FECAL MICROBIOTA TRANSPLANT IN CLOSTRIDIUM DIFFICILE INFECTION:
INTRODUCTION:
Data from a retrospective review of patient records in Canada showed that, coincident with the emergence of the 027 strain outbreak in Quebec, the 60-day probability of CDI recurrence with metronidazole increased significantly from 20.8% (between 1991 and 2002) to 47.2% (in 2003–2004; p <0.001), suggesting a possible link with the 027 strain [9]. Among patients infected with the 027 strain of C. difficile in the two randomized controlled trials (RCTs) that compared fidaxomicin with vancomycin, rates of recurrence were significantly higher than those seen in patients infected with other strains (27.4% vs. 16.6%, respectively; p 0.002) [10]. In fact, infection with the 027 strain emerged as a significant risk factor for recurrence in a multivariate analysis of these data (OR 1.57; 95% CI 1.01–2.45; p 0.046) [10].
RECURRENT CLOSTRIDIUM DIFFICILE INFECTION (CDI):
Recurrence is defined as the return of symptoms within 8 weeks after successful treatment. It is estimated that CDI recurs in 25 % of patients, regardless of the type of duration of treatment [\cite{Cohen_2010}. Most recurrences occur within the first 30 days of completing a course of anti-CDI antibiotic therapy, and may arise from a resumption of the primary infection (relapse) or from a new exposure to C. difficile (re-infection). The term, recurrent CDI is used to denote both relapses and reinfection, since these are not generally differentiated in clinical practice.
Previous recurrence, is by itself, a risk factor for further recurrences, with studies showing that risk of recurrence more than doubles after 2 or more episodes [\cite{Bauer_2011}. Advancing age is another risk factor for recurrence as demonstrated by Pepin J et al. [\cite{Pepin_2005}. In a recent systematic analysis, most frequent independent risk factors associated with recurrent CDI were age≥65 years (risk ratio [RR], 1.63; 95% confidence interval [CI], 1.24-2.14; P=.0005), additional antibiotics during follow-up (RR, 1.76; 95% CI, 1.52-2.05; P<.00001), use of proton-pump inhibitors (PPIs) (RR, 1.58; 95% CI, 1.13-2.21; P=.008), and renal insufficiency (RR, 1.59; 95% CI, 1.14-2.23; P=.007). The risk was also greater in patients previously on fluoroquinolones (RR, 1.42; 95% CI, 1.28-1.57; P<.00001) [\cite{Deshpande_2015}. Studies have shown that development of antibodies against C difficile toxins are associated with decreased risk for recurrence. Kyne et al. showed that patients with recurrence had significantly lower concentration of IgG antibody against toxin A at day 12 after onset of diarrhea. [\cite{Katchar_2007}. Another study demonstrated that this IgG deficiency was specifically subclasses IgG2 and IgG3. These suggest that patients with immunodeficiency are more susceptible to recurrent CDI [\cite{Kyne_2001}. Underlying disease severity was also shown to be a risk factor for acquiring nosocomial CDI and also its recurrence. Among hospitalized patients receiving antibiotic therapy and expected to stay in hospital for ≥2 days, the probability of acquiring CDI was 27% in those with a Horn index score of 3 or 4 (severe or fulminant underlying disease), as compared with only 4% in those with scores of 1 or 2 [\cite{Kyne_2002}. In a study validating clinical prediction for recurrent CDI, Age >65 years, the presence of severe underlying disease (modified Horn index score of 3 or 4) and the use of additional antibiotics after discontinuation of CDI therapy emerged as factors that are independently associated with an increased risk of recurrence [\cite{Kelly_2012}. Infection with hyper virulent 027 strain may also render an increased risk for recurrence \cite{Petrella_2012}.
Role of microbioata in CDI recurrence:
CDI recurrence most likely involves two mechanisms: the resistance of C. difficile to metronidazole and vancomycin, and the phenomenon of dysbiosis. Dysbiosis is associated with several diseases such as antibiotic associated diarrhea, irritable bowel syndrome, inflammatory bowel disease, CDI recurrence. Antibiotics generate dysbiosis that is characterized by a reduced diversity of the microbiota, development of opportunistic species, loss of resistance to colonization and increased synthesis of pro-inflammatory cytokines. These disturbances promote colonization and infection with C. difficile, which further contributes to the dysbiosis. Standard antibiotic treatments and recurrent episodes contribute to the development of a vicious cycle [\cite{Zanella_Terrier_2014}].
FECAL MICROBIOATA: The human gut is a habitat of diverse group of organisms, and each individual has a unique signature gut flora composed of 100-1000 species of microbes, predominantly of bacterial species [Zoetendal EG, Akkermans AD, De Vos WM. Temperature gradient gel electrophoresis analysis of 16S rRNA from human fecal samples reveals stable and host-specific communities of active bacteria. Appl Environ Microbiol 1998; 64: 3854–9] [
\cite{Qin_2010}]. The metagenomic explorations into the human gut microbiota have permitted a description of the complete repertoire of microbial genes, highlighting the dominance of bacteria, and also the fact that despite the individual specificity of human gut genome, there are some common features [
\cite{Arumugam_2011}]. Age related changes occur in the gut microbiome, in that infants’ gut microbioata is predominantly seeded with aerobes, and anerobes start predominantly within a few weeks of life, based on factors such as breast feeding, weaning, antibiotic use, etc. [
\cite{Aziz_2012}]. In adults, the gut microbioata appears to be predominated by three clusters – the Bacteroides, the Prevotella, and the Ruminococcus-dominated enterotypes [
\cite{Arumugam_2011}]. With advancing age, immune function declines, and there is a shift towards facultative anaerobes, and is driven by dietary factors, with the microbioata in turn, significantly influencing inflammatory tone and health status [
\cite{Claesson_2010}] The gut microbioata has three major functions- metabolic, protective and trophic. Shifts, or an imbalance in, gut bacterial colonies can precipitate specific disease inducing activity (dysbiosis) or may engender disease protective activity (probiosis). Among the GI diseases associated with alteration in gut flora are acute diarrhea, irritable bowel disease, inflammatory bowel diseases, and certain malabsorption syndromes. Evidence also suggests that altered flora may initiate colon cancer [
\cite{Rowland_2009}]. Antibiotics can have short term effects on gut flora and cause diarrhea due to overgrowth of C. difficile or Vancomycin resistant enterococci.
\cite{Aziz_2012}.
\cite{Zhang_2015}(Zhang 2015)(Zhang 2015)(Zhang 2015)(Zhang 2015)(Zhang 2015)(Zhang 2015)(Zhang 2015)(Zhang 2015)(Zhang 2015)(Zhang 2015)(Zhang 2015) \cite{Rodriguez_2015} FECAL MICROBIOATA TRANSPLANT: FMT was first described in the fourth century when a Chinese doctor administered feces by mouth to patients to treat food poisoning or severe diarrhea, with report of success. Subsequent reports of similar success stories from sixteenth century Ming dynasty are found in literature [\cite{Zhang_2012}]. More modern descriptions date back to 1958 when EIseman and colleagues treated pseudomembranous enterocolitis with fecal enemas with improvement [Eiseman, B., W. Silen, G. S. Bascom, and A. J. Kauvar. “Fecal Enema as an Adjunct in the Treatment of Pseudomembranous Enterocolitis.” Surgery 44, no. 5 (November 1958): 854–59]. The aim of FMT is restoration of ‘normal’ flora to the human gut such that colonization resistance is restored. In a study comparing fecal samples pre and post FMT showed marked differences at both the phylum and genus levels. It suggested that fecal microbiota in post-FMT samples resembles the community of each respective donor rather than the community observed prior to FMT, and that an imbalance of the microbiome during recurrent CDI is at least partially returned to healthy status following FMT despite inter-individual differences in community structure observed prior to FMT [\cite{Seekatz_2014}].
FMT carries a risk for transmission of infectious diseases from donor to recipient, and hence rigorous screening tests are recommended to reduce these risks. Donor stool should be screened for C difficile toxin, enteric bacterial pathogens and parasites such as Giardia ( Giardia a antigen test). Donor blood is screened for hepatitis A (IgM), B (hepatitis B surface antigen, anti–hepatitis B core [IgG and IgM], and anti–hepatitis B surface antigen) and C (HCV antibody) viruses, HIV types 1 and 2, and syphilis. Screening for Helicobacter pylori is also prudent regardless whether FMT is performed via the upper or lower route. Recipients are tested for HIV types 1 and 2; hepatitis A, B, and C; and syphilis. Donors should be excluded if they have received antibiotics within the past 3 months. High-risk sexual behaviors, a body piercing or tattoo in the previous 3 months, or recent incarceration also exclude one from being a donor. A history of chronic diarrhea, constipation, IBD, IBS, colorectal polyps or cancer, immunocompromise, morbid obesity, metabolic syndrome, atopy, and chronic fatigue syndrome are additional donor exclusions because they conceivably may be transmittable by inoculation with intestinal microbiota \cite{Brandt_2013}. FMT can be performed with a related or unrelated donor. Studies have not shown significant differences in the results between the two [\cite{Brandt_2012}]. FMT can be administered via upper GI (nasogastric, nasoenteric, or upper endoscopic) or lower GI (colonoscopic or via enema) routes. Although there have no randomized controlled trials comparing the two routes, an analysis of fourteen studies concluded that FMT delivered via the lower GI seems to be the most effective route for the prevention of recurrence/relapse of CDI [\cite{Furuya_Kanamori_2017}]. However FMT via the upper GI tract route does carry some advantages such as shorter procedure time, longer retention time in the large bowel, and no need of bowel preparation, and is an effective option for the treatment of refractory or severe complicated CDI in patients with old age and a poor medical condition who are not eligible for FMT through the lower GI tract route \cite{Gweon_2016}
FMT IN C DIFF:
Guidelines differ in their strength of recommendation of FMT in C.difficile. While it is only briefly mentioned in Infectious Diseases Society of America (IDSA), these are old and the updated version is in process. It is included among the American College of Gastroenterology (ACG) guidelines, though as a conditional recommendation supported by moderate quality evidence. In more recent guidelines, its grade of recommendation for multiple CDI recurrences is equal (World Society of Emergency Surgery - WSES: 1-B) or even higher (European Society of Clinical Microbiology and Infectious Diseases- ESCMID: A-I) than that of vancomycin or fidaxomicin (1-B and B-II in the WSES and ESCMID guidelines, respectively). Intestinal microbiota transplantation is also considered by the Australasian Society for Infectious Diseases (ASID) as equally valid as a treatment option for multiple recurrences as fidaxomicin or vancomycin, and further as a good second-line therapy choice after vancomycin failure in refractory CDI \cite{Feh_r_2016}].
There are few randomized trials comparing FMT to standard treatment. In an one of the earliest trials, 43 patients were randomized to one of three therapeutic groups - oral vancomycin and bowel lavage followed by infusion of donor feces; standard vancomycin regimen; and standard vancomycin regimen with bowel lavage. The trial was terminated prematurely since most patients in both control groups had a relapse. Donor feces cured 15 of 16 patients (94%) while resolution of infection occurred in only 4 of 13 patients (31%) in the vancomycin-alone group and in 3 of 13 patients (23%) in the group receiving vancomycin with bowel lavage. Donor-feces infusion was statistically superior to both vancomycin regimens (P<0.01) (Nood 2013). In an open label randomized clinical trial, subjects were assigned to FMT group (short course of vancomycin followed by FMT via colonoscopy) or vancomycin group (10 days of standard dose, followed by 125-500 mg/day every 2-3 days for 3 weeks). At the end of 1 year, Eighteen of the 20 patients (90%) treated by FMT exhibited resolution of C. difficile-associated diarrhea. In FMT, five of the seven patients with pseudomembranous colitis reported a resolution of diarrhea. Resolution of C. difficile infection occurred in 5 of the 19 (26%) patients in vancomycin (P < 0.0001). No significant adverse events were observed in either of the study groups \cite{Cammarota_2015}]. A recent meta-analysis that included 8 observational studies with 611 patients, showed a primary cure rate of 91 %, with an overall recurrent rate of 5.5 %, thus reiterating that FMT is highly effective for recurrent CDI. One of the factors for recurrence after FMT was advanced age (>65 years) \cite{Li_2015}
FMT in patients with comorbidities, particularly immunocompromised patients has not been studied extensively except in case series and retrospective studies, and there is still some hesitancy in using FMT in this population. A multi-center retrospective series of 80 immunocompromised patients that included patients with HIV, solid organ transplant recipients, patients on immunotherapy for IBD, showed a primary cure rate of 78 %, and 8 of 12 patients who underwent repeat FMT for recurrence had cure \cite{Kelly_2014}. In the RCT by Nood et al., a patient with recent renal transplant who had begun to experience graft rejection, was taken out of the FMT group and started on oral vancomycin, however he had failed this , and was subsequently cured by FMT \cite{van_Nood_2013}. More recently, a small retrospective study showed that although the rate of success among solid organ transplant (SOT) recipients was not as high as in immunocompetent patients, a repeat FMT in recurrence helped, thus proposing the use of sequential FMT in SOT patients \cite{Alrabaa_2017}. Similar results were obtained for hematopoietic and stem cell transplant recipients \cite{Webb_2016} .
FMT in IBD
\cite{Fischer2016}