Blood Systems Trypanosoma cruzi and Chagas Disease Studies and Potential Strategies for Targeted Testing of Donors Blood Products Advisory Committee CBER FDA April 26, 2007 Michael Busch Brian Custer
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.
Cutoff Confirmed Negative by RIPA Sensitivity = 99.7% (753/755) 1 1 Specimens from 12 Latin American countries Ortho ® T. cruzi ELISA Test System Pre-clinical Sensitivity
Ortho ® T. cruzi ELISA Test System Pre-clinical Specificity Tobler et al Transfusion, 2007 Specificity - 100% Seroprevalence - 3/10,192 10,192 sequential donations from blood donors residing in the El Paso, Texas area RIPA Positive RIPA Negative
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)
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:
For each of the three additional questions four responses options are included:
N – No
M – Mexico
C – Central America and/or South America
B – 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
Race/Ethnicity 907 (4.8) 2,968 (4.2) Other/Missing 12,187 (64.0) 55,200 (78.8) Caucasian/White 338 (1.8) 768 (1.1) Asian/Pacific Islander 300 (1.6) 671 (1.0) Native American 4,199 (22.1) 8,710 (12.4) Hispanic/Latino 1,098 (5.8) 1,772 (2.5) African American/Black First Time Number (%) Repeat Number (%) Group
Country of Birth 4 (0.02) 9 (0.01) Refused 4,463 (23.5) 21,479 (30.6) Missing/Unknown 354 (1.9) 1,234 (1.8) All other countries 83 (0.4) 150 (0.2) Central or South America 599 (3.2) 748 (1.1) Mexico 13,512 (71.1) 46,469 (66.3) USA First Time Number (%) Repeat Number (%) Country
Responses to 1R 6 (0.06) 38 (0.04) Unknown/Unsure 30 (0.1) 51 (0.06) No Response 24,425 (95.4) 85,277 (97.8) No 40 (0.2) 118 (0.1) Both Mexico and Central/South America 234 (0.9) 534 (0.6) Central/South America 860 (3.4) 1,196 (1.4) Mexico First Time Number (%) Repeat Number (%) Donor: 3 months or more in Mexico, Central or South America
Responses to 1S 75 (0.3) 128 (0.2) Unknown/Unsure 31 (0.09) 27 (0.04) No Response 17,051 (93.7) 67,710 (97.5) No 17 (0.09) 34 (0.05) Both Mexico and Central/South America 153 (0.9) 350 (0.5) Central/South America 935 (5.0) 1,221 (1.8) Mexico First Time Number (%) Repeat Number (%) Donor’s Mother: 3 months or more in Mexico, Central or South America
Responses to 1T 28 (0.04) Unknown/Unsure 30 (0.04) No Response 65,155 (94.5) No 44 (0.06) Both Mexico and Central/South America 248 (0.4) Central/South America 3,425 (5.0) Mexico Repeat Number (%) Donor: Travel to Mexico, Central or South America since last donation
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?