2. Fecal Microbiota Transplantation
Patients are ready, are we?
Teri Crumb BSN, RN, CCRC
Sachin Kunde MD, MPH
Bennett Samuel MHA, BSN, RN
September 18, 2013

3. Disclosure
No relevant financial relationships with commercial interests The research study was funded by HDVCH foundation

4. Objectives
Understand Fecal Microbiota Transplantation (FMT)
FMT research study at HDVCH
Implications for nursing practice

5. What is FMT?
Infusion of human stool obtained from one subject (healthy donor) into the gastrointestinal tract of another subject (recipient or patient)
Fecal transplantation
Fecal bacteriotherapy
Fecal microbiota transplantation
Modes of delivery
Enema
Colonoscopy
Upper endoscopy
NG/NJ

6. An experimental therapy from the “bottom up”
The origin of the idea for FMT

7. Clostridium difficile Infection
The number one cause of nosocomial diarrhea
Rate of nosocomial CDI in the US has doubled from 21 per 100,000 to 61 per 100,000 between 1996 and 2003
Cases with serious and refractory infection and surgical complications are increasing (2.5% emergency colectomy)
10% of cases require ICU admission
Mortality rate: 16%
McDonald et al, Emerg Infect Dis. 2006; Pépin et al, CMAJ. 2005

8. Inflammatory bowel diseases (IBD)
1.4 million in the US population
~25% are diagnosed during childhood (≤20 years)
Equal distribution
Crohn’s disease
Ulcerative colitis
Estimated annual disease-attributable direct costs are $6.3 billion (significantly higher in children compared to adults)*
*Kappelman MD, Gastroenterology, 2008

9. Ulcerative colitis (UC)

10. UC Intestinal manifestation Systemic involvement
Extra intestinal manifestation
Treatment options
Medical
Surgical

11. Switch video to Emma

12. Pathogenesis
Epigenetics: Epidemiological factors in a genetically susceptible host
Gut microbiome
Imbalanced host-commensal microbiota interaction in human intestines*
Decrease in “helpful (non-pathogenic)” and rise in “detrimental (pathogenic)” bacteria**
*Fava et al, World J Gastro, 2011; Gophna et al, J Clin Microbiol, 2006
**Manichanh et al, Gut, 2006; Frank el al, Proc Natl Acad Sci, 2007

13. Human gut microbiome in IBD
90%
Firmicutes: Clostridiales
Bacteroidetes
10%
Firmicutes: Bacillus
Proteobacteria
Actinobacteria
Fusobacteria
Verrucmicrobia

14. Role of gut microbiome in IBD
Animal modes of inflammation require bacteria (Strober W 2002,Sellon RK 1998) Antibiotics have therapeutic efficacy in Crohn’s disease (Sarton RB 2004), pouchitis (Shen B 2001, Gionchetti P 1999), and UC (Ohkusa T 2010) Probiotics have therapeutic efficacy in pouchitis (Gionchetti P 1999), and UC (Kruis W 2004) Diverting the fecal stream from the inflamed gut induces healing in CD (Rutgeerts P 1991, Lee E 1975) Reinfusion of intestinal content into surgically excluded bowel triggers recurrence (D’Haens GR 1998)

15. Human microbiome
Harris el al, J Obesity, 2012

16. FMT in CDI and IBD FMT is not a novel therapy
Clostridium difficile infection
First fecal transplant (Eiseman et al, 1958)
>300 cases published with cure rate of 92% (Gough et al, 2011)
Ulcerative colitis
Bennet et al (Lancet, 1989, n=1)
Borody et al (J Clin Gastro, 2003, n=6)
FMT has lasting efficacy
Donor flora establishes itself in the recipient’s gut within 2 weeks and can sustain at least for 6 months (Grehan et al 2009)

17. Phase I clinical trial Hypothesis
FMT can induce clinical response in children with IBD associated colitis
Aim
To assess if FMT can induce clinical response in children with IBD colitis using Pediatric Ulcerative Colitis Activity Index (PUCAI)* at one month and at 6 months after FMT
*Turner et al, Gastroenterology, 2007

18. Study design – data collection instruments
PUCAI
For donors
For subjects
Questions
Circle your response (only one per question)
Do you have abdominal / tummy pain No
Yes, but I can ignore it
Yes, and I cannot ignore it
Do you have any blood in stool
Small amount; present in less than half of the stool
Small amount; present in most of the stool
Large amount; blood makes up more than half of the stool content
How are your stools?
Formed
Partially formed
Completely unformed (diarrhea)
How many stool you have daily? (average over last 2 days)
0-2
3-5
6-8
>8
Do you get up at night to have bowel movement
Yes
Do your symptoms affect your daily activity
Occasionally
Always (severe restricted activity)
Questions
Circle your response
If “yes” please specify
Did you have any GI conditions such as irritable bowel disease (IBS) inflammatory bowel disease (IBD) or diarrhea in last 4 weeks No
Yes
Have you ever been diagnosed with stomach or intestinal cancer or
autoimmune diseases
Have you ever been diagnosed with any chronic (long standing) gastro-intestinal (GI) condition
Have you used antibiotics or probiotics in last 4 weeks?

19. Institutional review board (IRB) and financial support
Study design - methods
Post FMT
1 month and 6 month follow up and data collection
FMT
Logistics of procedure
Mode of delivery: Enema
5 treatment sessions
Sample preservation
Subject and donors
n=10
Donor selection and screening
Baseline data collection
Institutional review board (IRB) and financial support

20. Donor screening and testing
Food and Drug Administration (FDA) Guidelines
Syphilis
HIV I & II
American Blood Bank Association Questionnaire
Stool fungal smear
Stool culture for enteric pathogen
American Gastroenterological Association Guidelines (Bakken et al, 2011)
Stool C. difficile toxin assay
Stool ova and parasite screen
Hepatitis A, B, C
Cytomegalovirus
Epstein-Barr Virus

21. The unexpected…

22. Study participants Age 15.2 ± 4.4 Gender Female 4 Male 6
Disease Extent
     Extensive 1
     Left-sided
     Pancolitis
     Proctitis 2
STARTED 10
COMPLETED 9
Not Completed 1
Donors' Age
     18-40 2
     40-60 8
Donors' Gender
     Female 4
     Male 6

23. Results
Clinical response to FMT observed by changes in clinical disease activity using PUCAI scores.
Subject 7 was not included in this analysis due to intolerance to fecal enemas.
Changes in PUCAI post-treatment were compared with baseline using the Wilcoxon signed rank test.
P value <0.05 was considered statistically significant.
The median PUCAI score significantly decreased after FMT compared with the baseline.
Kunde et al. JPGN, 2013

24. IN THE NEWS…

25. New York Times Article
“The causes of ulcerative colitis are more mysterious than those of clostridium difficile…, but there is some speculation that the condition can also be traced to pathogenic bacteria. A small study of children with ulcerative colitis, published this spring in The Journal of Pediatric Gastroenterology and Nutrition, found that 78 percent had a reduction in symptoms within a week of being treated with fecal transfers.”
The Journal of
Pediatric Gastroenterology and
Nutrition
Lee, Why I Donated My Stool, New York Times, 2013

26. FDA Public Workshop

27. Why is FMT important? State of Michigan Lab Identified CDI
Teaching (12)
Mid/West (9)
>200 beds (9)
ICU (16)
Per 10,000 patient days
17.41
10.52
15.62
23.01
Non-teaching (9)
Southeast (9)
<200 beds (12)
Med/Surg (13)
3.62
19.08
6.35
14.49
Folks, so why is FMT important. The Michigan Department of Community Health’s annual report gives us a glimpse into Lab Identified Clostridium difficile Infection per 10,000 patient days. In 12 teaching hospitals in Michigan the rate is 17.41, 9 hospitals in the Midwest with a rate of 10.52, 9 hospitals with more than 200 beds with a rate of and 16 hospitals with ICUs with a rate of Some researchers suggest that CDI is about 75% community acquired and 25% hospital acquired, but it is still the number 1 nosocomial infection. Clearly we have a problem.
Now a few numbers from Spectrum Health Lab Identified CDI
One positive test
7% ED
49.6% Inpatient
43.3% Outpatient
Recurrence
2 times – 66 (60%)
3 Times – 25 (23%)
4 Times – 13 (12%)
5 Times – 4 (4%)
6 Times – 0 (0%)
7 Times – 1 (1%)
8 Times – 1 (1%)
Spectrum Health Lab Identified CDI (Jan – Jul 2012)
453
One positive test
353 (76%)
Recurrence
110 (24%)
Michigan Department of Community Health Annual Report; Kerrie Verlee and Chau Nguyen, Spectrum Health Infection Control Dept. Epidemiologists.

28. What is FMT important?
IBD accounts for 700,000 physician visits, 100,000 hospitalizations, and disability in 119,000 patients
Over 25% of patients with UC require surgical intervention
Psychosocial impact
Inflammatory Bowel Disease, CDC, 2012
In the case of Inflammatory Bowel Disease…According to the Center for Disease Control and Prevention, IBD accounts for 700,000 physician visits, 100,000 hospitalizations, and disability in 119,000 patients.
Also, in Ulcerative Colitis, more than 25% of patients require surgical intervention.
Finally, the psychosocial impact can be devastating for many patients. As reported to NewsChannel5.com by a couple of patients: UC is “very inconvenient because I was bleeding a lot, going to the bathroom a lot”; Another patient said, “It’s hard to tell your friends what’s wrong, and you just kind of have to withdraw from life.”

29. Implications for Nursing Practice
Assessment Infection control Consent and education Donor screening and testing Route of administration Patient positioning Patient dignity and privacy Assessment during treatment Post-treatment assessment Long-term assessment and education
So, this brings us to Implications for Nursing Practice. Nursing practice has its foundations based on Quality and Safety, and Evidence. It’s neat then that we can take the FMT research at Spectrum Health and pass on these implications for nursing practice based on safety, quality and evidence.
Assessment: What are the signs and symptoms of CDI and IBD? Abdominal pain, frequency and urgency and quality and quantity of stool produced. Is there blood in the stool? Has the PCR testing for CDI been done? For IBD, a colonoscopy and sometimes biopsies need to be done to confirm diagnosis. How is the patient dealing with these symptoms? What can we (what can I do as your nurse) to support you and help you?
Sometimes we may have to think outside the box. For, example, female patients with IBD may also experience more gastrointestinal symptoms such as nausea, gas, and abdominal pain during their menstrual cycle, but the IBD symptoms such as bloody stools and the number of loose stools may not change. However, their feeling of well-being may be worsened around the time of the period. Knowledge of the cyclic alterations in gastrointestinal and systemic symptoms may be helpful in determining the true exacerbation of disease in female IBD patients.
Infection Control: Follow hospital infection control policies. Where there’s stool, the hand sanitizer is not going to cut it, so washing hands is a must. Also, teaching parents, and family members about ways to reduce the transmission of infection.

30. Consent/assent and education
“Children have a right to decide for themselves if they want to participate, and researchers have a responsibility to develop processes to ensure a child understands the assent process.”
Crumb, Teri. Monitor. 2012
Most people understand the concept of consent when working with adult patients or parents of pediatric patients. And as there are no federal guidelines about assent in the pediatric population, many have ignored it. Teri Crumb has written a wonderful piece about assent in the pediatric population in The Monitor: “Children have a right to decide for themselves if they want to participate, and researchers have a responsibility to develop processes to ensure a child understands the assent process.” In our case, not just as researchers, but as bedside nurses or clinic nurses. We know our patients well, we know if they have the mental capacity to understand a procedure, in this cast FMT, so, we must take the time to educate them and get an assent.

31. Donor screening and testing
Food and Drug Administration (FDA) Guidelines
Syphilis
HIV I & II
American Blood Bank Association Questionnaire
Stool fungal smear
Stool culture for enteric pathogen
American Gastroenterological Association Guidelines (Bakken et al, 2011)
Stool C. difficile toxin assay
Stool ova and parasite screen
Hepatitis A, B, C
Cytomegalovirus
Epstein-Barr Virus
Probably one of the biggest questions about FMT is the risk of transmission of infection. Teri already covered this slide, but as nurses this is a great opportunity to reassure our patients and family members that each donor goes through an extensive screening and testing process similar to a blood donor. In fact, we actually use the American Blood Bank Questionnaire. In addition to these tests, we ask donors to avoid foods that patients have allergies to. With the FDA, Blood Bank Questionnaire and the American Gastroenterological Association guidelines, it’s a pretty robust testing and screening process and so far there have been no reported cases of transmission of infection with FMT.

32. Route of administration and patient positioning
Enema and colonoscopy as route of administration
Left lateral decubitus position with elevated hips
Rotate 180° from left lateral to right lateral position then back to left lateral position during a 10-minute period
NG/NJ and upper endoscopy as route of administration
Sit upright at 45-90° angle
Monitor for signs of increased intra-abdominal pressure
Route of administration and patient positioning and key aspects to safe and effective FMT. Patients need to be placed in a left lateral decubitus position with elevated hips. After administration of FMT, the patients are asked to rotate 180° from left right to right lateral and then back to left lateral position during a 10-minute period. And this is so that we can use our friend gravity to ensure that the FMT preparation reaches all parts of the colon starting with the descending colon, to the tranverse colon and finally the ascending colon.
Some patients may have NG/NJ or an upper endoscopy as the route of administration. Patients will need to sit upright at a 45-90° angle to reduce the risk of regurgitation and aspiration. Patients will also need to be monitored for signs of increased intra-abdominal pressure to reduce the risk of nausea because aspiration of FMT may lead to severe infections.

33. Patient dignity and privacy
We already talked about the urgency and frequency of loose stools in patients with IBD and CDI. Patient dignity and privacy should be a key focus in taking care of these patients. And sometimes it’s just taking the time to order a bedside commode that makes all the difference for these patients.

34. Assessment during/after treatment
Gastrointestinal hemorrhage
IBD/C. difficile symptoms
IBD/C. difficile infectious symptoms
Constipation
Signs of an irritable colon
In our FMT study here at Helen DeVos Children’s Hospital, we had 7 out of 9 patients that had bloating/flatulence and 4 during the follow up period. Abdominal pain/cramping, diarrhea, blood in stool, and fatigue were some other reported symptoms possibly related to FMT. Two patients also had a fever during FMT. So, prior to their second FMT day, they were given prophylactic acetaminophen and diphenhydramine, which alleviated their symptoms. Another study by Gough et al, showed a few other symptoms. All these symptoms may be similar to what both IBD and CDI patients experience.
Kunde et al. JPGN, 2013; Gough et al. CID, 2011

35. Long-term assessment and education
IBD/C. difficile symptoms IBD/C. difficile infectious symptoms Adverse events/serious adverse events Nutrition Medications Clinical remission
The long-term assessments are similar to the primary assessment prior to FMT including frequency, urgency, blood in stool etc. Monitoring for adverse events or serious adverse events is key to ensure patient safety. Nutrition may be adjusted according to the patient’s needs and a dietician may need to be involved. The physician may choose to continue with medications in some patients, but discontinue medications in others. As nurses we need to pay attention to these details and education our patients on nutrition and medications. Finally, assess the patient for clinical remission not just with alleviation of symptoms, but possibly a colonoscopy/biopsies.

36. Next steps… C. difficile Clinical treatment Insurance coverage IBD
Many unanswered research questions
FMT in IBD is not as straightforward as FMT in CDI
Funding
Encapsulation of fecal microbiota?
FMT workgroup – collaborative efforts
For CDI at Spectrum Health we are working toward FMT as a standard of care for patients with reoccurring infections that are not resolved by antibiotic therapy. We are also working with insurance companies to shift patients costs to them rather than the patients themselves.
There are many unanswered questions for FMT in IBD. How exactly does it work? How long can clinical remission be achieved for? So it’s not as straightforward as FMT in CDI, which has had proven results since We are applying for grants to conduct future studies as insurance companies will not cover FMT treatment in IBD as of now.
We are also experimenting with encapsulation of fecal microbiota, which will be a unique and less convenient route of administration for all patients.
Finally, we have formed a network of hospitals across the US, known as the FMT workgroup to collaborate on research in FMT.