J Infect Chemother xxx (2015) 1e8

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Review article

Fecal microbiota transplantation (FMT) for Clostridium difficile infection: Focus on immunocompromised patients Stefano Di Bella a, *, Theodore Gouliouris b, Nicola Petrosillo a a b

2nd Division, National Institute for Infectious Diseases “L. Spallanzani”, Rome, Italy Department of Infectious Diseases, Cambridge University Hospitals, Cambridge, United Kingdom

a r t i c l e i n f o

a b s t r a c t

Article history: Received 6 November 2014 Received in revised form 15 January 2015 Accepted 16 January 2015 Available online xxx

Clostridium difficile infection (CDI) is an emerging problem worldwide associated with significant morbidity, mortality, recurrence rates and healthcare costs. Immunosuppressed patients, including HIVseropositive individuals, solid organ transplant recipients, patients with malignancies, hematopoietic stem cell transplant recipients, and patients with inflammatory bowel disease are increasingly recognized as being at higher risk of developing CDI where it may be associated with significant complications, recurrence, and mortality. Fecal microbiota transplantation (FMT) has proven to be an effective and safe procedure for the treatment of recurrent or refractory CDI in immunocompetent patients by restoring the gut microbiota and resistance to further recurrences. During the last two years the first data on FMT in immunocompromised patients began to appear in the medical literature. Herein we summarize the use of FMT for the treatment of CDI with a focus on immunocompromised patients. © 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Keywords: Clostridium difficile Immunocompromised Microbiota Fecal microbiota transplantation FMT

1. Importance of Clostridium difficile infection (CDI) in terms of morbidity, mortality and recurrences 1.1. Introduction During the last two decades, the burden of Clostridium difficile infection (CDI) has increased in terms of incidence, morbidity, mortality and costs [1e3]. C. difficile is currently the most frequent cause of nosocomial infectious diarrhea [4] and one of the commonest causes of healthcare associated infections overall [5]. The economic burden is substantial with annual management cost estimates of $800 million in the US and $3000 million in Europe [6]. Successful management is complicated by high rates of recurrence, occurring in 20e30% of patients despite appropriate first-line therapy and is as many as 40e60% following a first recurrence, with a subset of patients suffering multiple episodes [7]. Whilst the pathogenesis of CDI is incompletely understood, microbial virulence and host susceptibility conferred by the interplay between

* Corresponding author. National Institute for Infectious Diseases “L. Spallanzani”, Via Portuense 292, 00149 Rome, Italy. Tel.: þ39 0655170294; fax: þ39 0655170486. E-mail address: [email protected] (S. Di Bella).

deranged immunity and gut microbiome are thought to play a crucial role [8e10]. The changing epidemiology of CDI observed over the past decade seems to be attributable in part to the emergence of new virulent variants, in particular the global spread of C. difficile ribotype 027 (sometimes called “hypervirulent strain”, also known as NAP1/BI) [11]. C. difficile ribotype 027 is associated with severe disease and increased mortality among episodes of CDI [12,13] and have also been linked to higher recurrence rates [14]. Current understanding of the innate and acquired immune system in CDI is rapidly expanding, and the effect of acquired immunosuppression on the host response to C. difficile remains an active area of research. In particular, the role of humoral immunity against toxins A and B in preventing primary and recurrent CDI has been established in several clinical studies [10,15,16] and has led to novel therapeutic interventions [17]. Immunosuppressed patients are now recognized as contributing to the changing epidemiology of CDI with a growing segment of the population having significant defects in the immune system. Indeed, the total number of hematopoietic stem cell transplantations (HSCT) increased by 50% in Europe over the last 10 years with over 35,000 recorded in 2011 [18], whereas in the US solid organ transplantations increased from 12,623 in 1988 to 28,954 in 2013 [19].

http://dx.doi.org/10.1016/j.jiac.2015.01.011 1341-321X/© 2015, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Di Bella S, et al., Fecal microbiota transplantation (FMT) for Clostridium difficile infection: Focus on immunocompromised patients, J Infect Chemother (2015), http://dx.doi.org/10.1016/j.jiac.2015.01.011

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S. Di Bella et al. / J Infect Chemother xxx (2015) 1e8

In this review, we will briefly overview the epidemiology and outcomes of CDI in immunocompromised patients, and discuss treatment options with an emphasis of fecal microbiota transplantation (FMT). Discussion will be limited to the following categories of immunocompromised adults: human immunodeficiency virus (HIV)-infected individuals, solid organ transplant (SOT) recipients, cancer patients, hematopoietic stem cell transplant (HSCT) recipients, and patients with inflammatory bowel disease (IBD). Only articles in the English literature were considered. 2. Burden of Clostridium difficile infection in immunocompromised patients 2.1. Epidemiology Immunocompromised patients constitute a high-risk population for CDI [20e23]. Their increased susceptibility to CDI is multifactorial and includes generic accepted risk factors for CDI such as frequent requirements for antibiotic therapy, prolonged hospitalization and antacid treatment, and common occurrence of hypoalbuminemia, all known risk factors for CDI [24e26]. Within defined immunocompromised patient groups, increasing degrees of immunosuppression are associated with a greater risk for CDI [27e30]. Regarding specific categories of immunosuppression, HIVinfected patients in the pre HAART era were reported to have twice the risk of developing CDI compared to other hospitalized patients [21]. In a large US study spanning the introduction of HAART, data for 11,320 episodes of diarrheal illness in 44,778 HIVinfected patients was analyzed from 1992 to 2002. C. difficile was identified as the commonest cause of bacterial diarrhea, accounting for 53.6% (598 of 1115) of all bacterial agents reported [27]. The incidence rate ratio of CDI was 9.89 (95% CI 7.16e13.65) in patients with clinical AIDS compared to those without AIDS. In contrast to previous belief, the impaired humoral immunity seems to be the key determinant of the increased CDI incidence in HIV infection (Di Bella et al. submitted). The incidence of CDI in SOT recipients is elevated compared to other hospitalized populations [31,32]. Reported rates are 3e19% in liver, 3.5e16% in kidney, 1.5e7.8% in kidney-pancreas, 9% in small bowel, 8e15% in heart and 7e31% in lung transplant recipients, and are highest in the early post-transplantation period [33]. The role of impaired humoral immunity is understudied in SOT recipients but appears to also play a role. In a study of 235 patients who underwent heart transplantation, CDI incidence was 14.9%. Severe hypogammaglobulinemia was the only independent risk factor, conferring a 6-fold increased risk (RR 5.8; 95% CI 1.05e32.1) [29]. Patients with cancer are another immunocompromised group where CDI is of concern. Cancer chemotherapy has been associated with CDI through its damaging effects to the intestinal mucosa and the alterations it causes to the gut microbiota [34,35]. A recent multicenter survey of 11 US cancer centers demonstrated that the pooled rate of hospital-onset CDI in patients with solid and hematological malignancies was 15.8 per 10,000 patient-days, twice the rate reported for all US patients [36]. In another large single center study, hematological malignancy was identified as an independent risk factor for CDI [37]. HSCT recipients are a severely immunosuppressed group of patients with the highest reported rates of CDI amongst those suffering of malignancy [36]. A US study of 999 autologous and allogeneic HSCT recipients found that CDI was common in the early post-transplant period with a 1-year incidence of 9.2% [28]. The incidence was higher in allogeneic compared to autologous HSCT recipients (12.5% vs. 6.5% respectively). Prior chemotherapy (in addition to conditioning), broad-spectrum antibiotics, and acute

graft-versus host disease were independent predictors of CDI [28]. In another study of 98 patients undergoing allogeneic HSCT, prior C. difficile colonization detected by PCR targeting tcdB, and myeloablative conditioning regimens were significant predictors of CDI in the peritransplant period. However, the diarrhea was mild and indistinguishable from conditioning-related diarrhea, and the investigators raised the possibility that some of the infections may constitute inaccurate diagnoses [30]. IBD (Crohn's disease and ulcerative colitis) is an independent risk factor for CDI, with a 3-fold increased risk compared to non-IBD patients [38]. In a large population cohort of 10,662 IBD patients, Schneeweiss et al. showed that glucocorticoid initiation was associated with a significantly increased risk of CDI compared to initiation of other immunosuppressive agents [39]. Conversely, 521 patients treated with infliximab, an anti-tumor necrosis factor (TNF)-alpha monoclonal antibody, experienced no episodes of CDI. 2.2. Severity and outcomes CDI may be associated with increased rates of complications, recurrence, and mortality in some immunosuppressed patient groups [22,23]. In a large nationwide US study of 49,198 SOT recipients registered in 2009, CDI was an independent predictor of inhospital mortality, graft complications and colectomy [40]. Lung transplant recipients appear to be at particular risk for increased mortality and recurrence in some case series [41]. In another study, SOT recipients were at increased risk for fulminant colitis compared to general patients [31]. By contrast, a retrospective case control study found no significant differences in disease severity between SOT and non-transplant recipients [42]. However, when the whole cohort was analyzed, steroid exposure was associated with increased risk of recurrence at 60 days (RR 4.2, 95% CI 1.4e13.1) on univariable analysis. CDI is also associated with increased morbidity and mortality in patients with IBD [43]. By contrast, disease severity in HSCT recipients is often reported as mild [44]. Of note, severity scores utilizing white cell count cutoffs as a marker of severity are not applicable in neutropenic patients and potentially other immunosuppressed groups and have been shown to underestimate severity in patients with hematological malignancy [45]. Nevertheless, in a nationwide study including 344,507 HSCT hospital discharges in the US from 2000 to 2009, CDI was not associated with mortality [44]. Recurrence rates are not thought to be significantly different between HIV and the general population [21]. 3. Brief review of treatment options Treatment guidelines for CDI have been published by the Infectious Diseases Society of America and the European Society of Clinical Microbiology and Infectious Diseases [46,47]. Paradoxically, the mainstay of therapy is still based on antimicrobials that disrupt significantly the gut microbiota placing the patients at risk of relapse [48e50]. The first-line treatment in primary and first recurrence of CDI is metronidazole for mild disease whilst oral vancomycin is preferred for severe infection due to its proven superior efficacy [46,47]. Vancomycin use is recommended for treatment of multiple recurrences, usually administered as a pulsed or tapered regimen [51]. The global C. difficile epidemic of the last two decades and the increasing reports of metronidazole failures and CDI recurrence after vancomycin treatment [52,53] have fuelled research into novel therapeutic approaches. Among novel antibiotic options, fidaxomicin, a narrowspectrum macrocyclic antibiotic, has recently been approved for the treatment of CDI. In two randomized controlled trials

Please cite this article in press as: Di Bella S, et al., Fecal microbiota transplantation (FMT) for Clostridium difficile infection: Focus on immunocompromised patients, J Infect Chemother (2015), http://dx.doi.org/10.1016/j.jiac.2015.01.011

S. Di Bella et al. / J Infect Chemother xxx (2015) 1e8

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evaluating a total of over 1000 patients, it was demonstrated to have comparable cure rates to vancomycin but with significantly fewer patients experiencing a recurrence [54,55]. On subgroup analysis, this effect was also observed in patients treated for a first recurrence but not in infections caused by ribotype 027 [56]. Lower recurrence rates were mediated by a reduction in both relapse and reinfection [57] and were attributed to the relative preservation of the gut microbiome compared to vancomycin [48]. The European guidelines recommend fidaxomicin as an alternative agent for patients with primary and recurrent CDI (or those at risk for CDI recurrence) [47]. The choice between metronidazole, vancomycin or fidaxomicin remains a matter of debate dominated by cost and local epidemiology [58e60]. Apart from fidaxomicin, other antibiotic-based regimens have been proposed for recurrent CDI: rifaximin “chaser” [61], tigecycline and several others have been used in small case-series but lack a robust evidence base [62e65]. Non-antimicrobial strategies against recurrent CDI are aimed at boosting the host immune response and restoring the gut microbiota. Passive immunotherapy using pooled intravenous immunoglobulins has been proposed, particularly in the context of severe disease or intractable recurrences, however results from small uncontrolled studies have not always been encouraging [66,67]. More recently, a Phase 2 multicenter trial evaluated the use of intravenous monoclonal antibodies directed against toxins A and B as adjunctive therapy in addition to vancomycin or metronidazole. The study showed reduced recurrence rates of CDI in patients treated with the monoclonal antibodies compared to placebo (7% vs. 25% respectively, p < 0.001). This effect was also significant in cases caused by PCR ribotype 027 and in recurrent infections [17]. Currently, the fully humanized monoclonal antibodies actoxumab and bezlotoxumab are undergoing two phase 3 clinical trials to determine efficacy in preventing recurrent disease [68]. Arguably, the most promising option in terms of efficacy and safety in recurrent CDI is FMT [69]. This procedure, also known as fecal bacteriotherapy or donor feces transplantation, consists of the transfer of homogenized fecal suspension from a healthy donor to the gastrointestinal tract of a diseased recipient and will be examined in more detail below. The current European guidelines strongly recommend FMT (strength A) for treating multiple recurrences of CDI (among non-antibiotic treatment regimens) [47]. In addition, other experts recommend the procedure for refractory infections, including fulminant colitis non-responding to standard therapy [70].

The global epidemic of C. difficile and the growing understanding of the human microbiome, including its role in health and disease, have contributed to the re-emergence of this technique in recent years. FMT consists of transferring homogenized fresh feces (30e50 g) from a healthy donor into an individual with CDI, thus restoring the healthy gut microbiota resulting in clinical picture resolution. The exact mechanism through which healthy microbiota confer colonization resistance in the gut and protection from CDI remains to be elucidated but could involve niche competition, bacteriocin and protease production, alterations in bile acid composition, and interactions with the innate immune system [9,10,76,77]. The human intestinal microbiome is complex and diverse containing in excess of 1000 mostly unculturable strictly anaerobic bacterial species, and 150-fold more genes than the human genome. The study of the composition of these microbial communities, termed metagenomics, has been revolutionized with the advent of high-throughput technologies such as 16S rRNA gene next-generation sequencing [78]. In healthy individuals, intestinal bacteria belong to 7 phyla of which Firmicutes and Bacteriodetes predominate [78] and are thought to play a crucial role in metabolism, nutrition, and innate immunity [9]. Gut microbiota imbalance, also termed gut dysbiosis (usually as a result of antibiotic treatment), is thought to be the key in CDI pathogenesis [9]. In fact, bacterial diversity is markedly decreased in fecal samples of patients with recurrent CDI compared to healthy controls or to patients with a first episode of CDI and no relapses; they instead contain increased proportions of g-Proteobacteria (mainly members of the Enterobacteriaceae family) and reduced proportions of the Bacteroidetes and Firmicutes phyla [79e81]. FMT restores the normal composition of intestinal microbiota similar to the donor's [76,80e82]. This effect is rapid and durable, occurring within 3 days following FMT and being maintained for at least 6 months [83,84]. The precise identity of the beneficial bacterial species remains undefined, but limited data is starting to appear [83,85]. Using DNA microarray to study serial stool samples of 3 patients treated with FMT, Shankar et al. identified genera that were more abundant in pre-transplant patients but not in donors or post-FMT, including Enterobacter, Escherichia, Lactobacillus, Raoultella and Veillonella. By contrast, post-transplantation, other genera became more prominent, including Bacteroides, Blautia, Coprococcus, Faecalibacterium, Papillibacter, and Roseburia [83].

4. Evidence on the efficacy and safety of FMT treatment

During the last decade, the interest of the scientific community in FMT has increased dramatically. In 2011, 376 patients had been reported to undergo FMT [86]; at the beginning of 2013 this number rose to 536 patients [87]. Accumulated evidence has led to the wider acceptance of FMT as a treatment for recurrent CDI and its inclusion in national and international guidelines [46,63]. Several systematic reviews have been published, collecting the results of all existing works involving FMT for CDI. These studies demonstrate that FMT is highly effective in the treatment of antibiotic-refractory CDI with a cumulative success rate in resolution of diarrhea of ~90% [86e88]. In 2013, a Dutch randomized controlled trial of duodenal infusion of donor feces for recurrent CDI definitively established the superiority of FMT compared to vancomycin for the treatment of recurrent CDI. In fact, the trial was stopped early after an interim analysis demonstrated superiority of FMT: 13 of 16 (81%) patients had resolution of CDI after the first FMT compared to 4 of 13 patients (31%) receiving vancomycin alone and 3 of 13 patients (23%) receiving vancomycin with bowel lavage [80]. A further 2 of the 3

The oral administration of human fecal suspension is an ancient practice with its first recorded use during the Dong-jin dynasty in fourth century China for the cure of food poisoning or severe diarrhea [71]. In the 16th century, Chinese traditional medicine described the use of stool products euphemistically known as ‘yellow soup’ for the treatment of a range of gastrointestinal disorders [72]. In the 17th century, FMT was used in veterinary medicine in Europe to treat a number of gastrointestinal conditions and to boost resistance against enteric pathogens, a practice later termed “transfaunation” [71,73]. The first human use of FMT in modern medicine was reported in a 4-patient case series by Eiseman et al. in 1958 who used fecal enemas to treat pseudomembranous colitis, long before C. difficile was recognized as the causative agent of this condition [73]. Subsequently, FMT was only sporadically used until 2003, when the first series of patients with CDI treated with this procedure appeared in the medical literature [74,75].

4.1. Efficacy

Please cite this article in press as: Di Bella S, et al., Fecal microbiota transplantation (FMT) for Clostridium difficile infection: Focus on immunocompromised patients, J Infect Chemother (2015), http://dx.doi.org/10.1016/j.jiac.2015.01.011

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patients who failed initial FMT responded to a second infusion of donor feces resulting in an overall cure rate of 15/16 (94%). Furthermore, using a decision-analytic model, FMT was recently shown to be cost-effective for first-line treatment of recurrent CDI compared to other competing strategies, namely vancomycin, metronidazole or fidaxomicin [59]. Infection with C. difficile ribotype 027 seems to be a predictor of failure not only for antibiotic treatment but also for FMT. A study on 115 older adults who received FMT demonstrated that individuals infected with ribotype 027 strain were less likely to achieve a cure after FMT [89]. FMT is not standardized, protocols varying in different centers. Potential routes of administration include nasogastric or nasoduodenal tube, retention enemas (including self-administered enemas), and colonoscopy, with the latter used in most cases [76]. The best route of administration is still debated: a pooled analysis of 182 cases of recurrent CDI treated with FMT showed that colonoscopic FMT has a slightly higher cure rate than nasogastric FMT (93% versus 85%), although the difference was not statistically significant [90]. Feces are classified as human tissue and strict donor criteria apply to prevent transmission of communicable diseases and to optimize microbiota diversity [70]. In practice, partners or first-degree relatives have often been identified as donors, although unrelated donor use is expanding. 4.2. Safety Although FMT is relatively easy to perform, careful donor selection and rigorous screening is mandatory for safety issues similar to any other human tissue transplant: according to the Dutch trial, the donor screening should include serological tests for HIV; human T-cell lymphotrophic viruses 1 and 2; hepatitis A, B, and C virus; Epstein-Barr virus; cytomegalovirus; Treponema pallidum; Strongyloides stercoralis; Entamoeba histolytica; and stool tests for parasites; C. difficile and enterpathogenic bacteria [80]. However it is important to note that screening is not yet standardized and even more extensive protocols have been used. The systematic review on FMT for CDI conducted by Cammarota et al. and published in January 2014 reported no severe adverse events with FMT [87]. Common side effects reported in the Dutch trial on the day of donor infusion include belching in 3/16 patients, abdominal cramping pain in 2/16, and diarrhea not considered to be due to C. difficile in 15/16 patients. These symptoms were shortlived and resolved within 3 h [80]. It is important to underline that infective complications are still possible despite donor screening. Schwartz et al. in 2013 reported 2 cases of norovirus gastroenteritis after FMT in immunocompetent patients. Even though neither case was linked to the donor stool, one case was possibly acquired through environmental contamination by a symptomatic endoscopy suite employee [91]. Long-term follow-up data are lacking. Brandt et al. obtained follow-up data by means of a questionnaire for 77 patients a mean of 17 months (range 3e68) post FMT. Four patients reported new conditions including peripheral neuropathy, idiopathic thrombo€gren's syndrome, and rheumatoid arthritis; cytopenic purpura, Sjo however, it is not possible to determine any link to FMT [92]. Microbiota imbalances have been implicated in obesity, metabolic syndrome and colorectal cancer, and any predisposition FMT may confer towards these conditions remains unknown. Yet, any potential long term risk needs to be balanced against the benefits for individual patients. Despite the strong evidence supporting the use of FMT, its use is still limited to few centers. Esthetic practical and regulatory reasons could account for the slow uptake of this technique. Whilst FMT can be unappealing to doctors and patients, two patient surveys

actually showed that it is an acceptable treatment option for most patients [92,93]. In a long term questionnaire-based follow-up study of patients treated with FMT, 97% of respondents would undergo the procedure again in the event of another relapse, and 53% would prefer to receive FMT as first-line therapy instead of antibiotics [92]. 4.3. Future directions Donor screening is time-consuming and could represent an obstacle to timely administration of FMT, particularly in cases of severe CDI. Practical issues with regards to expediting identification and screening of suitable donors have been addressed by establishing biobanks of “universal” donor material. Hamilton et al. identified a pool of volunteer donors and stored the fecal filtrate at 80  C in cryoprotectant until use. FMT was conducted in 43 patients who received the fecal extract via colonoscopy leading to a 95% overall success rate and durable microbiome engraftment, thus demonstrating the possibility to simplify the approach to FMT without losing efficacy [81,94]. In 2014, Youngster et al. confirmed a high overall cure rate (90%) using frozen inoculum from unrelated donors [95]. More recently, the same group of investigators published their findings of a pilot study using capsulized frozen fecal preparations in recurrent or refractory CDI with similarly positive results [96]. An alternative but related approach to traditional FMT is bacteriotherapy: it involves the transfer of a bacterial mixture (or synthetic microbial community) of characterized commensal bacteria thus minimising the risk of inadvertent pathogen transmission or antimicrobial resistance genes [76]. Tvede et al. were the first to describe the successful treatment of CDI using a bacterial mixture of 10 aerobic and anaerobic bacteria diluted in sterile saline. The mixture included strains of Escherichia coli, Clostridium bifermentans and Peptostreptococcus productus (now reclassified as Blautia producta) all of which displayed inhibitory activity in vitro against C. difficile [97]. In 2013, researchers described the use of bacteriotherapy to treat patients with recurrent CDI [98]. They used a modified continuous culture chemostat system to isolate, characterize and bank intestinal bacteria from donor feces. From the isolated strains, an echosystem of 33 nonpathogenic strains were administered into the colons of 2 patients with CDI achieving a long-term response. Bacteriotherapy has also been used experimentally in a mouse model of CDI [99]. The researchers designed a bacterial mix of 6 defined and phylogenetically diverse bacterial strains identified after culture passage of murine feces and showed it to be effective in clearing the mice of ribotype 027 C. difficile and restoring a diverse microbiota, comprised of additional commensal species not included in the mix. Importantly, administration of each of the 6 species individually or of different bacterial mixtures failed to achieve a similar response. These studies pave the way to future applications of bacteriotherapy through the rational design of safe, well-characterized and effective microbial ecosystems. 5. Data from the literature on FMT and immunocompromised patients At the beginning of this century immunocompromised patients were excluded from FMT, including from the trial by van Nood et al., for fear of possible complications, particularly the theoretical risk of invasive infection through bacterial translocation in the context of depressed intestinal mucosal defenses. In a guidance document published in 2011 by the FMT Working Group, immunosuppressed patients comprised the bulk of patients to whom considerations for

Please cite this article in press as: Di Bella S, et al., Fecal microbiota transplantation (FMT) for Clostridium difficile infection: Focus on immunocompromised patients, J Infect Chemother (2015), http://dx.doi.org/10.1016/j.jiac.2015.01.011

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increased risk of adverse events should be given [70]. Similarly, immunocompromised patients have been excluded from an ongoing trial involving FMT in the US (Kelly C, Brandt L. Fecal Transplant for Relapsing C. difficile infection. Accessed August 7, 2014 at: http://clinicaltrials.gov/ct2/show/NCT01703494? term¼FMTþprovidence&rank¼1). Until today 15 published case reports or case series have described the use of FMT in immunocompromised patients (Table 1) for a total of 132 treated patients. The most recent studies are briefly described below in chronological order. In the 2012 study by Hamilton et al. mentioned previously [94], 14 of the 43 patients had underlying IBD. In total, 4 patients needed a second infusion and 3 of them belonged to the IBD subgroup. No serious adverse events were noted. The same year, Neemann et al. reported the case of a nonneutropenic 21-year-old woman with allogeneic HSCT for acute leukemia who developed fulminant CDI. Despite treatment with metronidazole, vancomycin, immunoglobulins, fidaxomicin, rifaximin, and tigecycline, the disease continued to progress. On day 20 of CDI treatment FMT was performed via nasojejunal tube as a bowel salving intervention achieving prompt resolution of symptoms (sustained at 2 months of follow up) [100]. In 2013, Rubin et al. reported 8 cases of patients with malignancy and recurrent CDI treated with FMT, among a cohort of 75 patients [101]. Half of them had a clinical relapse after FMT; although small numbers this rate was higher compared to the relapse rate when considering the entire cohort (21%). The same year, the first successful use of FMT in two HIV patients with recurrent CDI was described with no reported adverse effects [102]. In February 2014, Friedman-Moraco et al. reported two cases of FMT performed in patients with renal and lung transplantation. Both patients experienced several CDI recurrences despite adequate antimicrobial treatment with metronidazole and/or vancomycin. These patients were successfully treated with 2 FMT each (sequentially), both via colonoscopy and via nasojejunal tube. The patients did not experience infectious complications related to FMT. In the discussion the authors hypothesized that SOT recipients

Table 1 Studies reporting FMT in immunocompromised patients. Author/Year

Total number of IC patients treated

Reason for immunosuppression

Aas et al. 2003 [74] Rubin et al. 2003 [101,112] Pathak et al. 2013 [112] Trubiano et al. 2014 [106] Kelly et al. 2014 [107] Neemann et al. 2012 [100] Ehlermann et al. 2014 [105] Firedman-Moraco et al. 2014 [103] Kelly et al. 2014 [107] Pathak et al. 2014 [112] Elopre et al. 2013 [102] Kelly et al. 2014 [107] Schunemann et al. 2014 [104] Aas et al. 2003 [74] Duplessis et al. 2012 [113] Hamilton et al. 2012 [94] Zainah et al. 2012 [114] Wettstein et al. 2013 [115] Pathak et al. 2014 [112] Kelly et al. 2014 [107] Quera et al. 2014 [111]

1 8 2 1 7 1 1 2 19 2 2 3 1 1 1 14 1 28 1 36 1

Cancer

HSCT SOT

HIV

IBD

AIDS: acquired immunodeficiency syndrome; HIV: human immunodeficiency virus; HSCT: hematopoietic stem cell transplantation; IBD: inflammatory bowel disease; IC: immunocompromised; SOT: solid organ transplantation.

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may have more severe alterations in their intestinal microbiota, therefore sequential FMT may be necessary to correct dysbiosis [103]. In March 2014, a report of FMT in AIDS was published; the authors described a 54-year-old male patient with AIDS and pseudomembranous colitis complicated by secondary peritonitis with paralytic ileus and toxic megacolon. His CD4 count was 54/ml (17%). The patient was treated successfully with two fecal instillations, via intestinal tube and colonoscopy. No adverse events were recorded over the ensuing weeks except a central venous catheter infection unrelated to the FMT according to the authors [104]. In May 2014, Ehlermann et al. reported the case of a heart transplanted patient with 3 recurrent episodes of CDI and severe cachexia treated successfully with FMT from the daughter without complications nor recurrences resulting in weight gain during the following months [105]. In July 2014, Trubiano et al. reported a FMT in a patient with relapsed aggressive diffuse large B-cell lymphoma. A 78-year-old man treated with radiotherapy, chemo-immunotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) and panobinostat (a histone deacetylase inhibitor) experienced three episodes of CDI despite therapy with metronidazole and/or vancomycin. FMT was performed using the son's feces via an upper gastrointestinal endoscopy on day 6 of vancomycin treatment with resolution of diarrhea (symptom-free at 30day follow-up) [106]. The same month the largest multicenter retrospective series on the use of FMT in immunocompromised patients with CDI was published. Kelly et al. collected 12-week outcome data from 16 centers in the US, Canada and Australia. Patients were included if they were immunocompromised and had undergone FMT to treat recurrent, refractory, severe, or complicated CDI unresponsive to standard therapy. Patients were defined as immunocompromised if they had: HIV infection, inherited or primary immune disorders, and immunodeficiency or iatrogenic immunosuppression including current or recent treatment with anti-neoplastic or immunosuppressive agents such as monoclonal antibodies to B ant T cells, anti-TNF-alpha agents, glucocorticoids, antimetabolites, calcineurin inhibitors, and mycophenolate mofetil. Eighty patients (75 adults and 5 pediatric) were included in the final analysis; 45% received immunosuppressive agents for IBD, 24% were SOT recipients, 19% had severe or end-stage chronic medical conditions, 9% received antineoplastic agents for cancer, and 3% had HIV/AIDS. The majority of patients were treated as out-patients following standard CDI therapy. Resolution of CDI occurred in 78% (62/80) of patients after a single FMT and in a further 10% after repeated FMT (for an overall cure rate of 88%) [107]. 12/80 (15%) of patients suffered a serious adverse event during the 12-week follow-up period. One death was related to aspiration pneumonia during sedation administered for the colonoscopic instillation of donor feces. No infections directly related to FMT were reported. Of concern, 14% of patients with IBD experienced flares of their disease after FMT, including one patient who required a colectomy [107]. To these cases should be added a separate case report of a patient with quiescent ulcerative colitis and concurrent CDI that was treated with FMT and experienced a flare of ulcerative colitis [108]. FMT has been used as an experimental treatment for IBD without CDI, therefore the link if any of FMT to IBD flares merits further investigation. Two recent meta-analyses explored the safety of FMT in patients with IBD (with or without CDI). The authors did not indicate an issue with colitis flares, although transient fever and rise in inflammatory markers were common (15% in Colman et al.) [109,110]. They identified only one published report with an infective complication involving a 61 year-old patient treated with mesalazine, azathioprine and infliximab for Crohn's

Please cite this article in press as: Di Bella S, et al., Fecal microbiota transplantation (FMT) for Clostridium difficile infection: Focus on immunocompromised patients, J Infect Chemother (2015), http://dx.doi.org/10.1016/j.jiac.2015.01.011

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disease [111]. The patient had experienced 6 episodes of E. coli bacteremia and 4 of CDI over a 4-year period. He received FMT through colonoscopy for the last CDI recurrence. E. coli bacteremia developed 24 h after FMT, however, in our opinion the relationship of this event to the procedure could not be ascertained. In summary, current evidence on the efficacy and safety of the use of FMT in immunocompromised patients with CDI is limited and only starting to emerge in the form of case reports or retrospective case series in heterogeneous groups of patients with inherent limitations due to potential reporting biases. The preliminary data is promising with an efficacy comparable to that reported in nonimmunosuppressed patients (>80% after firt FMT, >90% after second FMT), although a higher relapse rare in patients with cancer was observed in one study [101]. Severe adverse events in CDI patients with underlying IBD treated with FMT have been reported [107,108,111] but infective complications are rare. Further prospective studies are warranted to fully evaluate the role and safety of FMT in immunocompromised patients. 6. Conclusions Immunocompromised patients are at increased risk for CDI. FMT has been shown to be an effective and safe procedure in the treatment of recurrent/refractory CDI in immunocompetent patients. Literature on FMT in immunocompromised patients is still scant, however preliminary data are encouraging. In particular, experience to data does not suggests these patients are at increased risk of infective complications, however caution is reasonable in patients with underlying IBD. As the use of FMT expands in the near future, more data from its use in immunocompromised patients will be needed to further assess its safety. The evolution of FMT is going ahead towards standardized frozen stool preparations, pills, and bacteriotherapy using standardized, safe and rationally designed microbial ecosystems. Conflict of interest None for SDB and TG. PN received honoraria as speaker from: Pfizer, Wyeth, Sanofi Aventis, Astellas, MSD, Gilead, Novartis, GSK, Johnson & Johnson, Jansen Cilag, and as member of scientific board from MSD, Pfizer and Carefusion. References [1] Pepin J, Valiquette L, Alary ME, Villemure P, Pelletier A, Forget K, et al. Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity. CMAJ 2004;171:466e72. [2] Redelings MD, Sorvillo F, Mascola L. Increase in Clostridium difficile-related mortality rates, United States, 1999e2004. Emerg Infect Dis 2007;13: 1417e9. [3] Ananthakrishnan AN. Clostridium difficile infection: epidemiology, risk factors and management. Nat Rev Gastroenterol Hepatol 2011;8:17e26. [4] Poutanen SM, Simor AE. Clostridium difficile-associated diarrhea in adults. CMAJ 2004;171:51e8. [5] Magill SS, Edwards JR, Bamberg W, Beldavs ZG, Dumyati G, Kainer MA, et al. Multistate point-prevalence survey of health care-associated infections. N Engl J Med 2014;370:1198e208. [6] Bouza E. Consequences of Clostridium difficile infection: understanding the healthcare burden. Clin Microbiol Infect 2012;18:5e12. [7] Johnson S. Recurrent Clostridium difficile infection: causality and therapeutic approaches. Int J Antimicrob Agents 2009;33:S33e6. [8] Peniche AG, Savidge TC, Dann SM. Recent insights into Clostridium difficile pathogenesis. Curr Opin Infect Dis 2013;26:447e53. [9] Bibbo S, Lopetuso LR, Ianiro G, Di Rienzo T, Gasbarrini A, Cammarota G. Role of microbiota and innate immunity in recurrent Clostridium difficile infection. J Immunol Res 2014;2014:462740. [10] Buffie CG, Pamer EG. Microbiota-mediated colonization resistance against intestinal pathogens. Nat Rev Immunol 2013;13:790e801. [11] He M, Miyajima F, Roberts P, Ellison L, Pickard DJ, Martin MJ, et al. Emergence and global spread of epidemic healthcare-associated Clostridium difficile. Nat Genet 2013;45:109e13.

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Please cite this article in press as: Di Bella S, et al., Fecal microbiota transplantation (FMT) for Clostridium difficile infection: Focus on immunocompromised patients, J Infect Chemother (2015), http://dx.doi.org/10.1016/j.jiac.2015.01.011