TY - JOUR
T1 - Prognostic Performance of Peripheral Blood Biomarkers in Identifying Seropositive Individuals at Risk of Developing Clinically Symptomatic Chagas Cardiomyopathy
AU - Choudhuri, Subhadip
AU - Bhavnani, Suresh K.
AU - Zhang, Weibin
AU - Botelli, Valentina
AU - Barrientos, Natalia
AU - lñiguez, Facundo
AU - Zago, Maria Paola
AU - Garg, Nisha Jain
N1 - Funding Information:
This work was supported by a grant from the National Institute of Allergy and Infectious Diseases (R01AI136031) of the NIH to N.J.G. and a pilot grant from the Institute for Human Infections and Immunity at UTMB to S.B. and N.J.G. S.B. has received partial support from the Clinical and Translational Science Award (UL1 TR001439) from the National Center for Advancing Translational Sciences of the NIH, the Patient-Centered Outcomes Research Institute (ME-1511-33194), and the UTMB Claude D. Pepper Older Americans Independence Center funded by National Institute of Aging, NIH (P30 AG024832). M.P.Z. is a CONICET fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We are thankful for the support provided in recruitment, serology tests, and clinical categorization of the human subjects by the San Bernardo Hospital in Salta, Argentina. We are thankful to Somnath Chatterjee of the Indian Statistical Institute, Kolkata, for helpful suggestions on statistical analysis. N.J.G. provided financial support and conceived and guided the study. M.P.Z. organized recruitment and consent of patients and sample collection and processing. V.B., N.B., and F.I. were involved in patient exams and characterization of disease severity. S.C. performed the experiments, analyzed the data, and confirmed the reproducibility and accuracy of data presented in the manuscript. S.K.B. and W.Z. performed the bipartite network analysis of the proteome data sets. N.J.G. and S.C. wrote and edited the manuscript. All authors approved the submitted manuscript.
Funding Information:
This work was supported by a grant from the National Institute of Allergy and Infectious Diseases (R01AI136031) of the NIH to N.J.G. and a pilot grant from the Institute for Human Infections and Immunity at UTMB to S.B. and N.J.G. S.B. has received partial support from the Clinical and Translational Science Award (UL1 TR001439) from the National Center for Advancing Translational Sciences of the NIH, the Patient-Centered Outcomes Research Institute (ME-1511-33194), and the UTMB Claude D. Pepper Older Americans Independence Center funded by National Institute of Aging, NIH (P30 AG024832). M.P.Z. is a CONICET fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2021. Choudhuri et al.
PY - 2021/9
Y1 - 2021/9
N2 - Biomarkers for prognosis-based detection of Trypanosoma cruzi-infected patients presenting no clinical symptoms to cardiac Chagas disease (CD) are not available. In this study, we examined the performance of seven biomarkers in prognosis and risk of symptomatic CD development. T.cruzi-infected patients clinically asymptomatic (C/A; n = 30) or clinically symptomatic (C/S; n = 30) for cardiac disease and humans who were noninfected and healthy (N/H; n = 24) were enrolled (1 − β = 80%, α = 0.05). Serum, plasma, and peripheral blood mononuclear cells (PBMCs) were analyzed for heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), vimentin, poly(ADP-ribose) polymerase (PARP1), 8-hydroxy-2-deoxyguanosine (8-OHdG), copeptin, endostatin, and myostatin biomarkers by enzyme-linked immunosorbent assay (ELISA) and Western blotting. Secreted hnRNPA1, vimentin, PARP1, 8-OHdG, copeptin, and endostatin were increased by 1.4- to 7.0-fold in CD subjects versus N/H subjects (P < 0.001) and showed excellent predictive value in identifying the occurrence of infection (area under the receiver operating characteristic [ROC] curve [AUC], 0.935 to 0.999). Of these, vimentin, 8-OHdG, and copeptin exhibited the best performance in prognosis of C/S (versus C/A) CD, determined by binary logistic regression analysis with the Cox and Snell test (R2C&S = 0.492 to 0.688). A decline in myostatin and increase in hnRNPA1 also exhibited good predictive value in identifying C/S and C/A CD status, respectively. Furthermore, circulatory 8-OHdG (Wald x2 = 15.065), vimentin (Wald x2 = 14.587), and endostatin (Wald x2 = 17.902) levels exhibited a strong association with changes in left ventricular ejection fraction and diastolic diameter (P = 0.001) and predicted the risk of cardiomyopathy development in CD patients. We have identified four biomarkers (vimentin, 8-OHdG, copeptin, and endostatin) that offer excellent value in prognosis and risk of symptomatic CD development. Decline in these four biomarkers and increase in hnRNPA1 wouldbeuseful in monitoring the efficacy of therapies and vaccines in halting CD. IMPORTANCE There is a lack of validated biomarkers for diagnosis of T. cruzi-infected individuals at risk of developing heart disease. Of the seven potential biomarkers that were screened, vimentin, 8-OHdG, copeptin, and endostatin exhibited excellent performance in distinguishing the clinical severity of Chagas disease. A decline in these four biomarkers can also be used for monitoring the therapeutic responses of infected patients to established or newly developed drugs and vaccines and precisely inform the patients about their progress. These biomarkers can easily be screened using the readily available plasma/serum samples in the clinical setting by an ELISA that is inexpensive, fast, and requires low-tech resources at the facility, equipment, and personnel levels.
AB - Biomarkers for prognosis-based detection of Trypanosoma cruzi-infected patients presenting no clinical symptoms to cardiac Chagas disease (CD) are not available. In this study, we examined the performance of seven biomarkers in prognosis and risk of symptomatic CD development. T.cruzi-infected patients clinically asymptomatic (C/A; n = 30) or clinically symptomatic (C/S; n = 30) for cardiac disease and humans who were noninfected and healthy (N/H; n = 24) were enrolled (1 − β = 80%, α = 0.05). Serum, plasma, and peripheral blood mononuclear cells (PBMCs) were analyzed for heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), vimentin, poly(ADP-ribose) polymerase (PARP1), 8-hydroxy-2-deoxyguanosine (8-OHdG), copeptin, endostatin, and myostatin biomarkers by enzyme-linked immunosorbent assay (ELISA) and Western blotting. Secreted hnRNPA1, vimentin, PARP1, 8-OHdG, copeptin, and endostatin were increased by 1.4- to 7.0-fold in CD subjects versus N/H subjects (P < 0.001) and showed excellent predictive value in identifying the occurrence of infection (area under the receiver operating characteristic [ROC] curve [AUC], 0.935 to 0.999). Of these, vimentin, 8-OHdG, and copeptin exhibited the best performance in prognosis of C/S (versus C/A) CD, determined by binary logistic regression analysis with the Cox and Snell test (R2C&S = 0.492 to 0.688). A decline in myostatin and increase in hnRNPA1 also exhibited good predictive value in identifying C/S and C/A CD status, respectively. Furthermore, circulatory 8-OHdG (Wald x2 = 15.065), vimentin (Wald x2 = 14.587), and endostatin (Wald x2 = 17.902) levels exhibited a strong association with changes in left ventricular ejection fraction and diastolic diameter (P = 0.001) and predicted the risk of cardiomyopathy development in CD patients. We have identified four biomarkers (vimentin, 8-OHdG, copeptin, and endostatin) that offer excellent value in prognosis and risk of symptomatic CD development. Decline in these four biomarkers and increase in hnRNPA1 wouldbeuseful in monitoring the efficacy of therapies and vaccines in halting CD. IMPORTANCE There is a lack of validated biomarkers for diagnosis of T. cruzi-infected individuals at risk of developing heart disease. Of the seven potential biomarkers that were screened, vimentin, 8-OHdG, copeptin, and endostatin exhibited excellent performance in distinguishing the clinical severity of Chagas disease. A decline in these four biomarkers can also be used for monitoring the therapeutic responses of infected patients to established or newly developed drugs and vaccines and precisely inform the patients about their progress. These biomarkers can easily be screened using the readily available plasma/serum samples in the clinical setting by an ELISA that is inexpensive, fast, and requires low-tech resources at the facility, equipment, and personnel levels.
KW - Chagas cardiomyopathy
KW - Trypanosoma cruzi
KW - biomarkers ’ prognostic performance
KW - infectious disease
KW - predictive risk analysis
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U2 - 10.1128/Spectrum.00364-21
DO - 10.1128/Spectrum.00364-21
M3 - Article
C2 - 34479416
AN - SCOPUS:85115761281
VL - 9
SP - 1
EP - 14
JO - Microbiology spectrum
JF - Microbiology spectrum
SN - 2165-0497
IS - 1
ER -