Early detection and effective treatment of severe COVID-19 patients remain major challenges. In this paper, published on Cell, has been performed proteomic and metabolomic profiling of sera from 46 COVID-19 and 53 control individuals and then trained a machine learning model using proteomic and metabolomic measurements from a training cohort of 18 non-severe and 13 severe patients.

The model was validated using ten independent patients, seven of which were correctly classified. Targeted proteomics and metabolomics assays were employed to further validate this molecular classifier in a second test cohort of 19 new COVID-19 patients, leading to 16 correct assignments.

Molecular changes were identified in the sera of COVID-19 patients compared to other groups implicating dysregulation of macrophage, platelet degranulation and complement system pathways, and massive metabolic suppression. This study revealed characteristic protein and metabolite changes in the sera of severe COVID-19 patients, which might be used in selection of potential blood biomarkers for severity evaluation.

105 proteins were differentially expressed in the sera of COVID-19 patients, but not the non-COVID-19 patients. 93 proteins showed specific modulation in severe patients. Pathway analyses and network enrichment analyses of the 93 differentially expressed proteins showed that 50 of these proteins belong to three major pathways, namely activation of the complement system, macrophage function and platelet degranulation.

Data uncovered dysregulation of multiple apolipoproteins including
APOA1, APOA2, APOH, APOL1, APOD and APOM. Most of them are associated with macrophage functions and were down-regulated.

These molecular derangements may originate from binding of SARS-CoV-2 to alveola macrophages via the ACE2 receptor, resulting in release of IL-6 and TNF-α by macrophages. In response to elevated cytokines, especially IL-6 which triggers fever, various acute phase proteins (APPs) are released by liver.

Metabolomics data also provides plausible evidence for hepatic injury. The elevation of glucose, glucuronate, bilirubin degradation product and four bile acid derivatives in severe patients indicate potentially declined live detoxification function.

Data also revealed upregulation of multiple APPs, including CRP and major attack complexes (MACs) in the severe sera. CRP can activate the complement system and this on the one hand leads to enhanced cytokine and chemokine production, potentially contributing to “cytokine storm”; and on the other overly recruits macrophages from the peripheral blood, which could result in acute lung injury.

Because about 50% of platelets are produced in the lung, platelets may in turn respond to lung injury and activate macrophages by degranulation, which may further add to “cytokine storm”. A recent necropsy report revealed alveolar macrophage infiltration and activation in severe COVID-19 patients, supporting these findings.