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

Clinical Infectious Diseases - Tập 74 Số 9 - Trang 1525-1533 - 2022
Jana L. Jacobs1, William Bain2,3,4, Asma Naqvi1, Brittany Staines1, Priscila M. S. Castanha5, Haopu Yang6,3,7, Valerie F. Boltz8, Simon M. Barratt‐Boyes5, Ernesto T. A. Marques5, Stephanie L. Mitchell9, Barbara A. Methé6,3, Tolani F. Olonisakin3, Ghady Haidar1, Thomas W. Burke10, Elizabeth Petzold10, Thomas N. Denny11, Chris W. Woods10,11, Bryan J. McVerry3, Janet Lee2,3, Simon C. Watkins12, Claudette M. St. Croix12, Alison Morris6,3, Mary F. Kearney8, Mark S. Ladinsky13, Pamela J. Björkman13, Georgios D. Kitsios2,6,3, John W. Mellors1
1Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania USA
2Acute Lung Injury Center of Excellence, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
4Veteran's Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA
5Department of Infectious Diseases and Microbiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA
6Center for Medicine and the Microbiome, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
7School of Medicine, Tsinghua University, Beijing, China
8HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
9Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania USA
10Center for Applied Genomics and Precision Medicine, Duke University, Durham, North Carolina, USA
11Duke Human Vaccine Institute, Duke University, Durham, North Carolina, USA
12Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
13Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA

Tóm tắt

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.

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Tài liệu tham khảo

Zhu, 2020, A novel coronavirus from patients with pneumonia in China, 2019, N Engl J Med, 382, 727, 10.1056/NEJMoa2001017

Wu, 2020, A new coronavirus associated with human respiratory disease in China, Nature, 579, 265, 10.1038/s41586-020-2008-3

Wiersinga, 2020, Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review, JAMA, 324, 782, 10.1001/jama.2020.12839

Lamers, 2020, SARS-CoV-2 productively infects human gut enterocytes, Science, 369, 50, 10.1126/science.abc1669

Puelles, 2020, Multiorgan and renal tropism of SARS-CoV-2, N Engl J Med, 383, 590, 10.1056/NEJMc2011400

Solomon, 2020, Neuropathological features of Covid-19, N Engl J Med, 383, 989, 10.1056/NEJMc2019373

Song, 2021, Neuroinvasion of SARS-CoV-2 in human and mouse brain, J Exp Med, 218, e20202135, 10.1084/jem.20202135

Teuwen, 2020, COVID-19: the vasculature unleashed, Nat Rev Immunol, 20, 389, 10.1038/s41577-020-0343-0

Varga, 2020, Endothelial cell infection and endotheliitis in COVID-19, Lancet, 395, 1417, 10.1016/S0140-6736(20)30937-5

Wang, 2020, Detection of SARS-CoV-2 in different types of clinical specimens, JAMA, 323, 1843

Xiao, 2020, Evidence for gastrointestinal infection of SARS-CoV-2, Gastroenterology, 158, 1831, 10.1053/j.gastro.2020.02.055

Ziegler, 2020, SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues, Cell, 181, 1016, 10.1016/j.cell.2020.04.035

Hagman, 2021, SARS-CoV-2 RNA in serum as predictor of severe outcome in COVID-19: a retrospective cohort study, Clin Infect Dis

Hogan, 2020, High frequency of SARS-CoV-2 RNAemia and association with severe disease, Clin Infect Dis, 72, e291, 10.1093/cid/ciaa1054

Jacobs, 2021, Detection of SARS-CoV-2 RNA in blood of patients with COVID-19: what does it mean?, Clin Infect Dis

Prebensen, 2020, SARS-CoV-2 RNA in plasma is associated with ICU admission and mortality in patients hospitalized with COVID-19, Clin Infect Dis, 73, e799, 10.1093/cid/ciaa1338

Veyer, 2021, Highly sensitive quantification of plasma SARS-CoV-2 RNA sheds light on its potential clinical value, Clin Infect Dis, 10.1093/cid/ciaa1196

Xu, 2020, Relationship between serum SARS-CoV-2 nucleic acid (RNAemia) and organ damage in COVID-19 patients: a cohort study, Clin Infect Dis, 73, 68, 10.1093/cid/ciaa1085

Fajnzylber, 2020, SARS-CoV-2 viral load is associated with increased disease severity and mortality, Nat Commun, 11, 5493, 10.1038/s41467-020-19057-5

Andersson, 2020, SARS-CoV-2 RNA detected in blood products from patients with COVID-19 is not associated with infectious virus, Wellcome Open Res, 5, 181, 10.12688/wellcomeopenres.16002.2

Li, 2021, SARS-CoV-2 viremia is associated with distinct proteomic pathways and predicts COVID-19 outcomes, J Clin Invest, 131, e148635, 10.1172/JCI148635

Gutmann, 2021, SARS-CoV-2 RNAemia and proteomic trajectories inform prognostication in COVID-19 patients admitted to intensive care, Nat Commun, 12, 3406, 10.1038/s41467-021-23494-1

Bermejo-Martin, 2020, Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID-19, Crit Care, 24, 691, 10.1186/s13054-020-03398-0

Chen, 2020, Detectable serum severe acute respiratory syndrome coronavirus 2 viral load (RNAemia) is closely correlated with drastically elevated interleukin 6 level in critically ill patients with coronavirus disease 2019, Clin Infect Dis, 71, 1937, 10.1093/cid/ciaa449

Roltgen, 2020, Defining the features and duration of antibody responses to SARS-CoV-2 infection associated with disease severity and outcome, Sci Immunol, 5, eabe0240, 10.1126/sciimmunol.abe0240

Wang, 2020, Neutralizing antibodies responses to SARS-CoV-2 in COVID-19 inpatients and convalescent patients, Clin Infect Dis, 71, 2688, 10.1093/cid/ciaa721

Agarwal, 2020, Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial), BMJ, 371, m3939, 10.1136/bmj.m3939

Li, 2020, Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial, JAMA, 324, 460, 10.1001/jama.2020.10044

Salazar, 2020, Treatment of coronavirus disease 2019 (COVID-19) patients with convalescent plasma, Am J Pathol, 190, 1680, 10.1016/j.ajpath.2020.05.014

Simonovich, 2020, A randomized trial of convalescent plasma in Covid-19 severe pneumonia, N Engl J Med, 384, 619, 10.1056/NEJMoa2031304

Horby, 2021, Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial, medRxiv

Lundgren, 2021, A neutralizing monoclonal antibody for hospitalized patients with Covid-19, N Engl J Med, 384, 905, 10.1056/NEJMoa2033130

Horby, 2021, Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial, medRxiv

Martin-Vicente, 2021, Absent or insufficient anti-SARS-CoV-2 S antibodies at ICU admission are associated to higher viral loads in plasma, antigenemia and mortality in COVID-19 patients, medRxiv

McClain, 2021, Dysregulated transcriptional responses to SARS-CoV-2 in the periphery support novel diagnostic approaches, Nat Commun, 12, 1079, 10.1038/s41467-021-21289-y

Bain, 2021, COVID-19 versus non-COVID-19 acute respiratory distress syndrome: comparison of demographics, physiologic parameters, inflammatory biomarkers, and clinical outcomes, Ann Am Thorac Soc, 18, 1202, 10.1513/AnnalsATS.202008-1026OC

Consortium IC.

Tosiano, 2019, A simpler and more sensitive single-copy HIV-1 RNA assay for quantification of persistent HIV-1 viremia in individuals on suppressive antiretroviral therapy, J Clin Microbiol, 57, e01714, 10.1128/JCM.01714-18

Su, 2020, Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China, Kidney Int, 98, 219, 10.1016/j.kint.2020.04.003

Bernard, 2020, Endothelium infection and dysregulation by SARS-CoV-2: evidence and caveats in COVID-19, Viruses, 13, 29, 10.3390/v13010029

Atyeo, 2020, Distinct early serological signatures track with SARS-CoV-2 survival, Immunity, 53, 524, 10.1016/j.immuni.2020.07.020

Zohar, 2020, Compromised humoral functional evolution tracks with SARS-CoV-2 mortality, Cell, 183, 1508, 10.1016/j.cell.2020.10.052

Ganem, 2004, Hepatitis B virus infection, N Engl J Med, 350, 1118, 10.1056/NEJMra031087

Li, 2017, Current therapy for chronic hepatitis C: the role of direct-acting antivirals, Antiviral Res, 142, 83, 10.1016/j.antiviral.2017.02.014

Katzenstein, 1996, The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team, N Engl J Med, 335, 1091, 10.1056/NEJM199610103351502

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Clinical Infectious Diseases

Tập 74 Số 9

1525-1533

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