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Holland Laboratory
Tests Used In Blood Screening (II)Test Performance; Optimal Use ofReference Panels
David A. Leiby, PhDHead, Transmissible Diseases
WHO Consultation27-28 January 2009
WHO Headquarters, Geneva
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Common Serologic Assays for T. cruzi
indirect immunofluoresence (IFA) indirect hemagglutination (IHA) ELISA RIPA Western/immuno blots rapid tests*
* not used for blood screening
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U.S./Canadian Transfusion Cases:
1987: California - Mexican donor
1989: New York City - Bolivian donorManitoba - Paraguayan donor
1993: Houston - unknown donor
1999: Miami - Chilean donor
2000: Manitoba - German/Paraguayan donor
2002: Rhode Island – Bolivian donor
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Impact of Latin American Immigration
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LA Seroprevalence: 1996-98
% D
onor
s P
osit
ive
0.000
0.002
0.004
0.006
0.008
0.010
0.012
0.014
0.016
0.018
1996 1997 1998
1/9,900
1/7,200
1/5,400
Leiby et al., Transfusion 2002;42: 549-555
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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
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T. cruzi Ab Testing
Sample sent fromNTL for RIPA
Positive, Indeterminate, Negative
Index donation
Repeat Reactive Non-Reactive
No Actions
SSO collates test resultsand sends reports
Retrieve index frozen plasma or index retention sample (IRS)
Defer donor and enroll in Chagas follow-up study (CFS)
Current ARC Testing Algorithm
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Chagas Follow-Up Studies
RIPA Positive Donor
Donor follow-up: questionnaire2 clot tubes2 EDTA tubes3 heparin tube
T. cruzi Ab TestingRIPAPCR
Hemoculture
SSO collates test results and sends reports
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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
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T. cruzi Reactive Donors (01/29/07-11/30/08)
Total Cases RIPA Pos RIPA Reported
2633 639 (25%) 2597
17.8 million donations screened0.015% RR rateRR 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
24
2673
343
25115
95
219
19
64
58
70
41
25
17
30
464
29
PR
21
30
12
59
37
45
77
6
52
80
16 9
50
5541
39
25
33
13
31
39
35
23
21
12
8
4
9
15DC
2
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Continental U.S. Map: RIPA Positives (thru 11/30/08)
Total Repeat Reactive RIPA Positive RIPA Negative/Ind RIPA Pending/NT
2989 735 2135 / 45 74
>80% from ARC/BSL
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22 Month Experience – ARC
Donation Type No. Screened No. RIPA Positive Prevalence
Total Donors 5,459,496 235 1:23,232
Allogeneic 5,046,741 225 1:22,430
Autologous 65,960 6 1:10,993
Pheresis 346,795 4 1:86,699
Total Donations 12,059,270 235 1:51,316
Allogeneic 10,666,437 225 1:47,406
Autologous 99,863 6 1:16,644
Pheresis 1,292,970 4 1:323,243
2,482,904 donors contributed 2,317,801 person years(only intervals between donations that were tested were counted)
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+ - %
PCR
(EDTA)22 106 17
Hemoculture
(Heparin)9 105 8
PCR/Hemoculture Results for RIPA Pos Donors
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0
2
4
6
8
10
12
14
16
18
Do
no
r S
tatu
s
8/1
/2006
9/1
/2006
10/1
/2006
11/1
/2006
12/1
/2006
1/1
/2007
2/1
/2007
3/1
/2007
4/1
/2007
5/1
/2007
6/1
/2007
7/1
/2007
8/1
/2007
9/1
/2007
10/1
/2007
11/1
/2007
12/1
/2007
1/1
/2008
2/1
/2008
3/1
/2008
4/1
/2008
5/1
/2008
6/1
/2008
7/1
/2008
8/1
/2008
9/1
/2008
10/1
/2008
11/1
/2008
First Time (n=250, 63.45%) Repeat (n=144, 36.55%)
RIPA Confirmed Positive Donors (n=394)
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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 ECGirregularities and 1 with upper GI symptoms
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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
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0
5
10
15
20
25
30
n1 n6n11 n16 n21 v4 v9 v1
4v1
9v2
4v2
9v3
4v3
9v4
4v4
9v5
4v5
9v6
4v6
9v7
4v7
9v8
4v8
9v9
4
Testing Week (IND (n) Start 08/28/06, IVD (v) Start 01/29/07)
Ca
se
s
RIPA pos (N = 24 ) RIPA neg/pend (N = 625 )
RIPA Positive Donors
Prior Non-reactive/Untested Donations
16 with prior S/CO values: 0.12-0.98 5 with multiple prior negative donations8 QNS or NT donations Unlikely to be true “incident” infections!
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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
Test Performance
Sensitivity of Universal Testing (Ortho ELISA PI)
860/861 = 99.88% (95% CI = 99.35% to 100.00%)
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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
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Importance of Global Reference Standards
test validation quality control comparisons with other tests
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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
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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
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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