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Fecal Transplants in the World of Solid Organ Transplantation: A Revolutionary Treatment for Recurrent C.diff or an Infectious Nightmare Waiting in the Wings?


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Cameron Wolfe MBBS(Hons), MPH
Transplant Infectious Disease
Duke University
Durham, North Carolina, USA
cameron.wolfe@duke.edu




At first, it's hard not to be revolted at the idea of a fecal microbiota transplant (FMT). Yet, increasingly robust data suggests it is a remarkably effective treatment for recurrent Clostridium difficile colitis. Although there are limited reports of FMT in patients with solid organ transplants [1], the increasing frequency of C.diff infections in the general community [2] and the increased morbidity and mortality in immunosuppressed hosts mandates transplant clinicians familiarize themselves with the technique.

The incidence is highest in the first three months after transplant, and affects 1.5-31% of the transplant population, compared to 1-2 % of the general hospital population [3]. There are likely multiple factors at play, including greater use of antibiotics - especially in thoracic transplantation, significant immune dysregulation, and underlying multi-organ pathology.

The reported efficacy of FMT is striking (even recognizing selection and reporting bias - immunosuppressed patients were frequently excluded). In a systematic review published this year [4], a total of 536 patients were treated over 24 studies; 467 (87%) noted resolution of diarrhea, typically within just 1-2 days. 81% resolved when stool was instilled into the stomach; 86% into the duodenum/jejunum; 93% into the cecum/ascending colon; and 84% into the distal colon. No major side effects—other than aesthetics!—have been observed, although there are case reports of norovirus transmission [5].

To date, FMT does not have a set place in treatment algorithms, but is most frequently employed after multiple relapses. An individualized approach to treatment is prudent, using metronidazole for mild to moderate disease and vancomycin for more severe or recurrent episodes [6]. Tapered or pulsed vancomycin 'anti-germination' strategies are also employed frequently for recurrent disease. Minimizing antibiotic exposure is crucial for all patients with C.diff, given a common underlying causative and perpetuating factor is the imbalance of normal bowel flora.

There are no standardized methods of donor fecal microbiota collection, processing, dosing or administration. Typically, donor stool undergoes a blending process to liquefy the product and strain out solid matter. Administration can be via an naso-gastric or gastro-jejunal (NG/GJ) tube (eg: 80-100mls), via a retention enema, or via colonoscopy (250-300mls). Concerns over donor-derived infections also exist, and without unified FMT methodology and follow up, it is difficult to quantify true risk. Currently, most centers screen donor serum for Hep A, HIV, HBV, HCV and syphilis. Additionally, stool should be screened for C.diff (PCR), pathogenic bacteria (culture for salmonella, campylobacter etc) and parasites (combination of direct examination and antigen screen for giardia and cryptosporidia). Whether or not centers should screen donor stool for drug resistance, for example, VRE or carbepenemase-resistant Enterobacteriaciae is unclear. Pathogenic viruses such as norovirus can also be difficult to detect for many laboratories, yet they can cause catastrophic illness in SOT recipients. In theory, donors could also be screened for recent travel and even risk factors for window-period infections, in the same way we do for increased-risk organ donors.

We are beginning to understand the interplay between human bacteria and our immune system. In fact, the microbiota may have sustained effects on our physiological, metabolic, and immunologic phenotypes [7]. How this impacts alloimmunity and therefore rates of solid organ rejection remains unknown and is a fertile area for research. These and other important unanswered questions led the U.S. Food and Drug Administration (FDA) to recently request that clinicians apply for an IND prior to treatment with FMT. Although the FDA has since then backed away from this position, many desperate patients (suddenly faced with a treatment delay not to mention dreadful diarrhea) began trying at-home fecal instillations, often with the help of online recipes. No clinician enjoys dealing with the FDA, but the thought of completely unregulated fecal donations in our heavily immunosuppressed population is even more disconcerting.

In summary, fecal transplantation appears likely to increase in popularity over the next few years, even in patients with solid organ transplants. Research should be focused on immunosuppressed populations, particularly with regard to fecal dosing and administration, long-term safety (both for the patient and their graft) and C.diff relapse rate.

Hold onto your hat (and your nose!) - we are about to have a fun ride!

Disclosure Statement: The author has no conflicts of interest to report.


References:

  1. Friedman-Moraco RJ, Mehta AK, Lyon GM, et al. Fecal Microbiota Transplantation for Refractory Clostridium difficile Colitis in Solid Organ Transplant Recipients. American Journal of Transplantation 2014.
  2. Miller BA, Chen LF, Sexton DJ, et al. Comparison of the burdens of hospital-onset, healthcare facility-associated Clostridium dificile Infection and of healthcare-associated infection due to methicillin-resistant Staphylococcus aureus in community hospital. Infect Control Hosp Epidemiol. 2011 Apr;32(4):387-90.
  3. Riddle DJ, Dubberke ER. Clostridium difficile infection in solid organ transplant recipients. Curr Opin Organ Transplant 2008; 13:592-600.
  4. Cammarota G, Ianiro G, Gasbarrini A. Fecal Microbiota Transplantation for the Treatment of Clostridium difficile Infection: A Systematic Review. J Clin Gastroenterol. 2014 Jan 16.
  5. Schwartz M, Gluck M, Koon S. Norovirus gastroenteritis after fecal microbiota transplantation for treatment of Clostridium difficile infection despite asymptomatic donors and lack of sick contacts. AmJ Gastroenterol. 2013 Aug;108(8):1367.
  6. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of Amiera (SHEA) and the infectious diseases society of America (IDSA) Infect Control Hosp Epidemiol. 2010 May;31(5):431-55.
  7. Pamer EG. Fecal microbiota transplantation: effectiveness, complexities, and lingering concerns. Mucosal Immunol. 2014 Jan 8.



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