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Tests Used In Blood Screening (II) Test Performance; Optimal Use of Reference Panels

Tests Used In Blood Screening (II) Test Performance; Optimal Use of Reference Panels. David A. Leiby, PhD Head, Transmissible Diseases. WHO Consultation 27-28 January 2009 WHO Headquarters, Geneva. Common Serologic Assays for T. cruzi. indirect immunofluoresence (IFA)

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Tests Used In Blood Screening (II) Test Performance; Optimal Use of Reference Panels

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  1. Tests Used In Blood Screening (II)Test Performance; Optimal Use ofReference Panels David A. Leiby, PhD Head, Transmissible Diseases WHO Consultation 27-28 January 2009 WHO Headquarters, Geneva

  2. Common Serologic Assays for T. cruzi • indirect immunofluoresence (IFA) • indirect hemagglutination (IHA) • ELISA • RIPA • Western/immuno blots • rapid tests* * not used for blood screening

  3. U.S./Canadian Transfusion Cases: 1987: California - Mexican donor 1989: New York City - Bolivian donor Manitoba - Paraguayan donor 1993: Houston - unknown donor 1999:Miami - Chilean donor 2000: Manitoba - German/Paraguayan donor 2002: Rhode Island – Bolivian donor

  4. Impact of Latin American Immigration

  5. 1/5,400 0.018 0.016 1/7,200 0.014 0.012 1/9,900 0.010 % Donors Positive 0.008 0.006 0.004 0.002 0.000 1996 1998 1997 LA Seroprevalence: 1996-98 Leiby et al., Transfusion 2002;42: 549-555

  6. Models for Testing/Implementation • universal blood screening • screening + confirmatory assays • parallel testing (2-3 assays) • risk-factor models • birth in endemic country • lived in rural area, thatched roof, vector exposure, etc. • immunosuppressed patients • must identify recipients at greatest risk • test each donor only once/twice • logistically complex • needs cost/benefit analysis • analysis of sensitivity

  7. Current ARC Testing Algorithm Index donation T. cruzi Ab Testing Retrieve index frozen plasma or index retention sample (IRS) Defer donor and enroll in Chagas follow-up study (CFS) No Actions Sample sent from NTL for RIPA Positive, Indeterminate, Negative Repeat Reactive Non-Reactive SSO collates test results and sends reports

  8. Chagas Follow-Up Studies RIPA Positive Donor Donor follow-up: questionnaire 2 clot tubes 2 EDTA tubes 3 heparin tube T. cruzi Ab Testing RIPA PCR Hemoculture SSO collates test results and sends reports

  9. Donor Management Practices in U.S. • RRs notified/deferred • supplemental testing encouraged • no FDA licensed tests exists • RIPA most sensitive test available • donor counseling including donor follow-up studies encouraged • no donor reentry • refer RIPA positive donors to physicians • recipient tracing for RIPA positive donors

  10. T. cruzi Reactive Donors (01/29/07-11/30/08) 25 21 16 9 9 19 31 52 55 219 41 41 12 6 80 4 58 77 13 DC 115 64 15 25 2 39 37 17 39 70 8 50 464 25 21 95 30 23 24 PR 45 33 12 73 29 26 30 35 59 343 17.8 million donations screened 0.015% RR rate RR from 46 states (-DE, RI) RIPA pos (25%) from 38 states (+PR, DC) 60% from FL and CA (1:3700-1:7500) Overall: 1:27,000

  11. Continental U.S. Map: RIPA Positives (thru 11/30/08) >80% from ARC/BSL

  12. 22 Month Experience – ARC 2,482,904 donors contributed 2,317,801 person years (only intervals between donations that were tested were counted)

  13. PCR/Hemoculture Results for RIPA Pos Donors

  14. RIPA Confirmed Positive Donors (n=394)

  15. Donor Demographics to 11/30/08 RIPA Pos (N=394) • FT donors 250 (63%) • RPT donors 144 (37%) • Male 212 (54%) • Female 182 (46%) • Country of birth (N=149) • Mexico 44 • US 37 • El Salvador 24 • Bolivia 15 • Honduras 6 • Colombia 5 • Argentina, Guatemala 4 • Brazil 3 • Ecuador, Nicaragua 2 • Paraguay, Chile, Somalia 1 RIPA Neg/Ind (N=1490) • FT donors 414 (28%) • RPT donors 1076 (72%) • Male 898 (60%) • Female 592 (40%) • Country of birth (N=420) • US 400 • India 3 • China, Germany 2 • Thailand, Taiwan, Cuba, Hungary, New Zealand, Barbados, Ecuador, Panama, Ukraine, Venezuela, Canada 1 • Colombia 2* *21-37 years in Colombia, 1/2 with ECG irregularities and 1 with upper GI symptoms

  16. Autochthonous Transmission Summary • 45 potential autochthonous cases identified from screening US blood donors • 37 from the ARC • 7 appear to be likely cases • 5 parasitemic • 2 donors thoroughly investigated by CDC (MS) • another 7 have other risk factors • some may be false positive • continued investigation needed to determine frequency and risk factor (e.g., hunting, camping, time spent outdoors, etc.) • US-derived T. cruzi (USTC) study participants CDC, ARC and UBS • additional questionnaire re risk; CDC and ARC IRB approved

  17. RIPA Positive Donors Prior Non-reactive/Untested Donations 16 with prior S/CO values: 0.12-0.98 5 with multiple prior negative donations 8 QNS or NT donations Unlikely to be true “incident” infections!

  18. Test Performance IND/clinical trial (28/08/06 -28/01/07) • PPV = 32 RIPA pos/63 RR = 51%; pos in 2 states • RR rate = 63/148,969 = 0.042% • Prevalence = 32/148,969 = 1:4655 Nationwide screening (29/01/07-30/11/08) • PPV = 639 RIPA pos/2597 RR RIPA tested = 25%; pos in 38 states (+ PR, DC) • 60% from FL and CA (1:3700-1:7500) • RR rate = 2597 RRs/>17.8 x 106 donations = 0.015% • Projected prevalence = 1:27,000 Sensitivity of Universal Testing (Ortho ELISA PI) 860/861 = 99.88% (95% CI = 99.35% to 100.00%)

  19. Proposed Chagas Reference Standard • requirements • must include T. cruzi I and II • broad geographic reactivity • pooled vs. neat? • sensitivity in diluted samples • targeted antibody titers • stability over time • specified characteristics • 1 medium reactive from south • 1 medium reactive from north • 1 clear negative

  20. Importance of Global Reference Standards • test validation • quality control • comparisons with other tests

  21. Interested Parties • test manufacturers • evaluate candidate antigens • measure sensitivity • regulatory agencies • determine analytic sensitivity • reproducibility/proficiency • compare assays • blood establishments • assay evaluation • quality assessment • research institutions • diagnostic centers • facilitate comparison with other laboratories • internal controls

  22. Summary & Conclusions • significant number of U.S. blood donors infected with T. cruzi • 639 confirmed positives • nationwide distribution • 1:27,000 donors infected • current test performance • 99.88% sensitivity • 25% PPV • need for a global reference standard • test validation • quality control • assay comparison • reference standard characteristics • broad geographic reactivity is critical

  23. Acknowledgements American Red Cross • Susan Stramer, SSO • Greg Foster, SSO • David Krysztof SSO • Rebecca Townsend SSO • Megan Nguyen, HL • Melanie Proctor, HL • Ross Herron, West Div • Pamela Kahm, West Div • Norma Espinoza, West Div • Kay Crull, West Div Blood Systems Laboratories • Sally Caglioti • Frank Radar • Larry Morgan

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