Appendix B: Discussion and Survey

Volume: 27S1 • July 2001

Report of the Xenotransplantation Surveillance Workshop
Infection Control Database and Sample Archiving

What data elements are critical to xenotransplantation surveillance?

How to define "adverse events".

draft Proposed Canadian Standards for Xenotransplantation definition: an undesirable outcome directly or indirectly related to the xenograft (e.g. infection, disease transmission, graft failure)
any notable change in the recipient's health or well-being, reversible or not, requiring medical attention or intervention, inclusive of death, disability, disease transmission, infection, or hospitalization whether directly or indirectly related to the xenograft protocol

What are "serious" adverse events"?

What adverse events might be linked to infection?

death
cancer/autoimmunity
disabilities, including chronic fatigue, coma, paralysis, mental confusion, behavioural changes
graft rejection or failure of graft to thrive
rash, fever, GI changes, hepatitis, pneumonia, weight changes, etc.,
others

By what criteria should an adverse event warrant an investigation for potential zoonosis?

death
cancer/autoimmunity
disabilities, including chronic fatigue, coma, paralysis, mental confusion, behavioural changes
graft rejection or failure of graft to thrive
rash, fever, GI changes, hepatitis, pneumonia, weight changes, etc.,
others

What should be the timelines for reporting data to registry and for adverse events?

the Standards indicate 72 hours for data collection
recipient adverse events should be reported immediately (or without delay), but which is taken to mean no later than 72 hours
animal sources adverse events should also be reported immediately, but no later than 72 hours
for infection/potential zoonosis within 24 hours
other considerations

What recipient samples are needed for monitoring?

baseline, routine monitoring and that for investigative purposes for local and national archives
plasma (at least 5 aliquots of 0.5 mL times 2)
serum (at least 5 aliquots of 0.5 mL times 2)
PBMC (at least 3 aliquots of 1 x 10⁶ times 2)
urine (early morning specimen 3 mL)
other considerations

What donor animal samples are needed for monitoring by National Archives?

What samples are needed for monitoring of close contacts by National Archives?

What samples are needed for monitoring of health care workers by National Archives?

What schedule for recipient sampling would be best? (choose ONE of the following)

baseline, weekly for first 3 months, then monthly for next 9 months, then every 6 months for 2 years, then yearly (and for any serious adverse event)
BASELINE, every two weeks for first 3 months, then monthly for next 3 months, then annually (and for any serious adverse event)
other:

What schedule for close contact sampling would be best? (choose ONE of the following)

baseline, monthly for first 3 months, then annually (and for any serious adverse event investigation)
BASELINE, every 3 months, then annually (and for any serious adverse event investigation)
other:

What pre-clinical workup on the donor herd is needed?

screening for various pig pathogens, and sentinel animal herd program reveals no pathogens
as above but some sentinel animals are immunosuppressed for 2 months, with no pathogens identified
NHP are inoculated with animal donor blood and cells/tissues, and health is monitored for at least 2 years
immunosuppressed NHP are inoculated with animal donor blood and cells/tissues, and health is monitored for at least 2 years
coculture of donor samples with various relevant human indicator cell types (includes PBMC and activated PBMC) with screening for retroviruses, herpesviruses, and looking for viruses with EM, cytopathic effects, and other non-specific means for unknown pathogens
other
screen herds for evidence of viremia for endogenous retroviruses (PERVs, reverse transcriptase activity), for endemic herpesviruses (specifically pCMV & circoviruses as well as DNA polymerase for herpes viruses), hepatitis E, and others such as:
employ EM or other visual techniques for virion production

What surrogate markers for adverse effects potentially related to zoonosis might be useful?

RT-PCR for alpha-fetoprotein (AFP) on PBMC for early detection of cancer, immunosuppression (related to cancer or infection)
RNase L activity: activated protein secreted in urine
ribosomal RNA for bacteria
other surrogate markers of viral infection such as:

What methods might be used to detect unknown zoonotic agents?

representational difference assay, used to pick up HHV-8 in Kaposi's sarcoma (PCR based driver to amplify new sequences not found in pre-sample)
modified FISH using recipient lymphocyte chromosome preparations pre and post xenografting, label pre and post cDNA (cut with certain restriction enzymes) from PBMC with different fluorochromes
other

What preparation is needed to deal with a xenozoonotic outbreak?

develop SOPs at National Registry/Archives for testing, sample collection, quarantine and notification in conjunction with F/P/T health ministries
develop SOPs at Health Canada (TPP) for clinical holds/moratorium/inspections & international notification
have laboratory facilities & resources (budget, staff, contracts, etc.) ready for testing/sequencing at local and national levels
other


	Last Updated: 2001-08-09		Important Notices