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Volume: 27S1 July 2001
Report of the Xenotransplantation
Surveillance Workshop
Infection Control Database and Sample Archiving
Appendix B: Discussion and Survey
What data elements are critical to xenotransplantation surveillance?
- demographics of donor (s)
- demographics of recipient
- immunosuppressive regime
- transfusion/transplantation history
- previous or current infectious diseases and cancer
- serious adverse events
- other adverse events
- links to archived samples
- links to infectious disease testing & results
- links to animal sources
- exposure frequency & duration
- type of graft
- tolerance induction protocol (if applicable)
- others
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"?
- death
- cancer
- disabilities including chronic fatigue
- any event requiring hospitalization
- infection
- graft rejection
- others
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?
- plasma (at least 5 aliquots of 0.5 mL)
- serum (at least 5 aliquots of 0.5 mL)
- PBMC (at least 5 aliquots of 1 x 107)
- xenograft sample/biopsy
- other considerations
What samples are needed for monitoring of close contacts by National
Archives?
- plasma (at least 5 aliquots of 0.5 mL)
- serum (at least 5 aliquots of 0.5 mL)
- PBMC (at least 5 aliquots of 1 x 106)
- baseline, routine and for investigative purposes
- other considerations
What samples are needed for monitoring of health care workers by National
Archives?
- plasma (at least 5 aliquots of 0.5 mL)
- serum (at least 5 aliquots of 0.5 mL)
- PBMC (at least 5 aliquots of 1 x 106)
- baseline, routine and for investigative purposes
- other considerations
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
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