5

Decision

Considerations for Use of Fecal Microbiota Transplantation in Special Patient Populations

Rohma Ghani, MBBS, MRCP and Benjamin H. Mullish, MB, BChir, MRCP, PhD

As recognition of the utility of fecal microbiota transplantation (FMT) continues to grow, so does the scope of individuals who may potentially benefit from it.¹ Many special patient populations, including pediatric and immunocompromised patients, as well as pregnant patients, were excluded from early FMT clinical trials due to concerns about both the safety and efficacy of using a therapy containing live microorganisms within such patients. However, as experience grows and as longer-term data begin to emerge, there is increasing confidence about the optimal use of FMT in these patient groups. This chapter summarizes unique populations, focusing on the use of FMT for Clostridioides difficile infection (CDI; previously Clostridium difficile infection) and describing the use of FMT for non-CDI indications where experience exists. We will also explore common clinical scenarios that can pose challenges for treating clinicians.

Diagnosis of CDI in children may present a diagnostic challenge because colonization or transient carriage of C. difficile—without true toxin-producing infection—is common, and diarrhea is a common pediatric presentation with multiple possible etiologies. Particular risk factors for CDI in children include antimicrobial and proton-pump inhibitor use, enteral feeding, inflammatory bowel disease (IBD), recent surgery, malignancy, and immunosuppression (eg, due to organ transplantation).2 Although first-line treatment for pediatric CDI may be broadly similar in approach to adults, there are more notable differences in the treatment of recurrent CDI (rCDI); one relevant issue is that fidaxomicin is not yet approved by the US Food and Drug Administration in children younger than 12 years.²

FMT is therefore an attractive alternative option for the treatment of rCDI in children. However, one specific concern regarding the use of FMT in this group has been that the long-term consequences of manipulation of the gut microbiota remain largely unknown. In particular, given the range of clinical conditions in which an association with a perturbed gut microbiota has been described, there is a theoretical concern that the trade-off for successfully treating rCDI in a child with FMT may be transfer of a microbiota trait associated with increased future risk of an alternative condition. However, this remains theoretical, without any evidence that this has occurred in clinical practice.

The largest evidence base to date on FMT in children arises from a recent multicenter retrospective cohort study of 335 patients (age range: 11 months to 23 years) receiving FMT for CDI (Table 5-1).³ The remission rate after a single FMT was 81%; adverse events were generally similar in frequency and character to those occurring in adult FMT recipients. As such, it has been argued that for children with rCDI, the risk from the known detrimental effects of further antibiotics upon the gut microbiota is typically outweighed by the potential benefits of FMT, despite the currently limited knowledge of any potential long-term impact that FMT may have.³ In a recent joint position paper from North American and European pediatric gastroenterology societies, the use of FMT following standard-of-care antibiotics was recommended in children with CDI for similar indications to that typically recommended in adults.² FMT for children with potential non-CDI indications is a field in which there are a number of ongoing randomized trials, but where experience is generally limited, and no specific recommendations may be made at present.²

Immunocompromised patients are a group at higher risk of rCDI due to a number of factors, including their impaired humoral immunity and increased need for antibiotics. However, there were initial concerns regarding the safety of using microbiome therapies such as FMT within this vulnerable population. There is now evidence from a small number of patients in a randomized clinical trial,10 a growing number of case reports and case series,^5,11–14 and a systemic review¹⁵ that collectively demonstrates that, overall, FMT for rCDI is of similar safety and efficacy in patients with a wide variety of immunocompromised states in comparison to immunocompetent individuals (see Table 5-1). The reported literature includes patients with causes of immunocompromise including immunosuppressant agents (eg, chemotherapy, thiopurines, ciclosporin, anti–tumor necrosis factor therapy, corticosteroids), HIV infection (or other inherited or primary immunodeficiency syndromes), end-stage kidney disease, hematologic malignancy or solid organ tumors, or transplant of either a solid organ or bone marrow. Neutropenia does not obviously appear to increase the risk of adverse outcomes from FMT,¹² although experience still remains relatively limited, particularly in the case of severe neutropenia (absolute neutrophil count < 1000/uL). However, this evidence base represents heterogeneous study designs and relatively limited follow-up,¹⁵ and, therefore, the potential suitability of FMT for an immunocompromised recipient should still be considered on a case-by-case basis, balancing potential risk with benefit (Practical Pearl 5-1).

Solid organ transplant (SOT) recipients have been a particular discussion point regarding the suitability for FMT. Previously, when FMT was an emerging practice, the American Society of Transplantation advised against FMT in these patients,¹⁶ outlining theoretical concerns about transferring bacteria into a gut with a disrupted gut mucosal barrier and associated potential risks of bacterial translocation. In 2019, Cheng et al¹⁷ reported on 94 SOT patients who were treated with FMT for CDI. Overall, severe adverse events were noted to be around 3.4%, a rate comparable to the immunocompetent population. However, importantly, it was noted that 3 cytomegalovirus (CMV) seropositive patients underwent CMV reactivation shortly after FMT. These cases are notably different from the previously discussed concern regarding seroconversion in recipients who are negative for CMV. Furthermore, there have been 2 cases of extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli bacteremia in immunocompromised recipients (1 patient with cirrhosis and hepatic encephalopathy and 1 following bone marrow transplantation who died) after transmission from an ESBL E. coli–colonized donor.18,19 Importantly, the donor had not undergone appropriate ESBL stool testing, emphasizing the importance of screening for intestinal colonization of multi-drug–resistant organisms in all potential donors (see Chapter 6: “Donor: How Do You Select and Screen Candidate Donors for Fecal Microbiota Transplantation?”).^20–23

Immunocompromised patients should be considered candidates for FMT for recurrent, refractory, severe, and fulminant CDI. In patients who are severely immunocompromised (eg, organ transplant recipients on multiple immunosuppressive agents) and test negative for CMV, a CMV-negative donor should be identified if possible, and the patient should be counseled that risks of infection may be higher if the donor is CMV positive. It may be clinically rational to defer FMT until after completion of chemotherapy in cancer patients with multiply rCDI who remain asymptomatic during treatment with vancomycin.

Rates of CDI in patients with IBD, particularly those with ulcerative colitis, may be up to 8-fold higher than in patients without IBD.24 Furthermore, patients with IBD who develop CDI are more likely to develop adverse health outcomes, including higher rates of IBD flares, longer hospital stays, more CDI recurrences, and increased rates of failure of medical therapy for IBD, need for surgery, and mortality.²⁴ Treatment of CDI in patients with IBD itself presents particular challenges, including difficulty in distinguishing an IBD flare from CDI and uncertainty about the appropriateness of continuation of potent immunosuppressive IBD therapy during treatment for CDI.²⁴ Confirming active CDI in IBD patients is often a challenge that complicates the decision to perform FMT, particularly because it is not always clear whether symptoms are related to the C. difficile or the underlying disease process. Because a C. difficile polymerase chain reaction (PCR) assay does not distinguish colonization from active infection, one may consider using the more specific toxin enzyme immunoassay; however, some clinicians feel the presence of C. difficile in the setting of disease flare is an indication for standard-of-care CDI antibiotics, whether or not the toxin is detectable. CDI may exacerbate IBD activity, which often adds to the dilemma of decision and timing of FMT; therefore, we recommend optimization of IBD medications to eliminate that as a potential confounder. In addition, given the higher likelihood of adverse outcomes with CDI in IBD patients, FMT may be considered after 2 or more CDI episodes, even without history of severe CDI disease.

The initial data regarding outcomes of FMT in the treatment of CDI in patients with IBD were retrospective in nature. These data demonstrated overall reduced efficacy at preventing CDI recurrence in patients with IBD, with reports of IBD flare rates between 18% and 54%, although flares were poorly defined.^25–27 In contrast, a subsequent systematic review of randomized clinical trials and high-quality studies in which FMT had been administered to patients with IBD identified much lower rates of worsening of IBD activity, reported as 4.6% (see Table 5-1).^7,28 One potential explanation for the apparent disparity between these results from retrospective and randomized studies may have been the use of C. difficile PCR testing in the former group and potential misattribution of IBD flares as CDI episodes. A prospective multicenter cohort study of FMT in patients with rCDI and comorbid IBD by Allegretti et al²⁹ reported high rates of clinical cure of CDI, in keeping with cure rates in non-IBD patients, and also noted IBD disease activity improvement. There was only a single case of an IBD de novo flare (1/50) reported. Overall, FMT is felt to be safe and effective for the treatment of CDI in patients with IBD, but patients should be counseled about a small potential risk of disease flare.20 In IBD, a lower gastrointestinal route of administration is preferred because it may help assess IBD disease activity at the time of FMT. IBD patients with CDI may not have classic pseudomembranes, even in severe cases. Nonresponsive patients should also be assessed for alternate etiologies, including opportunistic infections, concomitant celiac disease, common variable immunodeficiency, or other immunodeficiency states. Routine mucosal biopsies should also be obtained to assess histologic disease activity at time of FMT, particularly in patients with inflammation on endoscopy to rule out CMV infection, and especially in patients on biologic agents or other immunosuppressive therapy. The existing evidence supports referral for FMT in IBD patients with rCDI and is supported by experts in best practice guidelines.²²

Pregnancy

There is limited experience regarding the use of FMT in this patient population. One case report describes successful administration of FMT for CDI in a pregnant patient at 18 weeks’ gestation via colonoscopy. Her symptoms resolved after a single FMT, with normal delivery of the baby at 39 weeks.⁶ Most authorities would recommend avoiding FMT during pregnancy unless there was a very compelling indication for its consideration.

Food Allergy and Anaphylaxis

Concerns have been raised regarding the potential triggering of food allergies in patients who receive stool from donors who may have food allergens for that recipient in their diet, and therefore also potentially within their stool. To date, there does not appear to be any published reports of an anaphylactic reaction post-FMT; however, most FMT studies have excluded potential recipients with a history of severe food allergy/anaphylaxis, and this is still viewed as at least a relative contraindication to receiving FMT from a universal donor in some clinical guidelines.^20,30

Where there is uncertainty as to whether a potential FMT recipient has a true food allergy, one approach may be referral for evaluation by an allergist for confirmation.²⁸ Should the allergy be confirmed, clinicians could consider preparing the FMT from the stool of a patient-identified donor who has omitted the potential allergens from their diet for 1 week.28 Similarly, where a recipient has celiac disease, it may be reasonable to consider FMT preparation from a patient-identified donor on a gluten-free diet.²⁰

Conversely, there is growing interest in the potential contribution of gut microbiota–host immune system interactions to the development of food allergy, and a Phase 1 open-label trial is in place to evaluate the use of FMT by capsule in the treatment of peanut allergy.³¹

Concomitant Antibiotics

One challenging scenario for clinicians is the administration of FMT to patients with rCDI who also have a strong indication for long-term, non-CDI antibiotics (eg, splenectomy, osteomyelitis), or recipients who develop a non-CDI–related indication that requires antibiotics shortly after receiving FMT. In this scenario, the central concern is that the use of antimicrobials may reduce engraftment of FMT-derived microbial communities within the host and, therefore, limit its effectiveness. Furthermore, there is now supporting evidence that this may also be the case in clinical practice; for instance, approximately 50% of the FMT failures from the Dutch Donor Feces Bank in preventing rCDI occurred in patients receiving antibiotics within 1 month of their FMT.³⁰ In addition, a retrospective study demonstrated that use of non–anti-CDI antibiotics within 8 weeks of FMT is associated with an approximately 3-fold risk of FMT failure.³²

One clinical message from such studies is to only administer non-CDI antibiotics to FMT recipients within the early post-FMT period (ie, up to 8 weeks) when there is a compelling indication. Where non-CDI antibiotics cannot be avoided, liaison with infectious disease/medical microbiology specialists is recommended to attempt to identify the most “microbiota-protective” antimicrobial regimen possible.²⁰

As the evidence base continues to grow, the potential utility of FMT also increases. To date, studies evaluating FMT in special populations have predominantly consisted of heterogeneous retrospective case series, and gaps in knowledge are therefore still wide. Reassuringly, efficacy of FMT for CDI in these populations appears generally similar to conventional recipients, and the reported rates of serious adverse events still appear to be low overall. Hopefully this will translate to such patients being included in future FMT trials where they may previously have been ineligible. The establishment of national FMT registries, such as those established in the United States33 and Germany,³⁴ will also provide a valuable resource for the further evaluation of the long-term safety and efficacy of FMT in special populations.

References

1.      Allegretti JR, Mullish BH, Kelly C, Fischer M. The evolution of the use of faecal microbiota transplantation and emerging therapeutic indications. Lancet. 2019;394(10196):420-431.

2.      Davidovics ZH, Michail S, Nicholson MR, et al. Fecal microbiota transplantation for recurrent Clostridium difficile infection and other conditions in children: a joint position paper from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2019;68(1):130-143.

3.      Nicholson MR, Mitchell PD, Alexander E, et al. Efficacy of fecal microbiota transplantation for Clostridium difficile infection in children. Clin Gastroenterol Hepatol. 2020;18(3):612-619.e1.

4.      Hourigan SK, Oliva-Hemker M. Fecal microbiota transplantation in children: a brief review. Pediatr Res. 2016;80(1):2-6.

5.      Abu-Sbeih H, Ali FS, Wang Y. Clinical review on the utility of fecal microbiota transplantation in immunocompromised patients. Curr Gastroenterol Rep. 2019;21(3):8.

6.      Saeedi BJ, Morison DG, Kraft CS, Dhere T. Fecal microbiota transplant for Clostridium difficile infection in a pregnant patient. Obstet Gynecol. 2017;129(3):507-509.

7.      Qazi T, Amaratunga T, Barnes EL, Fischer M, Kassam Z, Allegretti JR. The risk of inflammatory bowel disease flares after fecal microbiota transplantation: systematic review and meta-analysis. Gut Microbes. 2017;8(6):574-588.

8.      Chen T, Zhou Q, Zhang D, et al. Effect of faecal microbiota transplantation for treatment of Clostridium difficile infection in patients with inflammatory bowel disease: a systematic review and meta-analysis of cohort studies. J Crohn’s Colitis. 2018;12(6):710-717

9.      Cho S, Spencer E, Hirten R, Grinspan A, Dubinsky MC. Fecal microbiota transplant for recurrent Clostridium difficile infection in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2019;68(3):343-347.

10.    Lee CH, Steiner T, Petrof EO, et al. Frozen vs fresh fecal microbiota transplantation and clinical resolution of diarrhea in patients with recurrent Clostridium difficile infection a randomized clinical trial. JAMA. 2016;315(2):142-149.

11.    Rubin TA, Gessert CE, Aas J, Bakken JS. Fecal microbiome transplantation for recurrent Clostridium difficile infection: report on a case series. Anaerobe. 2013;19:22-26.

12.    Hefazi M, Patnaik MM, Hogan WJ, Litzow MR, Pardi DS, Khanna S. Safety and efficacy of fecal microbiota transplant for recurrent Clostridium difficile infection in patients with cancer treated with cytotoxic chemotherapy: a single-institution retrospective case series. Mayo Clin Proc. 2017;92(11):1617-1624.

13.    Agrawal M, Aroniadis OC, Brandt LJ, et al. The long-term efficacy and safety of fecal microbiota transplant for recurrent, severe, and complicated Clostridium difficile infection in 146 elderly individuals. J Clin Gastroenterol. 2015;50(5):403-407.

14.    Kelly CR, Ihunnah C, Fischer M, et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol. 2014;109(7):1065-1071.

15.    Shogbesan O, Poudel DR, Victor S, et al. A systematic review of the efficacy and safety of fecal microbiota transplant for Clostridium difficile infection in immunocompromised patients. Can J Gastroenterol Hepatol. 2018;2018:1-10.

16.    Dubberke ER, Burdette SD; AST Infectious Diseases Community of Practice. Clostridium difficile infections in solid organ transplantation. Am J Transplant. 2013;13(suppl 4:)42-49.

17.    Cheng YW, Phelps E, Ganapini V, et al. Fecal microbiota transplantation for the treatment of recurrent and severe Clostridium difficile infection in solid organ transplant recipients: a multicenter experience. Am J Transplant. 2019;19(2):501-511.

18.    US Food and Drug Administration. Important safety alert regarding use of fecal microbiota for transplantation and risk of serious adverse reactions due to transmission of multi-drug resistant organisms. June 13, 2019. Accessed June 13, 2020. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/important-safety-alert-regarding-use-fecal-microbiota-transplantation-and-risk-serious-adverse

19.    US Food and Drug Administration. Fecal microbiota for transplantation: safety communication – risk of serious adverse reactions due to transmission of multidrug resistant organisms. June 13, 2019. Updated June 18, 2019. Accessed June 13, 2020. https://www.fda.gov/safety/medwatch-safety-alerts-human-medical-products/fecal-microbiota-transplantation-safety-communication-risk-serious-adverse-reactions-due

20.    Mullish BH, Quraishi MN, Segal JP, et al. The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridium difficile infection and other potential indications: joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines. Gut. 2018;67(11):1920-1941.

21.    Cammarota G, Ianiro G, Tilg H, et al. European consensus conference on faecal microbiota transplantation in clinical practice. Gut. 2017;66(4):569-580.

22.    Kassam Z, Dubois N, Ramakrishna B, et al. Donor screening for fecal microbiota transplantation. N Engl J Med. 2019;381(21):2070-2072.

23.    DeFilipp Z, Bloom PP, Torres Soto M, et al. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant. N Engl J Med. 2019;381(21):2043-2050.

24.    Khanna S, Shin A, Kelly CP. Management of Clostridium difficile infection in inflammatory bowel disease: expert review from the Clinical Practice Updates Committee of the AGA Institute. Clin Gastroenterol Hepatol. 2017;15(2):166-174.

25.    Khoruts A, Rank KM, Newman KM, et al. Inflammatory bowel disease affects the outcome of fecal microbiota transplantation for recurrent Clostridium difficile infection. Clin Gastroenterol Hepatol. 2016;14(10):1433-1438.

26.    Chin SM, Sauk J, Mahabamunuge J, Kaplan JL, Hohmann EL, Khalili H. Fecal microbiota transplantation for recurrent Clostridium difficile infection in patients with inflammatory bowel disease: a single-center experience. Clin Gastroenterol Hepatol. 2017;15(4):597-599.

27.    Fischer M, Kao D, Kelly C, et al. Fecal microbiota transplantation is safe and efficacious for recurrent or refractory Clostridium difficile infection in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2016;22(10):2402-2409.

28.    Allegretti JR, Kassam Z, Osman M, Budree S, Fischer M, Kelly CR. The 5D framework: a clinical primer for fecal microbiota transplantation to treat Clostridium difficile infection. Gastrointest Endosc. 2018;87(1):18-29.

29.    Allegretti JR, Kelly CR, Grinspan A, et al. Outcomes of fecal microbiota transplantation in patients with inflammatory bowel diseases and recurrent Clostridioides difficile infection. Gastroenterology. 2020;s0016-5085(20)35008-3.

30.    Terveer EM, van Beurden YH, Goorhuis A, et al. How to: establish and run a stool bank. Clin Microbiol Infect. 2017;23(12):924-930.

31.    Zhao W, Ho HE, Bunyavanich S. The gut microbiome in food allergy. Ann Allergy Asthma Immunol. 2019;122(3):276-282.

32.    Allegretti JR, Kao D, Sitko J, Fischer M, Kassam Z. Early antibiotic use post-fecal microbiota transplantation increases the risk of treatment failure. Clin Infect Dis. 2017;66(1):134-135.

33.    Kelly CR, Kim AM, Laine L, Wu GD. The AGA’s Fecal Microbiota Transplantation National Registry: an important step toward understanding risks and benefits of microbiota therapeutics. Gastroenterology. 2017;152(4):681-684.

34.    Peri R, Aguilar RC, Tüffers K, et al. The impact of technical and clinical factors on fecal microbiota transfer outcomes for the treatment of recurrent Clostridioides difficile infections in Germany. United European Gastroenterol J. 2019;7(5):716-722.