blood systems trypanosoma cruzi and chagas disease studies
TRANSCRIPT
![Page 1: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/1.jpg)
1
Blood Systems Trypanosoma cruzi and Chagas Disease Studies and Potential Strategies for Targeted Testing of Donors
Blood Products Advisory CommitteeCBER FDAApril 26, 2007
Michael Busch
Brian Custer
![Page 2: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/2.jpg)
2
Outline
• BSRI/BSI T. cruzi & Chagas’ studies• Test performance evaluation study• Clinical evaluation studies• Analysis of donor testing strategies
– DHQ questions– Risk factors questions– Capacity for targeted testing– Formal decision analysis
• Experience to date (Feb. 26 – April 7)
![Page 3: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/3.jpg)
3
REDS II International – Brazil Chagas Study• Aim A. Define the natural history of Chagas disease in T. cruzi
seropositive blood donors, according to donor demographic parameters, time since donation and exposure, and presence of persistent parasitemia.
Hypothesis: T. cruzi seropositive donors will have an overall 10% to 20% increased rate of cardiac and gastrointestinal symptoms and ECG abnormalities relative to control donors, and the frequency of symptoms and signs will correlate with duration of infection and PCR positivity.
• Aim B. Characterize persistence of T. cruzi antibody reactivity over
time, relative to detection of parasitemia by PCR. Hypothesis: T. cruzi seropositive donors who are negative for parasitemia by PCR will demonstrate lower level antibody reactivity than PCR positive donors, and the reactivity levels will decline over time in the PCR-negative group.
• Aim C. Determine rate of seronegative T. cruzi infection by performing
coded PCR on seronegative populations from endemic and non-endemic regions and seropositve controls.
Hypothesis: In contrast to T. cruzi seropositive donors in which T. cruzi PCR will be positive in greater than 70% of subjects, parasite DNA will not be detected in ELISA negative donors from either endemic or non-endemic regions.
![Page 4: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/4.jpg)
4
• Data collected at each study visit– Patients’ medical history (baseline only)– Physical exam– Clinical tests (serology, ECG, chest x-ray, echo)
– T. cruzi infection diagnosis based on serology (complement fixation, indirect hemagglutination, immunofluorescence, and EIA)
![Page 5: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/5.jpg)
5
![Page 6: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/6.jpg)
6
![Page 7: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/7.jpg)
7
Evidence of Sero-reversion
![Page 8: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/8.jpg)
8
0
1
2
3
4
5
6
7
8
9
10
0 100 200 300 400 500 600 700 800
Sig
nal
/Cu
toff
Cutoff
Confirmed Negative by RIPA
Sensitivity = 99.7% (753/755)1
1 Specimens from 12 Latin American countries
Ortho® T. cruzi ELISA Test SystemPre-clinical Sensitivity
![Page 9: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/9.jpg)
9
10,192 sequential donations from blood donors residing in the El Paso, Texas area
0
1
2
3
4
5
6
7
0 2000 4000 6000 8000 10000 12000
Number of Samples
S/C
O
Tobler et al Transfusion, 2007
Ortho® T. cruzi ELISA Test SystemPre-clinical Specificity
RIPA PositiveRIPA Negative
Specificity - 100% Seroprevalence - 3/10,192
![Page 10: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/10.jpg)
10
![Page 11: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/11.jpg)
11
REDS II International – Brazil Chagas Study
• Case control study design in Sao Paulo and Montes Claros
Cases: 500 blood donors who tested T. cruzi AB positive 6 – 10 years ago (using tests other than the US approved Ortho test)
Controls: 500 blood donors who tested T. cruzi Ab negative from the same blood center 6 – 10 years ago, matched on gender, age (+/- 5 years), and repeat versus first time donor status
![Page 12: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/12.jpg)
12
• Death index search• New blood testing to establish current infection
status • Medical history, risk factor and symptoms
assessment• Clinical assessment
– Physical exam– ECG– Echocardiogram (potentially contrast)
• NHLBI Division of Cardiology– Centralized reading of ECG and Echo
REDS II International – Brazil Chagas Study
![Page 13: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/13.jpg)
13
BSI - Follow-up Studies
Repeat reactive index donation results lead to:
1. Donor symptoms and risk factors interview
2. Follow-up sample collection and testingT. cruzi ELISA, RIPA, and PCR testing
Other infectious agents:
Leishmania, Plasmodium, Paracoccidioides?
3. Clinical evaluation study
![Page 14: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/14.jpg)
14
BSI - Test Performance Evaluation
• Aims– 1a. Evaluate the performance characteristics of the T. cruzi
ELISA based on index donation supplemental assays (RIPA, and Leishmania IFA for RIPA-negative and indeterminate cases), and assess risk factors and symptoms among all ELISA repeat reactive donors compared to non-reactive donors, as well as among repeat reactive donors relative to their RIPA/IFA confirmation status
– 1.b. Confirm the T. cruzi infection status in index repeat reactive donors by obtaining a follow-up blood sample that will be tested by ELISA, RIPA, quantitative PCR and potentially a new recombinant T. cruzi antigen based antibody confirmation assay (LIPA)
![Page 15: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/15.jpg)
15
BSI - Clinical Evaluation
• Aim– Begin to define the clinical stage and natural history of Chagas
disease in T. cruzi seropositive U.S. blood donors according to: • Donor demographics• Estimated time since (last) exposure • Presence of persistent parasitemia
• Establish a group of confirmed seropositve donors, based on RIPA and/or PCR positive results, that represent the basis for a long-term cohort and outcomes study
![Page 16: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/16.jpg)
16
BSI - Clinical Evaluation
• T. cruzi RIPA positive donors recruited• MD visit or referral to local clinic for:
– Physical examination– ECG– Echocardiogram
• Additional testing of aliquots from samples collected in follow-up study– Other markers of T. cruzi infection or cardiac damage
![Page 17: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/17.jpg)
17
Decision Analysis Study
• Aim– Develop a decision analysis model based on the
combination of donor questioning and donation laboratory screening strategies to determine if any targeted testing strategy can meet safety objectives and assess which strategies are:
• Most effective• Most cost-effective
![Page 18: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/18.jpg)
18
Donor History QuestionnaireAll United Blood Services prospective donors asked to
provide:1. Race and ethnicity – Starting 2 years ago2. Country of birth – Added just before T. cruzi testing3. Three additional questions – Added Feb. 26, 2007
• 1R – Have you spent time that adds up to 3 months or more in Mexico, Central America or South America?
• 1S – Has your mother spent time that adds up to 3 months or more in Mexico, Central America or South America?
• 1T – Since your last donation have you traveled to Mexico, Central America or South America?
![Page 19: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/19.jpg)
19
Donor History Questionnaire
• For each of the three additional questions four responses options are included:
N – NoM – MexicoC – Central America and/or South AmericaB – Both Mexico and Central and/or South America
• Only results for 89,118 eligible allogeneic donors from February 26 – April 7, 2007 are presented in the following slides
![Page 20: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/20.jpg)
20
Race/Ethnicity
Group Repeat
Number (%)
First Time
Number (%)
African American/Black 1,772 (2.5) 1,098 (5.8)
Hispanic/Latino 8,710 (12.4) 4,199 (22.1)
Native American 671 (1.0) 300 (1.6)
Asian/Pacific Islander 768 (1.1) 338 (1.8)
Caucasian/White 55,200 (78.8) 12,187 (64.0)
Other/Missing 2,968 (4.2) 907 (4.8)
![Page 21: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/21.jpg)
21
Country of Birth
Country Repeat
Number (%)
First Time
Number (%)
USA 46,469 (66.3) 13,512 (71.1)
Mexico 748 (1.1) 599 (3.2)
Central or South America 150 (0.2) 83 (0.4)
All other countries 1,234 (1.8) 354 (1.9)
Refused 9 (0.01) 4 (0.02)
Missing/Unknown 21,479 (30.6) 4,463 (23.5)
![Page 22: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/22.jpg)
22
Responses to 1R
Donor: 3 months or more in Mexico, Central or South America
Repeat
Number (%)
First Time
Number (%)
Mexico 1,196 (1.4) 860 (3.4)
Central/South America 534 (0.6) 234 (0.9)
Both Mexico and Central/South America 118 (0.1) 40 (0.2)
No 85,277 (97.8) 24,425 (95.4)
No Response 51 (0.06) 30 (0.1)
Unknown/Unsure 38 (0.04) 6 (0.06)
![Page 23: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/23.jpg)
23
Responses to 1S
Donor’s Mother: 3 months or more in Mexico, Central or South America
Repeat
Number (%)
First Time
Number (%)
Mexico 1,221 (1.8) 935 (5.0)
Central/South America 350 (0.5) 153 (0.9)
Both Mexico and Central/South America 34 (0.05) 17 (0.09)
No 67,710 (97.5) 17,051 (93.7)
No Response 27 (0.04) 31 (0.09)
Unknown/Unsure 128 (0.2) 75 (0.3)
![Page 24: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/24.jpg)
24
Responses to 1T
Donor: Travel to Mexico, Central or South America since last donation
Repeat
Number (%)
Mexico 3,425 (5.0)
Central/South America 248 (0.4)
Both Mexico and Central/South America 44 (0.06)
No 65,155 (94.5)
No Response 30 (0.04)
Unknown/Unsure 28 (0.04)
![Page 25: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/25.jpg)
25
Donor compliance with DHQ questions
• 1,509 out of 89,118 (1.7%) allogeneic donors left these voluntary questions blank
– 350 First time donors (1.8%)– 1,159 Repeat donors (1.6%)
![Page 26: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/26.jpg)
26
Information Systems and Laboratory Capacity for Targeted Testing
• CMV testing (separate inventories)• WNV testing (type of testing)
• HLA considerations and expected special testing– Ever transfused?– Ever pregnant?
Used to flag donations that should not be used for plasma components
![Page 27: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/27.jpg)
27
First Time Only Targeted Testing in Europe (as of 2003)
Country Anti-HTLV Syphilis Anti-HBc
Belgium Y
Denmark Y
Finland Y
Luxembourg Y
Norway Y Y Y
Sweden Y Y Y
![Page 28: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/28.jpg)
28
Decision Analysis
Proposed strategies to model:• No screening – the baseline comparator strategy
– By including a no screening strategy we will be able to highlight the number of repeat reactive donors who are identified and the safety gain achieved using T. cruzi ELISA testing
• Screening of first time donors who report travel to or lived in Latin America for 3 or more months (excludes screening of repeat donors)
• Screening of all first time donors and only repeat donors with travel to Latin America since their last donation
• After a defined period of screening of every donation (for example 1 year) one-time screening of each donor who presents to donate following the implementation of T. cruzi screening AND screening of donors who report travel to Latin America since their last donation
• Ongoing screening of each donation from each donor • Other potential strategies or modifications to the above strategies?
![Page 29: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/29.jpg)
29
Decision AnalysisNext steps:• Sufficient data is not available at this time
– Continue to collect DHQ data and donor testing results
• Intend to capture and assess the importance of uncertainty in all aspects of T. cruzi testing
• Disease progression model development:
![Page 30: Blood Systems Trypanosoma cruzi and Chagas Disease Studies](https://reader035.vdocuments.net/reader035/viewer/2022062514/55932ea21a28ab72548b4594/html5/thumbnails/30.jpg)
30