Clinical heterogeneity and incomplete understanding of potentially druggable immune mediators of disease currently limit treatment of severe Covid-19, characterized by hypoxia, with the risk of rapid deterioration that may require intensive care support and, in some patients, progression to acute respiratory distress syndrome, multiorgan failure and death. Currently, opportunities for biomarker-led timed and targeted precision medicine approaches are limited by an incomplete understanding of pathogenesis and heterogeneity among patients with severe disease. To advance this, the COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium, led by the Knight group at University of Oxford presents a comprehensive multi-omic blood atlas in patients with varying COVID-19 severity and compare with influenza, sepsis and healthy volunteers.

Plasma protein COVID-19 signatures and subphenotypes

They use a comprehensive multi-modal integrated approach, applied to multiple well-defined cohorts of patients and health volunteers, complemented with the analysis of the Covid-19 plasma proteome. They performed high-throughput liquid chromatography using the 100 samples per day method on the Evosep One coupled to a timsTOF Pro mass spectrometer, producing data for 105 proteins on 257 individuals (340 samples) after QC.

Their proteomic analysis has identified specific plasma cytokine and chemokine levels as biomarkers of severe disease with evidence for acute phase inflammation, complement activation/attack, fibrin clots, proteases, serum amyloid, tissue necrosis, receptor mediated endocytosis and cholesterol transport as hallmarks. Moreover, they have discovered plasma protein signatures that can be used to stratify acute hospitalized COVID-19 cases into disease sub-phenotypes, with cluster membership informative for response state and associated with differential 28-day mortality. They have validated their finding in an independent dataset using a predictive set of seven plasma proteins (cytokines IL-6, IL-8; chemokines CCL2, CCL19, CCL20, CXCL10; and C-type lectin CLEC11A, a key growth factor for primitive hematopoietic progenitor cells). Patient stratification is important given the observed clinical heterogeneity within severe Covid-19. Such variability has historically been a major confounder of clinical trials for targeted immune therapy in other severe infections.

Collectively, their multi-omic integrated blood atlas comprehensively delineates the host immune response in COVID-19 from the start of the UK pandemic, prior to clinical trial-led implementation of approved treatments or vaccination. Integrative approaches such as described here will be important as we seek novel therapeutic targets and the opportunity for a precision medicine approach to treatment.

Link: https://www.medrxiv.org/content/10.1101/2021.05.11.21256877v1

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