Stool Banking 2020-2025Common Interest Group2018-2019

UEG Week 2018 Vienna -2019 Barcelona

GastroCongress Wellington 28-11-19

Josbert Keller Chairman

Chris JJ Mulder Co-ordinator

van Nood et al. NEJM 2013

Evidence is clear → Implementation

FMT for recurrent CDI

FMT Major Problem : Where to “find” Proper Stool

• Transfaunation

• Horses with diarrhea- infuse stool from healthy horse per rectum

• Cattle - per os as rumenFecal transplantation in veterinary medicine since the 17th

century

Fecal transplantation in Veterinary Medicinesince 17 th century (“healthy horse shit was everywhere”)

The Do-It-Yourself Approach

Source: “Fecal Transplant at Home — DIY Instructions,” The Power of Poop,

http://thepowerofpoop.com/epatients/fecal-transplant-instructions/

FMT: daily practice since 2012

OpenBiome in Boston = USA

“Its different than donating blood”Two rounds of rigorous screensDonating if possible 60daysCompensation 40 $ per stool

In the Netherlands ; METC : “No RE-Imbursement allowed”

2012 150 $2020 1250 $n > 100,000FMT’s

OpenBiome• Recommendations:

• PPI

• Informed Consent

• Direct observation of capsules

• Cost

• $385 – 30mL upper GI or 250mL lower GI

• $535 – 30 capsules

www.openbiome.org

Pricing 2015

OpenBiome• Recommendations:

• PPI

• Informed Consent

• Direct observation of capsules

• Cost

• Probably >1000$ – 30mL upper GI or 250mL lower GI

• Probably >1000$ – 30 capsules

www.openbiome.org

Pricing 2020

FMT: daily practice since 2012 , butDo we want to give American Shit ? What to payNetherlands Fecal Donor Bank 2015-2020

• Netherlands: FMT recurrent CDI : < 40 / yr

• Patients with 3th recurrence CDI : > 200-300/ yr

Hurdles :

▪ Donor screening & selection

• Lack of experience

• Time consuming

• Not standardized

▪ Reimbursement

▪ (legislation) Boston Non-Profit since 2012

© UEG. 2019

Stool Bank

• Aim Netherlands Donor Feces Bank, ndfb.nl

• To provide ready-to-use donor stool suspensions

• To improve safety and quality of FMT

• To increase cost-effectivenes

• Research / innovation

• (non profit)

10 Towards a European Stool Bank Model | Josbert Keller

Comparable to blood banks

Working group

• Gastroenterologist

• Microbiologist

• Infectious Disease specialist

• Biobanking!

Stool Banks

20-10-2019

Common Interest Group EHMSG UEG Sunday October 20, 2019

FMT and Stool banking

Fecal microbiota transplantation (FMT) is a new treatment strategy targeting a disturbed microbiota.

During this common interest group meeting, new developments and controversies related to FMT and stool banking were discussed.

Speakers:

Vehreschild Immunocompromised patients / MDRO

Liz Terveer Donor Screening Blastocystis

Cyriel Ponsioen Ready for IBD?

Peter Hvas Organisation, classification, costs, reimbursement

Zain Kassam FMT registries , standardization urgently needed

20-10-2019

Project meeting

UEG/EHMSG activity grant: towards a European Stool Bank Model

Sunday October 20, 10-13 AM

1. Subgroups 2018-2019:1. M Veherschild Donor screening2. Liz Terveer Processing and storage of suspension3. Harry Sokol Clinical application of FMT4. Hoegenauer / Ianiro Special circumstances, Contra-indications / Children5. Perttu Arkkila FU, quality assurance and legislation

3. General discussion

4. Future of FMT working group 2020-2025

UEG standards and guideline projectFMT & stool banking: Towards a European Stool Bank model

Josbert Keller, Ed Kuijper, Antonio Gasbarrini

“European” working group:

MJGT Vehreschild, A Gasbarrini, O Gridnyev, F Mégraud, PK Kump, R Nakov, SD Goldenberg, R Satokari, S Tkatch, M Sanguinetti, H Sokol, G Cammarota, A Dorofeev, JJ Keller, C Hoegenauer, O Gubska, G Ianiro, E Mattila, RE Ooijevaar, R Arasaradnam, SK Sarin, A Sood, L Putignani, L Alric, P Arkkila, CL Hvas, SMD Jørgensen, EJ Kuijper, J Kupciskas, A Link, CJJ Mulder, HRT Williams, A. Goorhuis, HW Verspaget, EM Terveer, GL Hold, H Tilg. J Dore, Z Kassam

Aim: providing a manual for stool banks in EuropeTemplates for SOP’s

Based on: available consensus reports (also Rome II) / guideline (BSG)

previous experiences (OpenBiome, NDFB, Denmark etc)

Stool Bank: organisational framework

Legislation, classification• The procurement and processing of donated faeces is best covered within the EU

Tissue and Cells Directive (2004/23/EC) with national oversight by national, competent authorities.

Stool for Fecal Microbiota Transplantation shouldbe classified as a transplant productNot as a drug

Reimbursement Treatment of patients

FMT solutions (1000-1700 euro per suspension)

UEGJ 2020 in press

Stool Bank: organisational framework

Legislation, classification• The procurement and processing of donated faeces is best covered within the EU

Tissue and Cells Directive (2004/23/EC) with national oversight by national, competent authorities.

Stool for Fecal Microbiota Transplantation shouldbe classified as a transplant productNot as a drug

Reimbursement Treatment of patients

FMT solutions (1000-1700 euro per suspension)

UEGJ 2020 in pressFDA considers this as a DRUG , Big Pharma is interested

Organization of stool banks

20-10-2019

The head of a stool bank should be qualified physician with a specialist registration- Which specialties are qualified for this position ? gastroenterology, infectious diseases, or Medical Microbiology?Other specialists possible? - Or only mention qualified specialist?

Auditing by local or preferably (in the future) national authorities should be part of the quality management of a stool bank-Such audits should check that the data are entered and maintained properly, and evaluate the working processes and quality assurance program of the stool bank. - To be discussed. How should auditing be organized?

Its imposed to the stool bank to evaluate and select third parties on the basis of their ability to meet the European standards- This could also be considered the task of the health authorities. Otherwise, the responsibilities of the stool banks are becoming tremendous.- Should we state that stool bank can only be responsible for the stool, - not for the FMT administration?

Organization of stool banks, adverse events, registration

20-10-2019

Adverse events (AE) and serious adverse events (SAE) should be documented.

In case of any SAE where a connection to the adverse event and FMT is made, the unit is obligated to notify the appropriate authority immediately- Who is the competent health authority in this case? - Do we need a Medical Advisory Board?- Where should SAEs be reported ? Is a medical advisory board mandatory ? - (Inter) National FMT registry ?

How long should data be kept donor/recipient ? And biological samples ?

Donor recruitment 2020-2025

20-10-2019

Unpaid donations should be preferredThey reduce the risk applicants providing false information during the screening process. Asking a donor to donate 60 donations is it ethical not to pay ?

Universal donors should be preferred to patient-selected donors CDIFF- Can/should we explain why? For logistic reasons only?- Evidence?

Disease specific donors might be preferredFor IBD , IBS , MS, Parkinson- Can we explain why? Prize implications ?- Evidence?

Donor Stool donation

20-10-2019

Once a donor has been approved, he or she should complete a second questionnaire before each donation- We should make a short questionnaire, including the question “ has anything changed”- Interview required?

- Questionnaire suffices?

At which interval should complete screening of blood and feces be repeated ?

If donor screening is performed as recommended in this document, direct testing of each suspension is not mandatory

multidonor pooling for suspensions ? Only for CDIFF ?

Immunocompromised patients

20-10-2019

Categories Arbitrary :A:-Current or foreseeable neutropenia within the next 14d, defined as <500 Neutrophils/µl-Scheduled for allogeneic SCT or having received allogeneic SCT within 100d-Active Graft versus Host Disease requiring immunosuppressive treatmentB:-Patients with <200 CD4 T-cells/µl-Prolonged use of corticosteroids at a mean dose of 0.3mg/kg/d of prednisone equivalent for >3 weeks-Treatment with other recognized T-cell immunosuppressants, such as cyclosporine, TNF-alpha blockers, specific monoclonal antibodies (e.g. alemtuzumab), MTX or nucleoside analogues during the last 90 days-Inherited severe immunodeficiency (e.g.chronic granuloumatous disease or severe combined immunodeficiency

Screening

20-10-2019

For all donors, screening for aerobic Gram-negatives with resistance to at least two of the following classes: aminoglycosides, fluoroquinolones, 3rd generation cephalosporins and carbapenems should be supplied.Detection of such organisms will not lead to donor exclusion but should be provided to the treating physician, in order to guide empirical treatment in case of infectious complications

Domination of the gut microbiota by potential pathogens preceeds translocation and bloodstream infection in severely immunocompromised patients.We recommend donor screening for the presence of a domination, defined as >30% of the microbiome represented by the same bacterial genus. Domination may be detected through molecular-based microbiome analysis or using a cultural approach.

-Feasible? … (would need sequencing for all stools…), Financial implications-“recommended” or “to be considered”? -Is there any evidence or even anecdote to support this recommendation?

Processing

20-10-2019

≥ 50 gr of stool to prepare a FMT suspension for rCDI treatment

Several experts report (mostly unpublished) positive results with < 50 gram donor feces. Reducing the amount to 30 gr of stool could be considered.

Cryopreservation of Encapsulated donor faecesEncapsulation may be feasible and could reduce the burden FMT for patients in the future.

Long-term storage of fecal suspensions −80°C ( > 2 yrs) should be discouraged.

Storage at −20°C is only acceptable for 2weeks .- To be discussed

A sample of the original donor feces and of the processed FMT suspension should be stored - 2 or 10 years?

Processing of FMT suspensions

20-10-2019

SOP for processing Accepted in Barcelona

Processing of FMT suspensions

Amount of feces 50-60 gram, alternatively: 30 gram

Processing aerobe or anaerobe

Dilutent NaCl 0.9%

Cryoprotectant Glycerol 10%

End volume 50-60 gram: 200 cc

30 gram: 100 cc

Storage -80, maxium 2 years

Timeframe between collection and storage < 6 hours (rapid processing preferred)

Treatment of patients

FMT suspension Frozen stool banked suspension

pre-treatment of patient 4-10 days vancomycin 125-250 mg qid

stop vancomycin one day before FMT

bowel lavage with macrogol on day before FMT*

Colonoscopy

Nasoduonal tube (infusion .. cc/ minute)

* For upper GI delivery, bowel lavage could be limited to 50% of the recommended dose for colonoscopic r

Clinical application of FMT

20-10-2019

Stool banks can offer expert consultation at the request of the treating physician

Antibiotics should be stopped on the day before FMT (> 24 hours before FMT).

Duodenal >>> Colonic infusion

Before Duodenal infusion, a reduced load 2 instead of 4 liter Kleanprep® ??

One study suggest that treatment with enemas more often requires repeated infusions (49) but low volume enemas were used (50ml) and no bowel lavage was performed. In clinical practice, success rates appeared higher with large volume enemas (300-500ml) and bowel lavage (unpublished).

Capsules appear effective, but are held back by their limited availability.

Etc Etc Etc

20-10-2019

Indications for FMT

Indication Current evidence References

Recurrent Clostridioides difficile 6+ randomised trials: 90% effect

van Nood E, N Engl J Med 2013;368:407Cammarota G, AP&T 2015;41:835

Kelly CR, Ann Intern Med 2016;165:609Lee CH, JAMA 2016;315:142Jiang ZD, AP&T 2017;45:899

Hvas CL, Gastroenterol 2019;156:1324

Refractory Clostridioides difficile Recommended based on cohort studies Fischer M, Am J Gastroenterol 2016;111:1024

Multidrug resistance (MDRO) Case reports and series: proof of concept

Singh R, Clin Microbiol Infect 2014;20:O977Manges AR, Infect Dis 2016;48:587

Stalenhoef JE, Open Forum Infect Dis 2017;4:ofx047Singh R, BMC Res Notes 2018;11:190

Grosen AK, Case Rep Nephrol Dial 2019;9:102

Ulcerative colitis4 randomised trials: 9-30% effect, althoughtemporary and not clearly superior to placebo

Moayyedi P, Gastroenterol 2015;149:102Rossen NG, Gastroenterol 2015;149:110

Paramsothy S, Lancet 2017;389:1218Costello SP, JAMA 2019;321:156

Chronic/relapsing pouchitisCase studies and terminated clinical trial: conflicting data

Nishida A, Clin Case Rep 2019;7:782Herfarth H, Inflamm Intest Dis 2019;4:1

Hepatic encephalopathy (HE) 1 randomised pilot trial: marked effect Bajaj JS, Hepatology 2017:66:1727

Irritable bowel syndrome (IBS)4 published randomised studies: conflicting data (meta-analysis: no effect)

Halkjær SI, Gut 2018;67:2107Johnsen PH, Lancet Gastroenterol Hepatol 2018;3:17

Holster S, Clin Transl Gastroenterolog 2019;10:e-00034Aroniadis OC, Lancet Gastroenterol Hepatol 2019;4:675

Ianiro G, AP&T 2019: PMID 31136009

Autism spectrum diseasesCase studies and 1+ open label study: effect on bowel GI symptoms

Kang DW, Microbiome 2017;5:10

FMT Stoolbanking

Jørgensen SMD et al, Eur J Gastroenterol 2017: 29:e36

Cost and reimbursement

• Stool bank• Donor recruitment and screening

• Laboratory processing

• Component storage

• Distribution

• FMT centre• Clinical application

• Follow-up

• Handling of complications

Jørgensen SMD et al, Eur J Gastroenterol 2017: 29:e36

Donor rekruttering

Klinisk applikationProcessering

Rekruttering, screening,

inklusion/eksklusion

Donation, bearbejdning og

utensilier

Transplantation,

overvågning og opfølgning

Donor Laboratory Clinic

€ 1,029 € 665 € 1,401

Total

€ 3,095Colonoscopy € 3,326 Nasojejunal tube € 2,864

E Dehlholm-Lambertsen, BK Hall et al. Therapeutic Advances in Gastroenterology, 2019;12:Epub

FMT cost in Denmark 2019

© UEG. 2019

Advice for recurrent CDI

Title of presentation | Presentation by [Enter details in 'Header and Footer' field]32

Processing of FMT suspensions

Amount of feces 50-60 gram, alternatively: 30 gram

Processing aerobe or anaerobe

Dilutent NaCl 0.9%

Cryoprotectant Glycerol 10%

End volume 50-60 gram: 200 cc

30 gram: 100 cc

Storage -80, maximum 2 years

Timeframe between collection and storage < 6 hours (rapid processing preferred)

Treatment of patients

FMT suspension Frozen stool banked suspension

pre-treatment of patient 4-10 days vancomycin 125-250 mg qid

stop vancomycin one day before FMT

bowel lavage with macrogol on day before FMT*

Colonoscopy

Duonal tube (infusion .. cc/ minute)

No data to give such a recommandationSome good experience reported with :- 25 g for lower GI delivery- 12.5 g for upper GI delivery.

No data to give such a recommandation

How long if stored at 4°C?

Enema, duodenal, capsules

FMT in patients with active Ulcerative Colitis

Outcome Transplant Group n=38

Placebo GroupN=37

P value

Remission 9 (24%) 2 (5%) 0.05

Mayo Score 6.0 6.3 0.80

IBDQ score 61.0 66.2 0.34

Moayyedi, P, Gastroenterology 2015: 149:102-9

• UC pts, randomized to 50 mL retention enema, anonymous donor,

• 1x/wk for 6 weeks vs placebo enema

• Pancolitis - more common in transplant group

• Primary outcome - remission with Mayo score of < 2; and an

endoscopic Mayo score of 0, week 7.

• Secondary outcome - change in QOL, assessed with the IBDQ

• Trial stopped early for futility.

• Stool from patients receiving FMT had greater microbial diversity

than at baseline

• Promising strategy (16-23%)

Further investigation:• Subgroups patients

• Specific donor characteristics

• Optimazation of protocol

• Investigation of changes in microbiota

• In Ludhiana Ajit Soot is treating >>40-50

UC patients with interval FMT

for more than 2 yrs, every 2 months

Conclusions: FMT in IBD

India ; Stoolbanking in Ludhiana and Delhi

20-10-2019

20-10-2019

Are you a super pooper?22 January 2019 Health and Medicine, Liggins InstituteFecal transplants could be used to treat intestinal disorders like inflammatory bowel disease – and perhaps even help prevent Alzheimer’s and cancer –if we can unlock the secrets of the gut-rejuvenating 'super donor', say researchers at the Liggins Institute.

Dr Justin O’Sullivan

Conclusion : “The Do-It-Yourself Approach is over…..”

Source: “Fecal Transplant at Home — DIY Instructions,” The Power of Poop,

http://thepowerofpoop.com/epatients/fecal-transplant-instructions/

In India they have organised good stoolbanking

Working group NDFB

• Daily board:Dr. JJ Keller Gastroenterologist, MCH-Bronovo & LUMCProf. dr. EJ Kuijper Medical microbiologist, LUMC

• Working group:Drs. EM Terveer Medical microbiologist, LUMCProf. dr. ir. HW Verspaget Cell biologist Gastroenterology - Biobank, LUMCDr. MP Bauer Internist, LUMCDrs. YH van Beurden PhD candidate Gastroenteroloy, VUmcProf. dr. CMJE Vandenbroucke-Grauls Medical microbiologist, VUmcProf. dr. CJJ Mulder Gastroenterologist, VUmcDr. E van Nood Internist, HavenziekenhuisDr. A Goorhuis Infectious diseases specialist, AMC

• Dr. MGW Dijkgraaf Research methdologist, AMCDr. J Seegers Moleculair Biologist, consultant

• Prof. dr. WM de Vos Microbiologist, Wageningen University• R. Ooijevaar PhD candidate VUMC

• Medical advisory board:Em. prof. dr. JE Degener Medical microbiologistEm. prof. dr. P Speelman Infectious diseases specialist

•

• www.ndfb.nl• j.keller@haaglandenmc.nl

NDF 2017