Infectious Disease Screening of the Organ Donor: Balancing Risks ...

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  • 10% of transmissions resulted in Death; ~25% due to bacteria; Mortality rate with bacterial transmission ~20%
  • Infectious Disease Screening of the Organ Donor: Balancing Risks ...

    1. 1. INFECTIOUS DISEASE SCREENING OF THE ORGAN DONOR: BALANCING RISKS OF TRANSMISSION WITH WAIT LIST MORTALITY
    2. 2. OBJECTIVES 1. To review the goals and current approach to pretransplant screening for infection in the potential organ donor 2. To discuss some of the challenges and limitations of current screening methods 3. To discuss approaches to safely optimize utilization of the “marginal” donor
    3. 3. WHAT ARE THE GOALS OF SCREENING?  To identify conditions which may disqualify the donor (e.g. HIV)  To identify and initiate treatment for active infection prior to donation (e.g. bacteremia)  To stratify the risk of infection and optimal prevention strategies (e.g. CMV)
    4. 4. DEFINING WHAT WE WANT TO PREVENT  Epidemiology in donors  What incidence would be needed to require testing?  Is the prevalence sufficiently high for the PPV of test to be useful  Is the infection transmissible by organ transplant?  Organ specific risk?  Does transmission result in significant morbidity/mortality?  Treatable/untreatable?  Available monitoring protocols?  Is there a reliable and logistically applicable test available for screening?  Serology vs. NAT  Incidence of false positives vs. false negatives  Prospective or Retrospective?  What level of risk is “acceptable”?
    5. 5. UNIQUE SCREENING ISSUES IN DECEASED DONORS  Donor history  Second hand story  No standardization  Incomplete Data Collection  Restricted timeline  Different Screening Paradigm – individual testing  Serology-based Screening  Challenges due to hemodilution  Variable NAT capacity and practice  No expectation for “Zero Risk”  Risk-benefit ratio for organs differs from blood/tissues
    6. 6. SEROLOGIC SCREENING: LIMITATIONS  Can have false negative results  Window Period  Dilution of antibodies  IV fluid  Not all develop & maintain antibody response  False positives  Blood products  Kids up to 18 months – maternal antibody  Screening of a low risk population
    7. 7. PATHOGENS TRANSMITTED WITH ORGAN TRANSPLANT AST ID Guidelines. AJT. 2009 True incidence of DDDT unknown; estimated to be uncommon (~1%) Ison et al AJT 2007
    8. 8. DTAC: SUMMARY OF REPORTED CASES: 2005 - 2009 Disease Types # of Donor Reports # of Recipients w/ Confirmed Tx # of DDD-Attributable Recipients Deaths Malignancies 128 32 7 Viruses 86 31 8 Bacteria 38 26 7 Fungi 30 26 8 Mycobacteria 26 10 2 Parasites 21 13 3 Other Diseases 9 3 1 Total 338 141 33 Additionally, there were a large number of “expected” transmissions with CMV and toxoplasmosis reported to DTAC but not included in the above numbers.
    9. 9. Significant Organ Shortage 0 20000 40000 60000 80000 100000 Patients Waiting at Year End Deceased Donor Transplants Deceased Donors Recovered Waiting List Deaths* *Waiting list deaths includes removals for death, too sick to transplant, and those non-transplanted removals identified to have died within seven days of removal from linkage to SSDMF data. Based on OPTN data as of April 16, 2010. Organ Transplants 28,465 Waitlist Candidates 105,567 Deaths on Waitlist 9,848 2009 DATA
    10. 10. DONOR RISK ASSESSMENT  Medical & Social History  Review of charts  Interview of next of kin  Physical Examination  Organ Procurement Coordinator (external)  Surgeons (internal)  Laboratory Screening  Serology  Antigen detection  Nucleic Acid Testing (NAT)
    11. 11. DONOR ASSESSMENT: HISTORY
    12. 12. SUGGESTED DATA TO COLLECT REGARDING ELIGIBILITY OF ORGAN DONORS AST ID Guidelines. AJT. 2009
    13. 13. ASPECTS OF ID SCREENING THAT RELY HEAVILY ON HISTORY  Tuberculosis - No currently approved donor screening methods  TST: Cannot be implemented with deceased donors  Interferon-g Release Assays – no studies  History and risk factor identification  CXR, gross assessment of lungs +/- pathology  Endemic fungal or parasite risk – serology/other case-by-case  Place of birth, travel history  Unusual neurologic presentations  Increased Risk Donor
    14. 14. STANDARD SCREENING TESTS AND IMPACT ON ORGAN UTILIZATION
    15. 15. STANDARD SCREENING TESTS  HIV Antibody  Hepatitis B – HBsAg, anti-HBc +/- anti-HBs  Hepatitis C Antibody  Human T-cell lymphotrophic virus (HTLV-1/2) Antibody  Syphilis EIA  Cytomegalovirus IgG  Epstein Barr virus antibody (EBNA IgG)  Toxoplasma IgG (hearts)  Blood and urine cultures; respiratory cultures (lung)  Depending on Risk  West Nile virus NAT  HIV, HCV NAT  others
    16. 16. CASE 1  Donor MSSA bacteremia, septic pulmonary emboli, meningitis  On antibiotics ~36 hrs prior to offer  Repeat BC drawn – negative at offer
    17. 17. THE BACTEREMIC DONOR OR DONOR WITH MENINGITIS  Donor bacteremia, particularly with virulent organisms (e.g. S. aureus, Pseudomonas, Candida), may result in early posttransplant sepsis or mycotic aneurysm  95 bacteremic donors  No transmission with mean 3.8 days directed antimicrobial therapy posttransplant1  Organs successfully transplanted from donors with meningitis with appropriate antimicrobial therapy2  Guidelines3  Donor infection should be controlled  Directed posttransplant antibiotics to recipient(s); 2-4 weeks if virulent organism 1Freeman et al. Transplantation. 1999 2Lopez-Navidad et al. Tansplantation. 1997 3AST ID Guidelines. AJT. 2009
    18. 18. CASE 1 CONTINUED  60M, OLT Mar/10 for HCV/EtOH; status 3  Donor MSSA bacteremia (Abx ~36 hrs)  BC still 1/3 positive at procurement (retrospect)  Received iv cloxacillin prophylaxis  Transplant OR end of case 2100h  Blood cultures 2130h – MSSA in 1/2 (confirmed donor-derived by PFGE)  Clinically stable, cloxacillin continued 4 weeks, well  2 renal recipients – post-op BC negative; 2 weeks iv cloxacillin
    19. 19. DISEASE TRANSMISSION ASSOCIATED DEATH DTAC: 2005-2009 (33/338)  Malignancies:  Lung Cancer (2) • Lymphoma (2)  Melanoma (1)  Bacteria:  Pseudomonas (3) • Acinetobacter (1)  Serratia (1) • Bacteroides (2)  Viruses:  LCMV (5) • HIV/HCV (2)  HIV (1)  Fungi:  Coccidiomycosis (3) • Aspergillus (2)  Candida (2) • Mucor (1)  Tuberculosis: 2  Parasites:  Balmuthia (2) • Strongyloides (2)  Chagas (2)
    20. 20. CASE 2  28F, born in Romania  MVC, closed head injury  History unremarkable  Living in Canada since age 9  No high risk activity  Anti-HCV POSITIVE
    21. 21. GENERALLY DO NOT TRANSPLANT HCV+ ORGAN INTO HCV- RECIPIENT  Essentially universal transmission from HCV-Ab+/RNA+ donors  HCV RNA often not available prior to procurement  Risk from HCV RNA negative donors not defined  No prophylaxis; posttransplant treatment complex, low success rates, common A/Es  Has been associated with fibrosing cholestatic hepatitis (FCH), rapidly progressive fibrosis, increased mortality  May be considered in high status patients with informed consent
    22. 22. GOOD OUTCOMES WITH HCV+ LIVER ALLOGRAFTS IN HCV+ RECIPIENTS •Highly selected donors •Impact of genotype? Northup et al. Transpl Int. 2010 OPTN/SRTR database. 56 275 OLT Apr 94-Feb 08 19 496 HCV+ recipients and 934 HCV+ donors
    23. 23. NON-HEPATIC TRANSPLANT OF HCV+ ORGAN TO HCV+ RECIPIENT Abbott, KC et al. J Am Soc Nephrol. 2003 Gasink, LB. JAMA. 2006 Heart TransplantRenal Transplant N=2525 AHR 1.43 (1.02 to 2.02)
    24. 24. TRANSPLANT OF DONOR HCV+ KIDNEYS TO HCV+ RECIPIENTS IMPROVES SURVIVAL COMPARED TO WAITLIST Abbott, KC et al. AJT. 2004
    25. 25. UNDERUTILIZATION OF HCV+ ORGANS: UNOS 1995-2009 •Of 6830 HCV+ candidates, 29% received HCV+ RTx •HCV+ Kidneys 2.6 times discard rate •HCV D+/R+ waited 395 d less Kucirka, LM. AJT. 2010
    26. 26. CASE 3  45 y M, NDD donor after SAH  History unremarkable  Worked as lab technician  Serology: Anti-HBc total POSITIVE  Anti-HBc IgM, HBsAg, Anti-HBs negative
    27. 27. YOU SUGGEST: A. Accept all organs B. Accept all organs except liver C. Decline all organs D. Additional testing is required E. Call Transplant ID
    28. 28. THE ANTI-HBC POSITIVE DONOR  Transmission 50-80% in HBV naïve in absence of prophylaxis 1,2,3  Prophylaxis reduces transmission in both anti- HBc/anti-HBs+ (3%) and naïve (12%) 3  Lamivudine more effective than HBIg (2.6% vs 19%) 3  No benefit of combination (2.8%) 3 NON-HEPATIC  Transmission 0-5.2% in HBV naïve in absence of prophylaxis 4,5  Immune recipients (anti- HBs+) risk eliminated  HBV DNA in donor serum may be used to stratify risk 6  Non-immune recipients of anti-HBc/HBV DNA+ organ managed with Lamivudine X 12 mo or HBIg X 3-6 mo 6 LIVER 1Wachs, ME et al. Transplantation. 1995; 2Dickson, RC et al. Gastroenterology. 1997; 3Cholongitas, E et al. J Hepatol. 2010; 4Madayag, RM et al. Transplantation. 1997; 5Fabrizio, F et al. J Nephrol. 2002; 6Chung RT et al. AJT. 2001
    29. 29. VARIABLE UTILIZATION AND PREVENTION STRATEGIES IN OLT RECIPIENTS OF ANTI-HBC+ DONOR In a survey of US transplant centers in 2001, 57% indicated they would utilize these organs in HBV naïve recipients1 1Burton, JR et al. Liver Transpl. 2003 Variation in strategies for prevention persist2 2Perrillo, R. Liver Transpl. 2009
    30. 30. CASE 4  62 yo farmer from rural Saskatchewan  Previously healthy  No travel or other risk history  No prior transfusions  Massive intracerebral hemorrhage  HTLV 1/2 POSITIVE
    31. 31. HTLV IN ORGAN TRANSPLANTATION  Human T-cell lymphotrophic virus 1 (HTLV-1)  Endemic in Caribbean, parts of SA, W Africa, Asia and Oceana  Transmission: breast feeding, sexual, IDU, blood (up to 0.05% US blood donors HTLV 1/2+)  Acute T-cell leukemia/lymphoma (2-5%); HTLV- associated myelopathy (<1%); no effective therapy  HTLV-2: no clear disease association  Organ Transplant and HTLV-1  Several case reports DDDT (ATL/HAM)  Several small series of HTLV D+/R- with no transmission; absolute risk uncertain
    32. 32. HIGH RATE OF FALSE POSITIVE HTLV SEROLOGY IN US ORGAN DONORS http://optn.transplant.hrsa.gov/CommitteeReports/board_main_AdHocDiseaseTran smissionAdvisoryCommittee_7_7_2009_15_25.pdf
    33. 33. 10,000 potential organ donors screened 100 positive screening tests 50 positive confirmatory tests 1-10 HTLV 1 positive donors 100 potential donors may be ruled out, of whom only 1-10 likely actually have HTLV-1. 90-99 of the donors ruled out would carry no risk of HTLV-1 transmission. OPTN policy requiring HTLV screening for potential organ donors eliminated in Nov, 2009
    34. 34. POTENTIAL DOWNSIDE TO DONOR SCREENING: WNV  WNV has been transmitted by organ transplant rarely but high rate of morbidity/mortality  1 donor transmission was blood WNV NAT negative, but tissues in recipients positive  Rate of WNV infection has dropped in NA  Is WNV testing of organ donors worth performing?  Shift testing paradigm based on epidemiology? Kiberd BA, Forward K. Am J Transplant. 2004.
    35. 35. CASE 5  38 M NDD donor  Known history of IDU  Found down in public washroom with a syringe still in arm  HIV, HCV and HBV serology all negative
    36. 36. THE “INCREASED RISK DONOR” (IRD): EXCLUSIONARY CRITERIA FOR DONATION OF CELLS, TISSUES, OR ORGANS a) men who have had sex with another man in the preceding five years; b) persons who report nonmedical intravenous, intramuscular, or subcutaneous injection of drugs in the preceding five years; c) persons with hemophilia or related clotting disorders who have received human- derived clotting factor concentrates; d) persons who have engaged in sex in exchange for money or drugs in the preceding five years; e) persons who have had sex in the preceding 12 months with any persons described in Items a) to d) or with a person known or suspected to have HIV, clinically active HBV, or HCV; f) persons who have been exposed in the preceding 12 months to known or suspected HIV-, HBV-,and/or HCV-infected blood through percutaneous inoculation or through contact with an open wound, nonintact skin, or mucous membrane; g) current inmates of correctional systems (including jails and prisons) and individuals who have been incarcerated for more than 72 consecutive hours during the previous 12 months; h) persons who within 12 months of donation have undergone tattooing, ear piercing, or body piercing in which shared instruments were used; and i) persons who have had close contact within 12 months preceding donation with another person having clinically active viral hepatitis (e.g., living in the same household, where sharing of kitchen and bathroom facilities occurs regularly). Canadian Standards Guidelines
    37. 37. RISK STRATIFICATION OF DONORS  Simplistic US (and Canadian) System  Based on 1994 exclusionary criteria for HIV*  Adult Behavioral Factors  Pediatric Risk Factors  Laboratory Risk Factors  OPTN-defined high risk vs. standard risk  Based on HIV risk but applied to HIV, HBV, & HCV  Linked with consent requirement  But without guidelines about what information to provide  Multiple transmissions (including HCV) from standard risk donors *MMWR. 1994; 43 (RR-8); 1-17.
    38. 38. SCREENING FOR INFECTIOUS DISEASES Exposure Viremia Serologic conversion WINDOW Serologic testing Nucleic acid testing Virus Sero Window Enhanced Serology NAT Window HBV 35-44 days n/a 20 days HCV 70 days 40-50 days 7 days HIV 17-22 days 7-16 days 7 days
    39. 39. NUCLEIC ACID TESTING  Directly detects the pathogen  Can reduce the “window” period  VERY sensitive  Contamination is a potential problem  Highly technical  Proficiency is linked with volume  May be associated with false positive testing  With resultant loss of donors  Expensive
    40. 40. RESIDUAL RISK OF BBP AFTER SEROLOGY: AVERAGE RISK DONOR USA1 Northern Alberta2 HIV 1/55,000 Unable to assess HCV 1/42,000 1/46,000 HBV 1/34,000 1/26,000 1Zou NEJM 2004; 2Zahariadis et al. AJT. 2007
    41. 41. ESTIMATED RISK OF HIV/HCV AFTER SEROLOGY IN IRDS  IDU – HIV  0.48-2.11 per 1000  IDU - HCV  14-65.2 per 1000 Humar et al. AJT. 2010
    42. 42. RESIDUAL RISK: ARE ALL “HIGH RISK DONORS” THE SAME? Estimated % of Seronegative, NAT negative Donors with Infection CDC Risk Group Average High Risk HIV IVDU 0.07 0.11 MSM 0.10 0.38 CSW 0.31 0.93 Inmates 0.01 0.02 HCV IVDU 0.59 1.28 MSM 0.01 0.04 CSW 0,28 0.65 Inmates 0.04 0.18 Schweitzer et al. Am J Transplant. 2007;7:1515-1525.
    43. 43. “TRANSPLANT” VS. “DISCARD” POLICY RESULTS IN IMPROVED OUTCOMES  More kidney transplants (990 vs. 740)  Greater number of QALYs (5.6 vs. 5.1)  Lower cost of care Schweitzer et al. Am J Transplant. 2007;7:1515-1525.
    44. 44. HIV/HCV NAT CONSENSUS RECOMMENDATIONS Deceased Donors  Insufficient evidence to recommend routine NAT for all donors (III)  NAT testing of average-risk donors not likely to identify true-positives frequently enough to offset false- positives; benefits may not outweigh potential disadvantages (II-2)  For IRDs NAT should be considered to reduce risk of transmission and potentially increase organ utilization (II-2)  For IRDs, the highest yield of NAT is for HCV due to substantial reduction in window (II-1) and significant differences in HCV prevalence (II-2) Follow up of Recipients  All recipients receiving organs from IRDs should have periodic testing for HIV, HCV, HBV post- Tx (III), regardless of whether prospective NAT done. Testing for HIV/HCV should include NAT as seroconversion may be delayed or absent  For average risk donor recipients, further study needed to determine if additional post- Tx testing warranted Humar et al. AJT. 2010
    45. 45. VARIATION IN UTILIZATION AND PRACTICES WITH ORGANS FROM HIGH RISK DONORS  Consent:  Verbal 33%  Verbal and written 52%  14% no special consent  Post-Tx F/U in recipients  Serology 60% of centers  NAT 50% Ison, MG et al. Clin Transplant. 2009
    46. 46. USE OF IRD DONORS AT U OF A 2008-MAY 2010  19 Increased Risk Donors Utilized  12 local, 7 distant  14 drug use indication  All HIV/HCV NAT negative  Recipients (48):  14 kidney 3 kidney-pancreas  11 lung 1 small bowel  11 liver 1 islet  7 heart  Follow-up HIV/HCV antibody and NAT, HBsAg, anti-HBs, anti-HBc @ 3, 6 months  No transmissions
    47. 47. CONCLUSIONS  Donor transmission of disease uncommon, but potentially devastating consequences  Marginal Donor Utilization Optimized:  Thorough understanding of risks and risk stratification  Use of NAT  Appropriate prophylaxis and follow up of recipient  Need rapid assays of high sensitivity for organs (NO TEST WILL PREVENT ALL TRANSMISSION)  Cost-effectiveness analysis and formal technology assessment needed to inform evidence based recommendations regarding implementation of new screening tests
    48. 48. CASES REPORTED TO THE OPTN 7 60 97 105 152 0 20 40 60 80 100 120 140 160 2005 2006 2007 2008 2009
    49. 49. POTENTIAL DISEASE TRANSMISSION REPORTS FOR DECEASED DONORS 3/2006-12/2009 BY DSA 0.0% 0.5% 1.0% 1.5% 2.0% 2.5% 3.0% 3.5% PercentofDonorsReported NOTE: Includes reported potential disease transmission cases March, 2006 through April 23, 2010, on deceased donors recovered March, 2006 through December, 2009. 2 DSAs with ZERO reports

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