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Severe Acute Respiratory Syndrome Coronavirus 2 Viremia Is Associated With Coronavirus Disease 2019 Severity and Predicts Clinical Outcome

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 D. and Mellors, John W. (2022) Severe Acute Respiratory Syndrome Coronavirus 2 Viremia Is Associated With Coronavirus Disease 2019 Severity and Predicts Clinical Outcome. Clinical Infectious Diseases, 74 (9). pp. 1525-1533. ISSN 1058-4838. PMCID PMC9070832. doi:10.1093/cid/ciab686.

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Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA (vRNA) is detected in the bloodstream of some patients with coronavirus disease 2019 (COVID-19), but it is not clear whether this RNAemia reflects viremia (ie, virus particles) and how it relates to host immune responses and outcomes. Methods: SARS-CoV-2 vRNA was quantified in plasma samples from observational cohorts of 51 COVID-19 patients including 9 outpatients, 19 hospitalized (non–intensive care unit [ICU]), and 23 ICU patients. vRNA levels were compared with cross-sectional indices of COVID-19 severity and prospective clinical outcomes. We used multiple imaging methods to visualize virions in 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 using electron tomography and immunostaining. Plasma vRNA levels were significantly higher in ICU > non-ICU > outpatients (P < .0001); for inpatients, plasma vRNA levels were strongly associated with higher World Health Organization (WHO) score at admission (P = .01), maximum WHO score (P = .002), and discharge disposition (P = .004). A plasma vRNA level >6000 copies/mL was strongly associated with mortality (hazard ratio, 10.7). Levels of vRNA were significantly associated with several inflammatory biomarkers (P < .01) but not with plasma neutralizing antibody titers (P = .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 correlate strongly with disease severity, patient outcome, and specific inflammatory biomarkers but not with neutralizing antibody titers.

Item Type:Article
Related URLs:
URLURL TypeDescription
Jacobs, Jana L.0000-0002-0322-585X
Bain, William0000-0001-8506-0552
Yang, Haopu0000-0001-6858-1778
Boltz, Valerie F.0000-0001-8872-5599
Barratt-Boyes, Simon0000-0002-8869-4945
Marques, Ernesto T. A.0000-0003-3826-9358
Methé, Barbara0000-0001-8711-1448
Olonisakin, Tolani F.0000-0002-8342-3409
Haidar, Ghady0000-0003-0634-8211
Burke, Thomas W.0000-0003-0592-5822
Petzold, Elizabeth0000-0001-8207-4406
Denny, Thomas0000-0002-7364-8276
McVerry, Bryan J.0000-0002-1175-4874
Lee, Janet S.0000-0002-6812-6043
Watkins, Simon C.0000-0003-4092-1552
St. Croix, Claudette M.0000-0003-0794-4939
Morris, Alison0000-0002-7290-6536
Kearney, Mary F.0000-0003-3839-6576
Ladinsky, Mark S.0000-0002-1036-3513
Bjorkman, Pamela J.0000-0002-2277-3990
Mellors, John W.0000-0002-3737-9742
Alternate Title:SARS-CoV-2 Viremia is Associated with COVID-19 Severity and Predicts Clinical Outcomes
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; Editorial decision: 02 August 2021; Published: 10 August 2021; Corrected and typeset: 20 September 2021. We thank the patients and patient families who 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 thank Lorraine Pollini for her careful review of the manuscript. Disclaimer. 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 (NHLBI); or the National Institutes of Health (NIH) nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. This work was supported in part by pilot coronavirus disease 2019 (COVID-19) awards received from the University of Pittsburgh Clinical and Translational Science Institute, the National Center for Advancing Translational Sciences, and the NIH (UL1TR001436 to G. D. K. and E. T. A. M.); a George Mason Fast grant (to P. J. B.); NIH/ NHLBI (P01HL114453 to B. J. M. and J. S. L.); NIH/National Institute of Allergy and Infectious Diseases (NIAID; U01AI066569 and UM1AI104681 to C. W. W., T. W. B., and E. P.); the US Defense Advanced Projects Agency (N66001-09-C-2082 and HR0011-17-2-0069 to C. W. W., T. W. B., and E. P.); the Virology Quality Assurance (75N93019C00015 to T. D.); in whole or in part by federal funds from the National Cancer Institute, NIH (under contract 75N91019D00024, task order 75N91020F00003 to J. W. M.), and intramural funds from the National Cancer Institute (to M. F. K.); NIH/NHLBI (agreement 1OT2HL156812-01 to W. B.); the US Department of Veterans Affairs Biomedical Laboratory R&D Career Development Award (IK2 BX004886 to WB.); and the University of Pittsburgh Vascular Medicine Institute, the Hemophilia Center of Western Pennsylvania, and the Institute for Transfusion Medicine (to W. B). Potential conflicts of interest. H. Y. reports a scholarship to pursue study in the United States from the China Scholarship Council outside the submitted work. G. H. reports grants from NIH and Karius and personal fees for reviewing a legal case from Meyers, Rodbell & Rosenbaum, PA, outside the submitted work. T. W. B. reports grants from NIH/NIAID and Defense Advanced Research Projects Agency (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 and discloses clinical adjudication of severity outcomes in the ENSEMBLE study of COVID-19 vaccine. C. W. W. reports personal fees from Duke University and Durham VA Health Care System for employment; grants from DARPA, NIH/Antibacterial Resistance Leadership Group (ARLG), equity/founder from Predigen, Inc, Sanofi, and NIH/Vaccine and Treatment Evaluation Unit (VTEU); personal fees from bioMerieux for consulting; personal fees from Roche Molecular Sciences for advisory board participation; personal fees for consulting from Biofire, Giner, Biomeme, FHI Clinical, and Arena; personal fees from Janssen for Data and Safety Monitoring Board (DSMB); and personal fees from Regeneron for advisory board participation 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 the University of Pittsburgh from NIH, USAID, Gilead Sciences, Inc, and Janssen Pharmaceuticals; serves or has served as a consultant for Gilead Sciences, Inc; has served as a scientific advisory board member for Merck, Accelevir Diagnostics, and Xi’an Yufan Biotechnologies; owns share options in Co-Crystal Pharmaceuticals, Inc, and Infectious Diseases Connect; is a part-time employee and shareholder of Abound Bio, Inc; and is employed by the University of Pittsburgh. His holdings and roles in Co-Crystal Pharmaceuticals, Infectious Diseases Connect, and Abound Bio are unrelated to the current work. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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
Issue or Number:9
PubMed Central ID:PMC9070832
Record Number:CaltechAUTHORS:20210816-230140809
Persistent URL:
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 D Kitsios, John W Mellors, Severe Acute Respiratory Syndrome Coronavirus 2 Viremia Is Associated With Coronavirus Disease 2019 Severity and Predicts Clinical Outcomes, Clinical Infectious Diseases, Volume 74, Issue 9, 1 May 2022, Pages 1525–1533,
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 May 2022 17:52

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