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SARS-CoV-2 RNAemia and proteomic trajectories inform prognostication in COVID-19 patients admitted to intensive care

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Clemens Gutmann, Kaloyan Takov, Sean A Burnap, Bhawana Singh, Hashim Ali, Konstantinos Theofilatos, Ella Reed, Maria Hasman, Adam Nabeebaccus, Matthew Fish, Mark Jw McPhail, Kevin O'Gallagher, Lukas E Schmidt, Christian Cassel, Marieke Rienks, Xiaoke Yin, Georg Auzinger, Salvatore Napoli, Salma F Mujib, Francesca Trovato & 17 more Barnaby Sanderson, Blair Merrick, Umar Niazi, Mansoor Saqi, Konstantina Dimitrakopoulou, Rafael Fernández-Leiro, Silke Braun, Romy Kronstein-Wiedemann, Katie J Doores, Jonathan D Edgeworth, Ajay M Shah, Stefan R Bornstein, Torsten Tonn, Adrian C Hayday, Mauro Giacca, Manu Shankar-Hari, Manuel Mayr

Original languageEnglish
Article number3406
JournalNature Communications
Volume12
Issue number1
DOIs
Accepted/In press28 Apr 2021
PublishedDec 2021

Bibliographical note

Funding Information: M.M. and A.M.S. are British Heart Foundation (BHF) Chair Holders with BHF program grant support (CH/16/3/32406, RG/16/14/32397, and CH/1999001/11735, RE/18/2/ 34213, respectively). C.G., E.R., and B.S. are funded by BHF PhD studentships (FS/18/60/ 34181, FS/17/65/33481, and FS/19/58/34895). M.H. is funded by an interdisciplinary PhD studentship from King’s BHF Centre of Research Excellence. M.F. is funded by a National Institute of Academic Anesthesia BJA-RCOA PhD Fellowship WKR0-2018-0047. M.J.W.M. is grateful to the Biomedical Research Centre at Guy’s and St. Thomas’ NHS Foundation Trust for support. K.O.G. is supported by a UK Medical Research Council Clinical Research Training Fellowship (MR/R017751/1). B.M. was supported by an NIHR Academic Clinical Fellowship in Combined Infection Training. K.J.D. was supported by a King’s Together Rapid COVID-19 Call award, by an MRC Discovery Award (MC/PC/15068), Huo Family Foundation and the Fondation Dormeur, Vaduz. The NIHR Collaboration for Leadership in Applied Health Research and Care South London at King’s College Hospital NHS Foundation Trust, awarded to J.D.E. who is also supported by a charitable donation from the Lower Green Foundation. R.F.L. is funded by a Spanish Ministry of Economy and Competitiveness Grant BFU2017-87316. M.G. is supported by the European Research Council (ERC) Advanced Grant 787971 “CuRE” and by Program Grant RG/19/11/34633 from the BHF. M.M.’s research was made possible through the support of the BIRAX Ageing Initiative and funding from the EU Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 813716 (TRAIN-HEART), the Leducq Foundation (18CVD02), the excellence initiative VASCage (Centre for Promoting Vascular Health in the Ageing Community, project number 868624) of the Austrian Research Promotion Agency FFG (COMET program–Competence Centers for Excellent Technologies) funded by the Austrian Ministry for Transport, Innovation and Technology; the Austrian Ministry for Digital and Economic Affairs; and the federal states Tyrol (via Standortagentur), Salzburg, and Vienna (via Vienna Business Agency), two BHF project grant supports (PG/17/ 48/32956 and SP/17/10/33219) and the BHF Centre for Vascular Regeneration with Edinburgh/Bristol (RM/17/3/33381). M.M. and S.R.B. acknowledge support as visiting professors as part of the Transcampus TU Dresden King’s College London Initiative. The work of A.C.H. is supported by a Cancer ImmunoTherapy Accelerator award from CRUK; the Wellcome Trust (106292/Z/14/Z); the Rosetrees Trust; King’s Together Seed Fund; The John Black Charitable Foundation; Royal Society Grant IES\R3\170319 and the Francis Crick Institute, which receives core funding from Cancer Research UK (FC001093), the MRC (FC001093) and the Wellcome Trust (FC001093). M.S.H. is supported by the National Institute for Health Research Clinician Scientist Award (CS-2016-16-011). The research was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

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Abstract

Prognostic characteristics inform risk stratification in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). We obtained blood samples (n = 474) from hospitalized COVID-19 patients (n = 123), non-COVID-19 ICU sepsis patients (n = 25) and healthy controls (n = 30). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in plasma or serum (RNAemia) of COVID-19 ICU patients when neutralizing antibody response was low. RNAemia is associated with higher 28-day ICU mortality (hazard ratio [HR], 1.84 [95% CI, 1.22-2.77] adjusted for age and sex). RNAemia is comparable in performance to the best protein predictors. Mannose binding lectin 2 and pentraxin-3 (PTX3), two activators of the complement pathway of the innate immune system, are positively associated with mortality. Machine learning identified 'Age, RNAemia' and 'Age, PTX3' as the best binary signatures associated with 28-day ICU mortality. In longitudinal comparisons, COVID-19 ICU patients have a distinct proteomic trajectory associated with mortality, with recovery of many liver-derived proteins indicating survival. Finally, proteins of the complement system and galectin-3-binding protein (LGALS3BP) are identified as interaction partners of SARS-CoV-2 spike glycoprotein. LGALS3BP overexpression inhibits spike-pseudoparticle uptake and spike-induced cell-cell fusion in vitro.

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