections post-FMT. To date, there have only been 2 documented cases of CMV colitis in the context of FMT and no cases of EBV infection. One case report of CMV colitis occurred in a patient performing at-home, or DIY, FMT for the treatment of ulcerative colitis (UC).12 This patient did not have CDI and used unscreened stool sourced from their child. Another small study assigned UC patients to either treatment with feces from healthy donors or to a control group receiving autologous fecal microbiota. One patient did get CMV; however, interestingly they were in the control group receiving their own autologous FMT.13 Despite the unique features of these cases limiting their generalizability, the risks of both CMV and EBV should be clearly communicated to CMV/EBV-negative immunocompromised patients. In formed consent should also include information about the potential for transmission of severe acute respiratory syndrome coronavirus 2 via FMT, including FMT prepared from stool from donors who are asymptomatic for coronavirus 2019 (see Chapter 6: “Donor: How Do You Select and Screen Candidate Donors for Fecal Microbiota Transplantation?”).
Abdominal pain, appendicitis, peritonitis, and diverticulitis have been reported as possibly related to FMT in cases reported in the peer-reviewed literature.8,14–17 There is a theoretical risk of small intestinal bacterial overgrowth when FMT is delivered into the upper gastrointestinal (GI) tract; however, there have been no reported cases to date.
Allergy/Anaphylaxis to Antigens in Donor Stool
Although no cases of allergy or anaphylaxis have been reported in the literature, patients should be screened for food allergies before FMT. If a patient reports a severe food allergy or anaphylaxis, he or she should be evaluated by an allergist to confirm the allergy if there is clinical uncertainty; if confirmed, one may consider using material from a patient-selected donor who has abstained from the offending agent.
Rheumatoid arthritis, Sjögren’s syndrome, peripheral neuropathy, and idiopathic thrombocytopenic purpura have all been reported in the peer-reviewed literature as possibly related to FMT in a case series.18 There remains a paucity of long-term prospective follow-up evaluating the emergence of autoimmune conditions post-FMT; however, there are 2 retrospective series evaluating the long-term effects following FMT. A Finnish cohort study19 did not detect any increased risk of autoimmune diseases compared with standard-of-care (SOC), with a mean follow-up of 3.8 years. Another cohort from the United States (N = 208) with a mean follow-up of 2.8 years identified 2 cases of psoriatic arthritis and 1 case of mastocytosis.20
Noninfectious Disease Transmission
There is a theoretical risk of developing diseases that may be related to donor gut microbiota. These include obesity, metabolic syndrome, neurologic disorders, psychiatric conditions, and malignancy. Persons with these known conditions should be excluded from donating stool, although a theoretical risk of acquiring these conditions and other unknown microbiome-mediated diseases after FMT remains. In the Finnish cohort,19 there was no significant increase in cases of diabetes mellitus, neurologic diseases, malignancy, or allergies in the FMT cohort compared with those who received SOC. The cohort from the United States reported single cases of diabetes type 2, Alzheimer’s dementia, and new-onset anxiety disorder during the follow-up period.20
Inflammatory Bowel Disease Flare
In those with underlying inflammatory bowel disease (IBD), flares have been reported in retrospective studies in which FMT was performed for CDI, with reports as high as 30%.21 A meta-analysis revealed that among all reports of FMT performed in patients with IBD, the risk of worsening of underlying IBD was higher among the cohort receiving FMT for CDI.22 Patients receiving FMT for the treatment of IBD had negligible rates of IBD worsening. In a prospective trial of 50 IBD patients receiving FMT for the treatment of CDI, only 2% (1/50) of patients met criteria for a de novo flare (quiescent disease at FMT and a documented increase in partial Mayo score post-FMT). Notably, the majority of patients, both UC and Crohn’s disease, experienced improvement in their IBD symptoms. Risk of worsening of IBD should be discussed with your patients; however, if a patient has active IBD at the time of FMT, his or her IBD will likely still be active afterward, and further treatment plans should be discussed. At the time of writing, the large prospective AGA registry reported that among patients with 6 month follow-up, 2 patients (1%) were diagnosed with IBD.25
Long-Term Safety Outcomes
There is a paucity of data on the long-term safety outcomes of FMT. Therefore, a critical point to cover during your discussion is to ensure your patient fully understands that the long-term safety of FMT remains unknown. Of the available data, the long-term safety profile of FMT appears favorable; however, few prospective studies have followed up patients beyond 6 months.18,23,24 This lack of data is especially relevant for counseling pediatric patients. Preliminary results of the real-world AGA registry (N = 259) suggest a favorable safety profile; at 6 months, new diagnoses of irritable bowel syndrome (IBS) were made in 2 patients (1%) and inflammatory bowel disease in 2 patients (1%).25
The chosen delivery modality carries risks independent of FMT material. There have been serious adverse events reported in the peer-reviewed literature determined to be definitely related to the FMT procedure. These include aspiration after upper delivery of FMT and bowel perforation after colonoscopic delivery of FMT.26,27 Importantly, these adverse events were related to the FMT procedure and associated with the delivery modality. Risks related to the FMT procedure should be clearly discussed with the patient, and the choice of delivery modality may depend on the patient or specific clinical situation.
Setting Expectations Following Fecal Microbiota Transplantation
Although FMT has shown promising results in randomized clinical trials and in the real-world setting of CDI, patient expectations should be calibrated appropriately during the discussion. Two points that should be discussed are treatment failure and post-infection IBS (Practical Pearl 7-2).
The potential of treatment failure should be discussed explicitly. In a 328-patient cohort, predictors of FMT failure were severe or severe-complicated CDI, inpatient status during FMT, and previous CDI-related hospitalization. With each additional hospitalization, the odds of failure increased by 43%.28 Therefore, although FMT has been successful in clinical trials (number needed to treat = 3),29 there is potential for treatment failure or incomplete resolution of patient’s symptoms.
Post-Infection Irritable Bowel Syndrome
Patients with CDI have a high risk for developing post-infection IBS, particularly those with longer duration of CDI who might typically be assessed for FMT.30 Up to 25% to 30% of CDI patients develop post-infection IBS. These rates appear similar in FMT patients, where rates of 28% have been observed at 8-week follow-up.31,32 Pre-existing IBS, IBD, duration of CDI greater than 7 days, and raised body mass index have been associated with increased risk of post-infection IBS. Neither donor stool type nor delivery modality was associated with post-FMT IBS symptoms.26–28
Practical Pearl 7-2
Checklist for Discussing Fecal Microbiota Transplantation With Your Patient
Prepare the informed consent documentation
Ask about the patient’s ideas, concerns, and expectations of FMT
◦ Mild symptoms: Transient diarrhea, abdominal cramps/discomfort, nausea, fever, bloating, belching, vomiting, borborygmus, constipation, and excess flatulence
◦ Infection: Life-threatening sepsis, antibiotic-resistant infections, CMV and EBV infection in the immunocompromised patient
◦ Allergy or anaphylaxis
◦ Noninfectious disease transmission
◦ IBD flare
◦ Unknown risk
Discuss lack of evidence on long-term safety outcomes
Review procedure-related risks
◦ Treatment failure
◦ Post-infection IBS
Pre-FMT action items
◦ Cleaning high-touch surfaces at home
◦ Stop antibiotics approximately 2 days before FMT