Jana L Jacobs1, William Bain2,3,4, Asma Naqvi1, Brittany Staines1, Priscila M S Castanha5, Haopu Yang2,6,7, Valerie F Boltz8, Simon Barratt-Boyes5, Ernesto T A Marques5, Stephanie L Mitchell9, Barbara Methé2,6, Tolani F Olonisakin2, Ghady Haidar1, Thomas W Burke10, Elizabeth Petzold10, Thomas Denny11, Chris W Woods10,11, Bryan J McVerry2, Janet S Lee2,3, Simon C Watkins12, Claudette M St Croix12, Alison Morris2,6, Mary F Kearney8, Mark S Ladinsky13, Pamela J Bjorkman13, Georgios D Kitsios2,3,6, John W Mellors1. 1. Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. 2. Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. 3. Acute Lung Injury Center of Excellence, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 4. Veteran's Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA. 5. Department of Infectious Diseases and Microbiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA. 6. Center for Medicine and the Microbiome, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 7. School of Medicine, Tsinghua University, Beijing, China. 8. HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA. 9. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. 10. Center for Applied Genomics and Precision Medicine, Duke University, Durham, North Carolina, USA. 11. Duke Human Vaccine Institute, Duke University, Durham, North Carolina, USA. 12. Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 13. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
Abstract
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.
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.
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