Retrovirus Epidemiology Donor Study-II (REDS II) Natural History of Disease and Laboratory Findings in Trypanosoma Cruzi Antibody-Positive Brazilian Blood Donors (Chagas)
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April 25, 2017
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There were three specific clinical aims for the REDS-II Chagas study in Brazil: characterize the natural history of clinical Chagas disease in T cruzi seropositive blood donors; determine the persistence of T cruzi antibody reactivity over time; and determine the rate of “serosilent” T cruzi infection in seronegative populations from endemic regions.
Since 1989, the NHLBI has sponsored epidemiologic, laboratory, and survey research in the field of blood supply safety and transfusion research through the Retrovirus Epidemiology Donor Study (REDS) program. In 2006, the program initiated international components in Brazil and China to extend the scope of blood safety research as part of the REDS-II program. In Brazil, Chagas disease was one of the public health concerns addressed by the REDS-II program. Chagas disease is caused by the parasite Trypanosoma cruzi. T cruzi transmits via hematophagous triatomine insects (“kissing bugs”), but can transmit vertically during pregnancy, peripartum, blood transfusion, or organ transplantation.
In the endemic regions of Brazil, the majority of patients with acute Chagas disease were asymptomatic and most symptomatic patients presented with only minor clinical manifestations. The natural history of Chagas was poorly understood and therefore, counseling of asymptomatic seropositive patients was difficult. Furthering this difficulty was a lack of clinical predictors for severe clinical presentation of Chagas disease that could guide early treatment. As a result, cardiologists in Brazil refrained from treating asymptomatic patients due to the combination of uncertain prognosis and the toxicity of antitrypanosomal drugs.
This study presents the results from a large, retrospective cohort study with an average follow up of eleven years. The purpose of this study was to characterize the natural history of clinical Chagas disease, measure disease penetrance, and determine prognostic factors of Chagas cardiomyopathy among asymptomatic Trypanosoma cruzi-infected persons identified 10 years ago.
There were three groups enrolled in the study: seropositive blood donors, seronegative blood donors, and validation case studies.
Seropositive and seronegative donors were obtained from two blood donations centers in Brazil: Sao Paulo and Montes Claros. Seropositive blood donors were screened between 1998 and 2002 and confirmed positive for the T cruzi antibody at the time of donation. In Sao Paulo, screenings for the T cruzi antibody consisted of three (3) serological methods: ELISA, hemaglutination, and immunofluorescence. Only donors reactive to all three (3) assays at the time of donation were considered eligible for the study. In Montes Claros, ELISA and hemaglutination assays were utilized to screen donors. Only donors reactive to both assays at the time of donation were considered eligible for the study. Seronegative donors were matched to each seropositive donor by year of index donation, site, age, and sex.
There were 511 seropositive and 504 seronegative blood donors enrolled in the study. Of these, a total of 499 seropositive and 488 seronegative blood donors had complete data and were submitted for the expert panel review process. Among the 499 seropositive donors with complete data, 315 were referred to the expert panel and 120 were classified as Chagas cardiomyopathy. Among the 488 seronegative donors with complete data, 232 were referred to the expert panel and 24 were classified as having Chagas cardiomyopathy.
In addition, 101 previously diagnosed cases of Chagas cardiomyopathy from the Heart Institute of the University of Sao Paulo Medical School were included in the study to assess the sensitivity of cardiac outcomes measurements. The inclusion criteria for validation cases were: physician diagnosis of Chagas cardiomyopathy, no previous treatment of benznidazole, and no comorbidity (diabetes, hypertension, or renal failure). Of these cases, 101 were referred to the expert panel and 99 were classified as having Chagas cardiomyopathy by the expert panel.
Recruited individuals were administered a risk factor and healthy history questionnaire by a nurse at their respective site. Furthermore, a physical evaluation was performed by a nonblinded physician. Subjects were assigned to a New York Heart Association functional class on the basis of their responses to the questionnaire.
Subjects underwent Electrocardiogram (ECG) and Echocardiogram procedures. Resting 12-lead ECGs were recorded with the same model at both sites, interpreted blindly by researchers, analyzed by trained cardiologists electronically to ensure quality control, and classified by Minnesota code criteria. Echocardiograms were conducted to obtain and determine the following measurements: left ventricle (LV) M-mode; LV ejection fraction; LV mass corrected by body surface area; left atrium, right atrium, and LV 2-dimensional image trace; LV regional wall motion; LV ejection fraction; diastolic function; presence of pericardial effusion; mitral, tricuspid, aortic, and pulmonary regurgitations; and tricuspid regurgitation peak velocity. Assessing researchers were blinded to serostatus.
Data were centralized by the coordinating center, and a predefined set of abnormalities in the echocardiogram or ECG measurements triggered the expert panel chart review. The expert panel was composed of three (3) Brazilian cardiologists blinded to subject’s serostatus with expertise in managements of Chagas disease. Each panelist was asked to classify a subject as having: Chagas cardiomyopathy, probable Chagas cardiomyopathy, possible Chagas cardiomyopathy, or no Chagas cardiomyopathy- based on the chart summary and findings from the coordinating center.
Responses from each panelist were sent separately to the coordinating center. If the panelists did not agree on patient classification, then a phone call was held until a consensus on classification was reached.
Among the 499 ,T cruzi seropositive subjects, 120 (24%) had definite Chagas cardiomyopathy, and among the 488 T cruzi seronegative subjects, 24 (5%) had cardiomyopathy, for an incidence rate of 1.85 per 100 person-years attributable to T cruzi infection. The false-positive diagnoses of Chagas-like cardiomyopathy among 5% of the T cruzi seronegative subjects illustrate the difficulty in distinguishing Chagas from other cardiac diseases, which can lead to overestimation of incidence in uncontrolled seropositive cohorts. Potential prognostic factors for Chagas cardiomyopathy, if confirmed in other studies, include male sex, a history of ECG abnormalities, and S3 gallop.
Sabino EC, Ribeiro AL, Salemi VMC, et al. Ten-Year Incidence of Chagas Cardiomyopathy Among Asymptomatic Trypanosoma cruzi–Seropositive Former Blood Donors. Circulation. 2013;127(10):1105-1115. doi:10.1161/CIRCULATIONAHA.112.123612.
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