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Longitudinal proteomic profiling of dialysis patients with COVID-19 reveals markers of severity and predictors of death

Title: Longitudinal proteomic profiling of dialysis patients with COVID-19 reveals markers of severity and predictors of death
Authors: Gisby, J
Clarke, C
Medjeral-Thomas, N
Malik, T
Papadaki, A
Mortimer, P
Buang, N
Lewis, S
Pereira, M
Toulza, F
Fagnano, E
Mawhin, M-A
Dutton, E
Tapeng, L
Kirk, P
Behmoaras, J
Sandhu, E
McAdoo, S
Prendecki, M
Pickering, M
Botto, M
Willicombe, M
Thomas, D
Peters, J
Item Type: Working Paper
Abstract: End-stage kidney disease (ESKD) patients are at high risk of severe COVID-19. We performed dense serial blood sampling in hospitalised and non-hospitalised ESKD patients with COVID-19 (n=256 samples from 55 patients) and used Olink immunoassays to measure 436 circulating proteins. Comparison to 51 non-infected ESKD patients revealed 221 proteins differentially expressed in COVID-19, of which 69.7% replicated in an independent cohort of 46 COVID-19 patients. 203 proteins were associated with clinical severity scores, including IL6, markers of monocyte recruitment (e.g. CCL2, CCL7), neutrophil activation (e.g proteinase-3) and epithelial injury (e.g. KRT19). Random Forests machine learning identified predictors of current or future severity such as KRT19, PARP1, PADI2, CCL7, and IL1RL1 (ST2). Survival analysis with joint models revealed 69 predictors of death including IL22RA1, CCL28, and the neutrophil-derived chemotaxin AZU1 (Azurocidin). Finally, longitudinal modelling with linear mixed models uncovered 32 proteins that display different temporal profiles in severe versus non-severe disease, including integrins and adhesion molecules. Our findings point to aberrant innate immune activation and leucocyte-endothelial interactions as central to the pathology of severe COVID-19. The data from this unique cohort of high-risk individuals provide a valuable resource for identifying drug targets in COVID-19.
Issue Date: 6-Nov-2020
URI: http://hdl.handle.net/10044/1/83799
DOI: 10.1101/2020.11.05.20223289
Publisher: Cold Spring Harbor Laboratory
Copyright Statement: The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
Sponsor/Funder: United Kingdom Research and Innovation
Medical Research Council (MRC)
Wellcome Trust
Community Jameel Imperial College COVID-19 Excellence Fund
Wellcome Trust
Funder's Grant Number: MR/S004068/1
MR/V027638/1
206617/A/17/Z
212252/Z/18/Z
Keywords: COVIdD-19
proteomics
COVID-19
Immunology
Infection
Proteomics
Immune System
Publication Status: Published
Appears in Collections:Department of Immunology and Inflammation
Faculty of Medicine



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