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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

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

common serologic assays for t cruzi
Common Serologic Assays for T. cruzi
  • indirect immunofluoresence (IFA)
  • indirect hemagglutination (IHA)
  • ELISA
  • RIPA
  • Western/immuno blots
  • rapid tests*

* not used for blood screening

slide3

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

slide5

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

slide6

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
slide7

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

slide8

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

slide9

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
slide10

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

slide12

22 Month Experience – ARC

2,482,904 donors contributed 2,317,801 person years

(only intervals between donations that were tested were counted)

slide15

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

autochthonous transmission summary
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
slide17

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!

slide18

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%)

proposed chagas reference standard
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
importance of global reference standards
Importance of Global Reference Standards
  • test validation
  • quality control
  • comparisons with other tests
interested parties
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
slide22

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
slide23

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