Fecal Microbiota Transplant for Treatment of Clostridium difficile Infection in Immunocompromised Patients

Colleen Kelly1, Chioma Ihunnah1,Monika Fischer2, Alexander Khoruts3,

Lawrence Brandt4, Anita Afzali5, Olga Aroniadis4, Amy Barto6, Thomas Borody7, Andrea Giovanelli8, Shelley Gordon9, Michael Gluck10, Elizabeth Hohmann11, Dina Kao12, John Y.

Kao13, Daniel McQuillen6, Mark Mellow14, Kevin Rank3, Krishna Rao13, Arnab Ray15, Margot Schwartz10, Namita Singh16, Neil Stollman8, Christina Surawicz5, David Suskind16, Stephen

Vindigni5, Ilan Youngster11

1 Brown Alpert Medical School, Providence, RI 2 Indiana University School of Medicine, Indianapolis, IN

3 University of Minnesota, Minneapolis, MN4Montefiore Medical Center, Bronx, New York

5University of Washington, Seattle, Washington6 Lahey Clinic Medical Center, Burlington, MA

7Centre for Digestive Diseases, Five Dock, New South Wales, Australia8 Northern California Gastroenterology Consultants, Inc. Oakland, CA

9California Pacific Medical Center, San Francisco, CA10Virginia Mason Medical Center, Seattle, WA.11Massachusetts General Hospital, Boston, MA

12University of Alberta, Edmonton, AB, Canada13University of Michigan, Ann Arbor, MI

14Integris Baptist Medical Center, Oklahoma City, Oklahoma15Ochsner Clinic Foundation, New Orleans, LA

16Seattle Children’s Hospital, Seattle, WA

Corresponding Author: Dr. Colleen Kelly

Brown Alpert Medical SchoolWomen’s Medicine Collaborative

Division of Gastroenterology146 West River StreetProvidence, RI 02904

T 401-793-7080F 401-793-7404

colleen_r_kelly@brown.edu

Guarantor of the article: Dr. Colleen Kelly

Specific author of contributions: Dr. Colleen Kelly - Involved in study design, planning, conducting, collecting and interpreting data for this study and drafting/editing the manuscriptDr. Chioma Ihunnah - Involved in planning, collecting and interpreting data for this study and drafting the manuscriptDr. Monika Fischer - Involved in data collection and drafting/editing of the manuscriptDr. Alexander Khoruts-Involved in data collection and drafting/editing of the manuscriptDr. Lawrence J. Brandt - Involved in data collection and editing the manuscriptDr. Anita Afzali - Involved in data collectionDr. Olga C. Aroniadis - Involved in data collectionDr. Amy Barto - Involved in data collectionDr. Thomas Borody - Involved in data collectionAndrea Giovanelli - Involved in data collectionDr. Shelley Gordon - Involved in data collectionDr. Michael Gluck –Involved in data collectionDr. Elizabeth Hohmann - Involved in data collectionDr. Daniel McQuillen - Involved in data collectionDr. Mark Mellow - Involved in data collectionDr. Dina Kao - Involved in data collectionDr. John Y. Kao - Involved in data collectionDr. Kevin Rank - Involved in data collectionDr. Krishna Rao- Involved in data collectionDr. Arnab Ray - Involved in data collectionDr. Margot Schwartz - Involved in data collectionDr. Namita Singh - Involved in data collectionDr. Neil Stollman - Involved in data collectionDr. Christina Surawicz - Involved in data collectionDr. David Suskind - Involved in data collection Dr. Stephen Vindigni – Involved in data collectionDr. Ilan Youngster - Involved in data collection

All above authors have approved the final draft submitted.

Financial Support: 1,4NIH 1R21DK093839-01A13NIH R21 AI091907

Potential Conflicts of Interest: Brandt L. Optimer Pharmaceuticals, Inc; Speaker’s Bureau and Research supportKhoruts A. CIPAC, Ltd Research SupportStollman N. Optimer Pharmaceuticals, Inc Speaker’s Bureau Kelly C. US endoscopy, Inc. Received consulting fees

Study Highlights: 1. WHAT IS CURRENT KNOWLEDGE C. difficile infection (CDI) is common in immunocompromised patients. Fecal Microbiota Transplantation (FMT) appears effective and is indicated for the treatment

of CDI not responding to standard therapies.2. WHAT IS NEW HERE FMT appears to be effective and safe in immunocompromised patients Immunocompromised patients do not appear to be at high risk of infection transmitted by

FMT Patients with IBD may experience disease flare following FMT, though whether this is

precipitated by the CDI, FMT itself or progression of the underlying disease state is not known.

ABSTRACT

Objectives: Patients who are immunocompromised (IC) are at increased risk of C. difficile

infection (CDI), which has increased to epidemic proportions over the past decade. Fecal

microbiota transplantation (FMT) appears effective for the treatment of CDI, though there is

concern IC pts may be at increased risk of having adverse events (AEs) related to FMT. This

study describes the multicenter experience of FMT in IC patients

Methods: A multicenter retrospective series was performed on the use of FMT in IC patients

with CDI that was recurrent, refractory or severe. We aimed to describe rates of CDI cure after

FMT as well as AEs experienced by IC patients after FMT. A 32-item questionnaire soliciting

demographic and pre- and post-FMT data was completed for 99 patients at 16 centers of which

80 were eligible for inclusion. Outcomes included (1) rates of CDI cure after FMT, (2) serious

adverse events (SAEs) such as death or hospitalization within 12 weeks of FMT, (3) infection

within 12 weeks of FMT and (4) AEs (related and unrelated) to FMT.

Results: Cases included adult (75) and pediatric (5) patients treated with FMT for recurrent

(54%), refractory (11%), and severe and/or overlap of recurrent/refractory & severe CDI (27%).

79% were outpatients at time of FMT. The mean follow-up period between FMT and data

collection was 11 months (range 3-46 months). Reasons for IC included: HIV/AIDS (3), solid

organ transplant (19), oncologic condition (7), immunosuppressive therapy for IBD (36), and

other IC due to medical condition/medication (15). The CDI cure rate after a single FMT was

78%, with 62 pts suffering no recurrence at least 12 weeks post-FMT. Eleven patients

underwent repeat FMT of which 8 had no further CDI. Thus, the overall cure rate was 89%.

Twelve (15%) had any SAE within 12 weeks post-FMT, of which 10 were hospitalizations. Two

deaths occurred within 12 weeks of FMT, one of which was the result of aspiration during

sedation for FMT administered via colonoscopy; the other was unrelated to FMT. None suffered

infections definitely related to FMT, but 1 patient developed an unrelated infection and 5 had

self-limited diarrheal illness which were probably unrelated, and no causal organism was

identified. Four (11% of IBD patients) experienced disease flare post-FMT. Three ulcerative

colitis (UC) patients underwent colectomy related to course of UC >100 days after FMT. One

patient had a superficial mucosal tear caused by the FMT colonoscopy and 3 patients reported

mild, self limited abdominal discomfort post-FMT.

Conclusions: This series demonstrates effective use of FMT for CDI in IC pts with few SAEs or

related AEs. Importantly, there were no infectious complications in these high-risk pts.

INTRODUCTION

Clostridium difficile infection (CDI) is responsible for 15-25% of nosocomial antibiotic-

associated diarrhea1 and has increased rapidly in the past decade2 to an incidence of 10.4 cases

per 1000 patient admissions.3 Immunocompromised (IC) patients are particularly at risk of CDI.

C. difficile is the most common cause of bacterial diarrhea in persons with HIV infection and has

its highest incidence in those with advanced HIV disease/AIDS.4 Organ transplant recipients are

also observed to suffer higher frequency of CDI. Retrospective case series of patients after solid

organ transplant (SOT) report an overall CDI incidence of 8% and incidence as high as 16% in

kidney transplant recipients.5 Furthermore, 40% of SOT patients who acquired CDI did not have

any recent antibiotic exposure, which suggests that IC status may be an independent risk factor

for CDI.5 Increased length of stays in hospitals and extended-care facilities in addition to

multiple exposures to broad-spectrum antibiotics increases the risk of CDI in this population of

patients.6,7 However disruptions of both the innate and adaptive immune responses are additional

factors, as signaling pathways involved with recruitment of neutrophils mitigate inflammation in

acute infection8 and patients with increased anti-toxin A and B IgG antibodies may be at

decreased risk of suffering recurrences of CDI compared with those who have reduced levels of

the antibody.9,10

Inflammatory bowel disease (IBD) patients develop CDI at a three-fold higher rate

compared to the general population and have an estimated 10% life time chance to contract C.

difficile.11,12 Recent increases in hospitalization, mortality, and colectomy rates in CDI IBD

patients are well demonstrated.13-16 Up to 19% of patients with an IBD flare test positive for C.

difficile.17 Immunosuppressive medications commonly used in this patient population multiply

the risk of CDI, above all, corticosteroids confer a threefold increase in CDI and twofold

increase in mortality.18,19 The strong association between IBD and CDI is hypothesized to be

based on disturbed mucosal barrier function and altered gut microbial flora.20

Recurrence is a common management problem and occurs in up to 20% of patients after

initial CDI treatment.21 Current guidelines recommend a tapering course of vancomycin after a

second recurrence, however up to 60% of patients do not respond to this treatment strategy or

develop further recurrence after the vancomycin is stopped.22 Initially described for treatment of

pseudomembranous enterocolitis in 1958,23 Fecal Microbiota Transplant (FMT) has proven to be

efficacious and safe in numerous case series24 and a recently published clinical trial.25 The use of

FMT among IC patients with CDI has been limited due to concerns about its safety in this

population. Published guidelines recommend avoidance of fecal transplant in SOT recipients

because of the theoretic potential for infection26 and caution even against the use of probiotics in

IC hosts because of the rare complication of superinfection (including bloodstream infections)

which has been reported from these “non pathogenic” organisms.27,28 A recent guidance issued

by the FMT working group specified that considerations for increased risk of adverse events

should be given to patients on major immunosuppressive agents and patients with

decompensated liver cirrhosis, advanced HIV/AIDS, recent bone marrow transplant, or other

cause of severe immunodeficiency.29 Furthermore, the FDA/Center for Biologics Evaluation and

Research recommended that patients who are immunocompromised for any reason be excluded

from the first randomized trial of FMT in this country.30 To date, no study has systematically

investigated the safety and efficacy of FMT in IC patients. We and colleagues at other medical

centers offering FMT have treated a number of IC patients with FMT. By this collective

experience we aim to describe rates of CDI cure in this population as well as adverse events

(AEs) experienced by IC patients after FMT.

METHODS

We performed a retrospective case series of IC patients with CDI who underwent FMT at

16 medical centers nationally and internationally. The study was approved by the Lifespan IRB

and the protocol was then made available to any center participating in the study for institution-

specific IRB approval. The methods used to administer FMT differed among sites, though most

(12 of 16) exclusively used an endoscopic lower GI route of administration. Informed consent

had been obtained from all patients prior to FMT. A 32-item data collection form was developed,

which elicited demographic data, CDI characteristics, and pre- and post-FMT data for each

patient. Patients were included if they were IC and had undergone FMT for recurrent, refractory,

severe or complicated CDI unresponsive to standard therapy. Definitions used to classify

recurrent, severe and complicated CDI for this study were based on recently published ACG

guidelines [Surawicz 2013].

1. Recurrent or relapsing CDI: At least three episodes of mild-to-moderate CDI and

failure of a 6-8 week taper with vancomycin with or without an alternative antibiotic (e.g.

fidaxomicin, rifaximin) or at least two episodes of severe CDI resulting in hospitalization

and associated with significant morbidity.

2. Refractory CDI: Moderate CDI not responding to standard therapy (vancomycin) for at

least a week

3. Severe CDI: WBC ≥ 15,000 cells/mm3, albumin < 3g/dl and abdominal tenderness

4. Complicated CDI defined by at least one of the following: admission to the ICU,

hypotension with or without the use of vasopressors, fever ≥ 38.5°C, ileus or significant

abdominal distention, mental status changes, WBC ≥ 35,000 cells/mm3, or < 2 cells/mm3,

serum lactate >2.2 mmol/L or any evidence of end-organ failure

At least 12 weeks of post FMT follow up data was required in order for the patient’s data to be

included in the analysis. We included patients who were immunocompromised at the time of

FMT as a result of or more of the following: HIV infection (any CD4 count), AIDS-defining

diagnosis or CD4<200/mm3, inherited or primary immune disorders, and immunodeficient or

immunosuppressed from a medical condition/medication including current or recent (<3 most)

treatment with anti-neoplastic agent or immunosuppressant medications (including but not

limited to monoclonal antibodies to B and T cells, anti-TNF agents, glucocorticoids,

antimetabolites (azathioprine, 6-mercaptopurine, methotrexate), calcineurin inhibitors

(tacrolimus, cyclosporine), mycophenolate mofetil).

Data collected included demographic information, reason for IC status, treatment with

immunosuppressant medication, other significant medical conditions, CDI treatments prior to

and around FMT, indication for FMT (recurrent, refractory or severe/complicated CDI), post

FMT mortality and hospitalizations, post FMT adverse events (AEs) and serious adverse events

(SAEs), and outcomes (CDI recurrence post-FMT, need for colectomy and response to second

FMT if required). Sixteen centers submitted data collection forms for 99 patients. Patients were

excluded from analysis if FMT was conducted for reasons other than CDI, if they did not meet

the criteria for IC or if they did not have a minimum of 12 weeks post-FMT follow-up,

The primary outcomes were CDI cure and any serious adverse events (SAEs) or adverse

events (AEs) within 12 weeks post-FMT. Cure was defined as absence of diarrhea, or marked

reduction in stooling frequency without need for further anti-CDI therapy. AEs were defined as

any untoward medical occurrence in a patient to whom FMT was administered. The AE did not

necessarily need to have a causal relationship with the treatment and thus we included

unfavorable signs or symptoms or disease temporally associated with the use of FMT, whether or

not related to the FMT. AEs could be clinically significant changes from baseline physical exam,

laboratory tests or other diagnostic investigations, complications related to the procedure used to

administer FMT, or new events or pre-existing conditions that became aggravated or worsened in

severity or frequency within 12 weeks post-FMT. SAEs were defined as any death, life

threatening experience, unplanned hospitalization, or important medical event within 12 weeks

after FMT. AEs and SAEs were determined to be related, probably or possibly related, or

unrelated to FMT. Secondary outcomes were CDI recurrence, need for colectomy, and response

to repeat FMT. Cure rates and percentages were calculated after one FMT and more than one

FMT for the population. Rates and percentages were also calculated for SAEs, AEs, and

inflammatory bowel disease (IBD) flares.

RESULTS

Study Patient Characteristics – Table 1a

Data collection forms were completed on 99 patients who had received FMT at one of the

study centers. Of these, 19 were excluded from analysis because they had undergone FMT for

indications other than CDI (15), did not meet criteria for IC (2), or were lost to follow-up prior to

having 12 weeks of post-FMT follow up (2). Eighty patients were included in the final analysis

(Table 1). The study population included similar numbers of men and women. The majority of

these patients were adults (75 of 80, 94%) and the mean age of the adults treated was 53 years

(range: 20-88 years). Reasons for IC included IBD patients treated with immunosuppressive

agents (37, 46.3 %), solid organ transplant recipients (19, 24%) and patients

immunocompromised because of severe or end-stage chronic medical conditions (17, 14%).

Additionally, there were 7 (8.9%) patients with cancer who were receiving antineoplastic agents

concurrently or within 3 months prior to FMT, and 3 (3.8%) patients had HIV/AIDs. Specific

immunosuppressant agents used, indications and numbers of patients exposed are listed in Table

1b. Recurrent CDI was the most common indication for FMT (44 of 80, 55%). Nine (11%) of

patients received FMT for refractory CDI and 27 (34%) met criteria for severe or complicated

CDI. FMT was conducted as a hospital inpatient in 17 (21.2%) patients and 63 (78.8%) received

FMT as outpatients.

Outcomes

Efficacy

Resolution of CDI occurred in 62 (78%) patients after a single FMT. Eleven patients who

either had recurrence or did not respond after one FMT underwent repeat FMT, of which 8 were

cured. Thus, overall cure (defined as resolution of CDI after one or more FMTs) within a

minimum of 12 weeks was observed in 70 (89%) patients.

Safety

SAEs were observed in 12 (15%) patients within 12 weeks post-FMT (Table 2a). Two

deaths occurred. One patient, whose diarrhea ceased after FMT, died secondary to progressive

pneumonia, for which he was being treated before FMT. The other died as a result of a

witnessed aspiration at the time of sedation for the colonoscopy used to administer the FMT.

There were 10 hospitalizations within 12 weeks of FMT. One patient was hospitalized with self-

limited abdominal pain, which occurred after the colonoscopy used to administer FMT and was

thus related to FMT. Three hospitalizations were unrelated to FMT and 1 case of influenza was

possibly related. Four patients were hospitalized with flares of IBD possibly related to FMT,

though more specific data regarding the course of their IBD prior to FMT was not obtained. One

catheter line infection requiring hospitalization occurred and was probably unrelated to FMT.

There were no infectious complications directly attributable to FMT. Three deaths were reported

outside of 12-weeks post-FMT and were not considered as SAEs. All occurred more than 6

months after FMT and were related to chronic progressive illnesses unrelated to CDI. Patients

with IBD did not have an increased rate of SAE (11%) compared to patients without IBD (18%).

We observed 13 patients with AEs (Table 2b). Of these, 4 were related, 6 were possibly related,

and 3 were unrelated to FMT. Three patients underwent colectomy, though none were for CDI.

One patient with ulcerative colitis (UC) had a colectomy less than 1 month post-FMT for

progressively worsening UC which had not improved after treatment of CDI. Another patient

with UC underwent colectomy 105 days post-FMT for indeterminate colitis and a third UC

patient had colectomy 293 days post-FMT for worsening UC.

Discussion and Limitations

This multicenter case series showed that 89% of IC patients achieved symptom resolution

after FMT for C. difficile infection and most CDI resolved after a single FMT. Rates of cure

were similar to those observed in previous studies.24,25 This population has previously been

excluded from FMT studies and possibly denied this effective therapy because of concern about

bacterial translocation and infection. In these 80 patients who underwent FMT at 16 centers,

there were no deaths or documented infections that occurred after FMT as result of the FMT

itself. One death occurred as a result of the procedure used to re-administer a second FMT in a

critically ill patient. We believe it is prudent to consider less invasive means of administering

FMT (such as enema or unsedated sigmoidoscopy) or delaying FMT in favor of traditional

medical management in unstable patients with severe or complicated CDI or significant

comorbidities. Administering vancomycin indefinitely to prevent further CDI recurrence is

another option when treating patients with a limited life expectancy in whom the risk of FMT

may outweigh benefits.

It is noteworthy that 14% of patients with IBD experienced complications post FMT in

the form of a disease exacerbation, one of which required a colectomy within 1 month of FMT.

No information about the course of IBD in these patients prior to FMT is known, and we cannot

say whether these flares were attributable to FMT, CDI or a progression of the underlying

disease. However, IBD flare after FMT to treat CDI in a patient with previously quiescent UC

has been reported31 and fevers along with temporary elevations of C reactive protein levels have

been described in small series of UC patients treated with FMT for IBD. 32,33 Certainly continued

studies regarding safety and efficacy of FMT in this population are warranted.

This study is the first to systematically report safety outcomes in FMT and the first to

address the question of efficacy and safety of FMT for CDI in IC patients. Physicians may be

reluctant to prescribe FMT in these patients in keeping with the presumption that they are “high

risk,” though there has not previously been evidence either for or against this belief in this

population. In fact, patients with recurrent CDI have been shown to have marked expansion of

members of the Enterobacteraceae family of Proteobacteria in their gut microbiota.34-36 which

are frequently relatively invasive pathobionts that may be responsible for other infectious

complications in these patients.37 In contrast, FMT leads to restoration of dominance of

Bacteroidetes and Firmicutes in the distal gut microbiota. It is reasonable to expect that

normalized gut microbial ecology should improve colonization resistance to potential pathogens

in IC patients.

IC patients have been excluded from clinical trials of FMT for concerns that seemed

reasonable yet were not supported by data. Prospective studies will enable real-time tracking of

patients and variables prior to and after FMT, which will help to eliminate biases, such as recall

or selection bias. In describing outcomes after FMT in this first series among IC hosts, many of

whom suffered from severe CDI, we hope to be an impetus for additional and prospective

studies. Furthermore, physicians may be encouraged to use FMT more frequently in this group

of patients. The multicenter design strengthened the study by increasing external validity,

minimizing any regional effects or skewing by individual clinician practices. There are no

standardized guidelines for the administration of FMT in terms of the amount of stool or routes

of administration. This study, performed at multiple sites, each with its own protocol for

administration, supports an overall curative effect seen among IC patients despite practice

variation. The FMT-performing clinicians closely followed each patient, enabling the collection

of good quality, complete data in this retrospective study.

Weaknesses of this study are related the retrospective design. The data points available

for the study were limited to data that was collected and available in the medical record at each

center. Patients were not solicited for adverse events which were only included in the study if

documented in the medical record at the study center. However, all centers provided sufficient

details to answer the 32-item survey tool required to analyze the primary outcomes. Additional

limits included potential selection and recall biases. More information on each patient’s

functional status and course of immunocompromising illnesses could be helpful in stratifying

patients as sickest to healthiest among this IC group. The multicenter design, while a strength,

also made standardization of data points challenging. Classification of CDI was based specific

criteria, though the data collection survey did not distinguish between severe and complicated

CDI or allow submitting centers to specify which criteria for severe or complicated disease were

fulfilled. Patients may have been classified as severe based on leukocytosis or low albumin (not

necessarily sepsis or organ failure). Furthermore, it is unknown at what time point FMT was

performed in these severe patients, such as after a course of vancomycin when they had

improved clinically but were at risk for further recurrence. The fact that the majority of these

FMTs were performed as outpatient procedures suggests that most patients in this series were not

acutely ill at the time of FMT. Ultimately, a prospective cohort study of patients with complex

CDI or a matched case-control series would be reasonable to further investigate the use of FMT

in CDI in IC patients, while minimizing some of these biases. In conclusion, this study showed

that FMT appears to be a safe and effective treatment for recurrent, refractory or severe CDI in

this high risk population of IC patients.

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Table1a. Study Patient Demographics and Pre-FMT DataTotal Number of Study Patients 80Adults 75 (94%)Women 38 (48%)Mean Adult Age (years) 53 (range 20-88)Mean Pediatric Age (years) 10.9 (range 6.5-16)Mean Follow-up (months) 11 (range 3-46)CDI Classification prior to FMT

Recurrent 44 (55%)Refractory 9 (11%)Severe/Complicated 1 (1%)Overlap (Severe/complicated & recurrent or refractory)

26 (33%)

Reason for ImmunocompromiseTreatment with immunosuppressive agents for IBD

36

Solid organ transplant recipients treated with immunosuppressive anti-rejection agents

19

HIV/AIDS 3Severe/end-stage chronic medical conditions including:

Rheumatoid arthritis (4) Autoimmune renal disorder Cirrhosis secondary to Hepatitis

C (2) ESRD on hemodialysis (HD)

and panhypopituitarism Cirrhosis (MELD 32) Decompensated cirrhosis

secondary to autoimmune hepatitis

NASH cirrhosis (2) End-stage COPD on chronic

steroids Polycystic kidney disease on

HD and allograft failure Sjogren’s disease

15

Table 1b. Immunosuppressant agents used concurrently or within 3 months of FMT, indication and number of patients exposed

Agent Indication Number of patients exposedInfliximab IBD 12

Adalimumab IBD 3Natalizumab MS 1Nataluzimab IBD 1

Certolizumab pegol IBD 1Prednisone SOT 6Prednisone COPD 1Prednisone IBD 15Prednisone RA 3

Hydrocortisone Autoimmune kidney disease 1Hydrocortisone Panyhypopituitarism 1Hydrocortisone IBD 1

Solumedrol IBD 2Methotrexate IBD 3Methotrexate RA 2Azathioprine IBD 10Azathioprine SOT 3

6-mercaptopurine IBD 1Sirolimus IBD 1

Tacrolimus SOT 15Mycophenolate mofetil SOT 6

Cyclosporine SOT 3Bevacizumab Cancer 1Adriamycin Cancer 1Fludarabine Cancer 1

5-FU Cancer 1Cisplatin Cancer 1

Bleomycin Cancer 1Dasatanib Cancer 1

Lenalidomide Multiple Myeloma 1Leflunomide RA 1

Plaquenil Sjogrens 1Rituximab RA 1

Table 2a. Serious Adverse EventsSerious Adverse Event (Etiology) Number of days post-FMT event occurred

DeathsPneumonia complicated by effusions present pre-FMT

13

Aspiration during sedation for colonoscopy to administer FMT

0

HospitalizationsFever, cirrhosis-related encephalopathy and pancytopenia

4

Abdominal pain-self limited; no antibiotics or sequelae

0

Crohn’s flare *<84UC flare *<84Crohn’s flare *<84CVA; nausea & vomiting 21UC flare *<28Fall and sustained hip fracture 84Influenza B 3Catheter infection *<84

*exact number of days post-FMT but within 12 week follow up period at which event occurred unknown

Table 2b. Adverse EventsAdverse Event Number of patients sustaining this AE

Self-limited diarrheal illness (non-CDI, not requiring hospitalization)

5

Fever 1Bloating & abdominal discomfort immediately post- FMT (lasting <48 hours)

3

Hip pain 1Pertussis 1Nausea (one month post-FMT) 1Mucosal tear during colonoscopy used to administer FMT repaired with clip; no sequelae

1