stool banking 2020-2025 common interest group 2018-2019 2019/presentations... · 2019. 12. 10. ·...
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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”
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• [email protected]
NDF 2017