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SARS-CoV-2 Viremia is Associated with COVID-19 Severity and Predicts Clinical Outcomes

Jacobs, Jana L. and Bain, William and Naqvi, Asma and Staines, Brittany and Castanha, Priscila M. S. and Yang, Haopu and Boltz, Valerie F. and Barratt-Boyes, Simon and Marques, Ernesto T. A. and Mitchell, Stephanie L. and Methé, Barbara and Olonisakin, Tolani F. and Haidar, Ghady and Burke, Thomas W. and Petzold, Elizabeth and Denny, Thomas and Woods, Chris W. and McVerry, Bryan J. and Lee, Janet S. and Watkins, Simon C. and St. Croix, Claudette M. and Morris, Alison and Kearney, Mary F. and Ladinsky, Mark S. and Bjorkman, Pamela J. and Kitsios, Georgios and Mellors, John W. (2021) SARS-CoV-2 Viremia is Associated with COVID-19 Severity and Predicts Clinical Outcomes. Clinical Infectious Diseases . ISSN 1058-4838. doi:10.1093/cid/ciab686. (In Press)

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Background: SARS-CoV-2 viral RNA (vRNA) is detected in the bloodstream of some patients with COVID-19 (“RNAemia”) but it is not clear whether this RNAemia reflects viremia (i.e., virus particles) and how RNAemia/viremia is related to host immune responses and outcomes. Methods: SARS-CoV-2 vRNA was quantified by ultra-sensitive RT-PCR in plasma samples (0.5-1.0 ml) from observational cohorts of 51 COVID-19 patients including 9 outpatients, 19 hospitalized (non-ICU), and 23 ICU patients, and vRNA levels compared with cross-sectional indices of COVID-19 severity and prospective clinical outcomes. We used multiple imaging methods to visualize virions in pelleted plasma. Results: SARS-CoV-2 vRNA was detected in plasma of 100%, 52.6% and 11.1% of ICU, non-ICU, and outpatients respectively. Virions were detected in plasma pellets by electron tomography and immunostaining. Plasma vRNA levels were significantly higher in ICU > non-ICU > outpatients (p<0.0001); and for inpatient, plasma vRNA levels were strongly associated with higher WHO score at admission (p=0.01), maximum WHO score (p=0.002) and discharge disposition (p=0.004). A plasma vRNA level >6,000 copies/ml was strongly associated with mortality (HR: 10.7). Levels of vRNA were significantly associated with several inflammatory biomarkers (p<0.01) but not with plasma neutralizing antibody titers (p=0.8). Conclusions: Visualization of virus particles in plasma indicates that SARS-CoV-2 RNAemia is due, at least in part, to viremia. The levels of SARS-CoV-2 RNAemia quantified by ultrasensitive RT-PCR correlate strongly with disease severity, patient outcome and specific inflammatory biomarkers but not neutralizing antibody titers.

Item Type:Article
Related URLs:
URLURL TypeDescription
Jacobs, Jana L.0000-0002-0322-585X
Bain, William0000-0001-8506-0552
Methé, Barbara0000-0001-8711-1448
Haidar, Ghady0000-0003-0634-8211
McVerry, Bryan J.0000-0002-1175-4874
St. Croix, Claudette M.0000-0003-0794-4939
Morris, Alison0000-0002-7290-6536
Ladinsky, Mark S.0000-0002-1036-3513
Bjorkman, Pamela J.0000-0002-2277-3990
Mellors, John W.0000-0002-3737-9742
Additional Information:© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model ( Received: 14 June 2021; Published: 10 August 2021. The authors wish to thank the patients and patient families that have enrolled in our research studies at the University of Pittsburgh. We also thank the physicians, nurses, respiratory therapists and other staff at the University of Pittsburgh Medical Center Presbyterian and Shadyside Hospital units for assistance with coordination of patient enrollment and collection of patient samples. We thank Heather Michael, Michelle Busch, Caitlin Schaefer and Cathy Kessinger for assistance with patient enrollment and processing research samples. We also wish to thank Lorraine Pollini for her careful review of the manuscript. This work was supported in part by pilot COVID-19 awards received from the University of Pittsburgh Clinical and Translational Science Institute (CTSI), the National Center for Advancing Translational Sciences and the National Institutes of Health [Award Number UL1TR001436 to G.D.K. and E.T.A.M.]; George Mason Fast Grant [P.J.B.]; NIH/NHLBI [Award Number P01HL114453 to B.J.M. and J.S.L.]; NIH/NIAID [Award Numbers U01AI066569 and UM1AI104681 to C.W.W., T.W.B., and E.P.]; the U.S. Defense Advanced Projects Agency [Award Numbers N66001-09-C-2082 and HR0011-17-2-0069 to C.W.W., T.W.B. and E.P.]; the Virology Quality Assurance (VQA) [Award Number 75N93019C00015 to T.D.]; in whole or in part by Federal funds from the National Cancer Institute, National Institutes of Health [under Contract No. 75N91019D00024, Task Order No. 75N91020F00003 to J.W.M.] and intramural funds from the National Cancer Institute [to M.F.K.]; National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) [Agreement 1OT2HL156812-01 to WB] and the United States Department of Veterans Affairs Biomedical Laboratory R&D Career Development Award [Award Number IK2 BX004886 to W.B.] and the University of Pittsburgh Vascular Medicine Institute, the Hemophilia Center of Western Pennsylvania, and the Institute for Transfusion Medicine [to W.B]. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, the National Center for Advancing Translational Sciences, the National Heart, Lung, and Blood Institute or the National Institutes of Health nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. Potential Conflicts of interest: H.Y. reports a scholarship to pursue study in the USA from China Scholarship Council outside the submitted work. G.H. reports grants from NIH, grants from Karius, personal fees for reviewing a legal case from Meyers, Rodbell & Rosenbaum, P.A. outside the submitted work. T.W.B. reports grants from NIH/NIAID, grants from DARPA during the conduct of the study; and equity options for consulting work from Predigen, Inc. outside the submitted work. J.S.L. discloses a paid consultantship with Janssen R&D unrelated to this work- disclose clinical adjudication of severity outcomes in the ENSEMBLE study of COVID-19 vaccine. C.W.W. reports personal fees from Duke University for employment, personal fees from Durham VA Health Care System for employment, grants from DARPA, grants from NIH/ARLG, equity/founder from Predigen, Inc., grants from NIH/VTEU, personal fees from bioMerieux for consulting, grants from Sanofi, personal fees from Roche Molecular Sciences for Advisory Board, personal fees from Biofire for consulting, personal fees from Giner for consulting, personal fees from Biomeme for consulting, personal fees from FHI Clinical for consulting, personal fees from Arena Pharmaceuticals for consulting, personal fees from Janssen for DSMB, and personal fees from Regeneron for Advisory Board outside the submitted work. B.J.M. reports grants from NIH/NHLBI, the Translational Breast Cancer Research Consortium, and the UPMC Learning While Doing Program during the conduct of the study; grants from Bayer Pharmaceuticals, Inc., and personal consultation fees from Boehringer Ingelheim, Inc. outside the submitted work. G.K. reports research funding from Karius, Inc. J.W.M. reports grants to University of Pittsburgh from NIH, USAID, Gilead Sciences, Inc., and Janssen Phamaceuticals; serves or has served as a consultant for Gilead Sciences, Inc. as Scientific Advisory Board Member, Merck, Accelevir Diagnostics and Xi'an Yufan Biotechnologies; owns share options in CoCrystal Pharmaceuticals, Inc. and Infectious Diseases Connect; is a part-time employee and shareholder of Abound Bio, Inc.; and is employed by University of Pittsburgh. His holdings and roles in Co-Crystal Pharmaceuticals, Infectious Diseases Connect and Abound Bio are unrelated to the current work. J.L.J. no conflict. W.B. no conflict. A.N. no conflict. B.S. no conflict. P.M.S.C. no conflict. V.F.B. no conflict. S.B.B. no conflict. E.T.A.M. no conflict. S.L.M. no conflict. B.A.M. no conflict. T.F.O. no conflilct. E.P. no conflict. T.D. no conflict. S.C.W. no conflict. C.M.S. no conflict. A.M. no conflict. M.F.K. no conflict. M.S.L. no conflict. P.J.B. no conflict.
Funding AgencyGrant Number
University of PittsburghUNSPECIFIED
National Center for Advancing Translational SciencesUNSPECIFIED
George Mason UniversityUNSPECIFIED
Defense Advanced Research Projects Agency (DARPA)N66001-09-C-2082
Defense Advanced Research Projects Agency (DARPA)HR0011-17-2-0069
National Cancer InstituteUNSPECIFIED
NIH Predoctoral Fellowship1OT2HL156812-01
Department of Veterans AffairsIK2 BX004886
Hemophilia Center of Western PennsylvaniaUNSPECIFIED
Institute for Transfusion MedicineUNSPECIFIED
Record Number:CaltechAUTHORS:20210816-230140809
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Official Citation:Jana L Jacobs, William Bain, Asma Naqvi, Brittany Staines, Priscila M S Castanha, Haopu Yang, Valerie F Boltz, Simon Barratt-Boyes, Ernesto T A Marques, Stephanie L Mitchell, Barbara Methé, Tolani F Olonisakin, Ghady Haidar, Thomas W Burke, Elizabeth Petzold, Thomas Denny, Chris W Woods, Bryan J McVerry, Janet S Lee, Simon C Watkins, Claudette M St Croix, Alison Morris, Mary F Kearney, Mark S Ladinsky, Pamela J Bjorkman, Georgios Kitsios, John W Mellors, SARS-CoV-2 Viremia is Associated with COVID-19 Severity and Predicts Clinical Outcomes, Clinical Infectious Diseases, 2021, ciab686,
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:110280
Deposited By: Tony Diaz
Deposited On:16 Aug 2021 23:59
Last Modified:16 Aug 2021 23:59

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