1. Optimal Donor & Recipient Screening Michael G. Ison, MD MS Divisions of Infectious Diseases & Organ Transplantation Transplant Infectious Diseases Service Northwestern University Feinberg School of Medicine Prince of Wales Hospital, Sydney – March 8, 2010 Transplantation Workshop

2. Disclosures Research Support° –Roche (oseltamivir)*– ViraCor* –Biocryst (peramivir)*– Cellex* –ADMAS (TCAD)*– Chimerix –ADMA (RSV Ig) Consultation –Abbott Molecular*– ViraCor* –NexBio (Fludase)*– Cellex* –Biota DSMB –Chimerix As of 2/10/10; °Paid to Northwestern University; *Related to topic.

3. Acknowledgment DTAC data was supported wholly or in part by Health Resources and Services Administration contract 234-2005- 370011C. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

4. Optimal Donor & Recipient Screening Goals of Screening –What are we trying to prevent? –How do we assess for risk? –How will the results be used? Methods of Screen –Unique features of donor screening –Testing logistics & methods –Potential gaps Optimal Screening Advice –Living Donors– Deceased Donors –Recipients

5. Current DDD Transmission Data 152 cases reported in 2009 Ison et al. Am J Transplant. 2009; 9: 1929-1935.

6. Reports to DTAC: 2006-2009* *Other (Each are single cases with no transmission): Basaloid, Brain – Spindle Cell, Cholangiocarcinoma, Dermatofibrosarcoma Protuberans, GIST, Kaposi’s Scarcoma, Lung – Bronchoalverolar, Lung – Small Cell, Lymphoma, Myeloid Sarcoma, Urothelial Cell *1/1/06 – 10/31/09

7. Reports to DTAC: 2006-2009* ∞ All but 3 cases non-reproducible NAT results: Donor not high risk, Sero -/NAT+ with 3 transmissions Donor high risk, Sero -/NAT + with 4 transmissions (HIV/HCV) and 1 death Donor HCV + vessel with 1 transmission † All but 2 cases non-reproducible NAT results: 1 Case with 4 transmissions of HCV/HIV and 1 death 1 patient with HIV infection post-transplantation *1/1/06 – 10/31/09

8. Reports to DTAC: 2006-2009 *1/1/06 – 10/31/09

9. Reports to DTAC: 2006-2009 § Expected Transmissions: 10 Toxoplasmosis, 7, EBV, 4 CMV. Data 1/1/06 – 10/31/09.

10. What are the Goals of Screening? Defining what we want to prevent –Epidemiology in Donors What incidence would be needed to require testing? Must be data in ORGAN donors –Is the Infection Transmissible? Organ specific risk? –Treatable/untreatable? –Available monitoring protocols? –Available testing platforms? Serology vs. NAT Incidence of false positives vs. false negatives Prospective or Retrospective? What level of risk is “acceptable?”

11. How will screening results be used? Two Types of Screening Assays –Rule in/out donors ( HIV ) False Positive = lose a donor –Risk stratify donor ( CMV, EBV, HBV, HCV ) –Transplant community needs to be educated on how to use these results Examples: –HBV utilization is highly variable even for HBV seroprotected donors –If Chagas serology used to r/o instead of risk stratify, graft loss in too high to use currently –HTLV utilization in the US Kaul et al. Am J Transplant. 2010. 10: 207-213.

12. Unique Donor Issues in Organs Restricted timeline Different Screening Paradigm Donor history –Second hand story –No standardization Serology-based Screening Variable NAT capacity and practice No standard policy with regard to hemodilution Incomplete Data Collection No expectation for “Zero Risk”

13. Significant Organ Shortage *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 July 31, 2009. Organ Transplants27,963 Waitlist Candidates100,775 Deaths on Waitlist9,474 2008 DATA

14. Screening Methods Medical & Social History –Manual review of patient’s chart –Interview of next of kin Physical Examination –Surface examination –Internal surgical examination Laboratory testing –Serology –Nucleic acid testing

15. ELISA: Indirect & Sandwich http://newenglandbiolabs.de/en/images/stories/cst_elisa_gross.jpg http://microvet.arizona.edu/Courses/MIC419/ToolBox/elisa3.jpg

16. Serology: Limitations Can have false negative results –Window Period –Dilution of antibodies Blood products IV fluid Not everyone develops and maintains antibody response of same magnitude

17. Screening for Infectious Diseases Screening limitations Exposure Viremia Serologic conversion WINDOW Serologic testing Nucleic acid testing VirusSero WindowNAT Window HBV60 days20 days HCV70 days7 days HIV23 days7 days AST IDCOP Guidelines. Am J Transplant. 2004; Suppl 4: 10-20.

18. Nucleic Acid Testing Directly detects the pathogen VERY sensitive –Contamination is an major problem –Highly technical –Proficiency is linked with volume Can reduce the “window” period May be associated with false positive testing –With resultant loss of donors

19. Risk Stratification of Donors Simplistic US System –Based on 1994 exclusionary criteria for HIV –OPTN-defined high risk vs. standard risk –Multiple transmissions (including HCV) from standard risk donors Comprehensive European System –Based on the Italian Classification Scheme Unacceptable Risk (Absolute Contraindications) Increased but Acceptable Risk Calculated Risk (i.e. HCV+, meningitis) Not Assessable Risk Standard Risk –Risk system for malignancy available Guide to Safety and Quality Assurance for the Transplantation of Organs, Tissues, and Cells 3 rd Ed. Council of Europe Publishing, Strasbourg, France. 2009.

20. Potential Gaps in Screening Medical & Social History –Must be standardized with internal validators –Assurance of access to all medical records Established standard for hemodilution Funding for donor screening –Support development of new assays and platforms –Assessment of new agents and their associated assays in the donor pool –Mechanism to disseminate data Effective biovigilence for organ recipients

21. Optimal Screening: Living Donor Essential Minimum –HIV serology and NAT –HBV sAg, sAb, cAb (?NAT) –HCV serology and NAT –TB (only for lungs?) Informs recipient management –CMV serology– RPR –EBV serology Depending on history & endemicity –Strongyloides, endemic mycoses, pathogens present in surrounding areas Fischer SA & Avery RK. Am J Transplant. 2009; 9 (s4); S7-18.

22. Optimal Screening: Deceased Donor Essential Minimum –HIV serology (NAT – all vs. high risk) –HBV sAg, sAb, cAb –HCV serology and NAT (for all) Informs recipient management –CMV serology– RPR –EBV serology –Toxoplasmosis for all heart and muscle transplants Depending on history & endemicity –Strongyloides, Chagas, endemic mycoses, pathogens present in surrounding areas Fischer SA & Avery RK. Am J Transplant. 2009; 9 (s4); S7-18.

23. Optimal Screening: Recipient Essential Minimum –HIV serology –HBV sAg, sAb, cAb –HCV serology and NAT –TB screening Informs recipient management –CMV serology– VZV & HSV serology –EBV serology– RPR –Toxoplasmosis for all heart and muscle transplants Depending on history & endemicity –Strongyloides, Chagas, endemic mycoses, pathogens present in surrounding areas Fischer SA & Avery RK. Am J Transplant. 2009; 9 (s4); S7-18.

24. Screening of Recipients Post-Tx Assessment of donor risk requires careful post-transplant follow-up –Biovigilence system to detect transmissions –Reporting systems to accept and investigate potential transmission reports Coordinate information sharing Share findings to inform best practices and policy Similar to OPTN Policy 4.6 and OPTN PSS/DTAC –Diligent clinicians to suspect and report cases –Routine assessment of key donors HIV, HBV, and HCV (potentially others) All vs. “at risk” Requires robust pre-transplant data

25. Post-Transplant Testing: US Experience °6/30/04 – 8/31/06 or 2/28/06 OrganHigh Risk° Pre-Tx HIV Pre-Tx HCV Post-Tx HIV Post-Tx HCV H-L 5 (7.9%)4 (80%) 0 (0%)1 (20%) Heart 333 (9.6%)232 (69.7%)278 (83.5%)26 (8.7%)26 (8.8%) Intestine 9 (2.4%)5 (55.6%)5 (55.5%)0 (0%) Kidney 1,865 (8.5%)1,107 (59.4%)1,523 (81.7%)40 (2.2%)44 (2.7%) K-P 203 (10.3%)109 (53.7%)5 (2.5%)7 (3.6%)9 (4.7%) Liver 1,210 (9%)762 (63%)501 (41.4%)50 (4.5%)77 (11.8%) Lung 214 (9.7%)175 (81.8%)2 (0.9%)9 (5.1%)15 (8.5%) Pancreas 82 (7%)48 (58.5%)1 (1.2%)2 (2.5%)3 (3.8%) Total 3,921 (8.8%)2,422 (62.3%)3,191 (81.4%)134 (3.7%)178 (5.9%)

26. What is Australia’s Plan? How are donor derived infections recognized? How are DDI’s reported? –Is this data collected? –How are the reports investigated? –How are findings handled? How is pertinent data shared? –When a new issue arises during implantation? –Post-transplant cultures or testing? Are donors recognized as donors? –Pertinent to how “late” results (TB, fungal) are reported to TC/OPO

27. What is Australia’s Plan? How do you manage a potential transmission? –Who will be the key contact For the hospital/transplant center? For the OPO as information is shared? For the media when questions arise? –How do you manage the media As a unified group of all affected centers and OPOs? Do you have a patient safety communication policy?

28. Questions? Michael G. Ison, MD MS 312-695-4186 mgison@northwestern.edu I am an organ donor! Are you?