Metabolic markers distinguish COVID-19 from other intensive care patients and show potential to stratify for disease risk

Abstract

Coronavirus disease 2019 (COVID-19) is a viral infection affecting multiple organ systems of great significance for metabolic processes. Thus. there is increasing interest in metabolic and lipoprotein signatures of the disease and early analyses have demonstrated metabolic pattern typical for atherosclerotic and hepatic damage in COVID-19 patients. However, it remains unclear whether these are specific for COVID-19 or a general marker of critical illness. To answer this question, we have analyzed 276 serum samples from 92 individuals using NMR metabolomics, including longitudinally collected samples from 5 COVID-19 and 11 cardiogenic shock intensive care patients, 18 SARS-CoV-2 antibody-positive individuals, and 58 healthy controls.COVID-19 patients showed a distinct metabolic serum profile, including changes typical for severe dyslipidemia and a deeply altered metabolic status compared to healthy controls. Specifically, VLDL parameters, IDL particles, large-sized LDL particles, and the ApoB100/ApoA1 ratio were significantly increased, whereas HDL fractions were decreased. Moreover, a similarly perturbed profile was apparent, even when compared to other ICU patients suffering from cardiogenic shock, highlighting the impact of COVID-19 especially on lipid metabolism and energy status. COVID-19 patients were separated with an AUROC of 1.0 when compared to both healthy controls and cardiogenic shock patients. Anti-SARS-CoV-2 antibody-positive individuals without acute COVID-19 did not show a significantly perturbed metabolic profile compared to age- and sex-matched healthy controls, but SARS-CoV-2 antibody-titers correlated significantly with metabolic parameters, including levels of glycine, ApoA2, and small-sized LDL and HDL subfractions. Our data suggest that NMR metabolic profiles are suitable for COVID-19 patient stratification and post-treatment monitoring.

Metabolomics analysis identifies glutamic acid and cystine imbalances in COVID-19 patients without comorbid conditions. Implications on redox homeostasis and COVID-19 pathophysiology

“…Immune-activated and oxygen-deprived cells show metabolic signatures associated with the increase in glycolytic pathways and glutamine metabolism that feed energetic and biosynthetic processes [ 44 – 47 ]. In this vein and in line with other studies [ 48 – 53 ] we observed decreased serum glutamine and high glutamic acid levels in patients with severe COVID-19. Further, applying pathway enrichment analysis, we detected statistical significance and enrichment ratio of glutamine/glutamate metabolism.…”

Metabolic and Lipidomic Markers Differentiate COVID-19 From Non-Hospitalized and Other Intensive Care Patients

“…The metabolic profile that we observe for COVID-19 compared with controls is largely in agreement with those previously published for cohorts in Spain and Australia (Bruzzone et al, 2020;Kimhofer et al, 2020). In general, several markers dysregulated in COVID-19 were reported earlier by others and in a preliminary study of ourselves (Schmelter et al, 2021), including increased levels of phenylalanine, glucose, and formic acid, as well as reduced levels of glutamine, histidine, and lactic acid. In opposite to the Spanish cohort, we do not see changes in ketone bodies, but the patients in our COVID-19 cohort did not receive glucose infusions, which is a likely cause for this difference, also reflected in lower glucose levels in our results.…”

“…Lipoprotein analyses showed increased very-low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) (sub)-fractions and decreased high-density (HDL) levels in both studies ( Bruzzone et al, 2020 ; Kimhofer et al, 2020 ). In a preliminary report, we have previously reported a very similar signature derived from nuclear magnetic resonance (NMR) metabolomics ( Schmelter et al, 2021 ) characterized by increased levels of glutamic acid, phenylalanine, and glucose, which is consistent with the findings of the two other studies ( Bruzzone et al, 2020 ; Kimhofer et al, 2020 ). These results seem to underline systemic defects associated with COVID-19 and demonstrate the suitability of metabolomics for the detection and potentially stratification of COVID-19 patients.…”

Exploration of Human Serum Lipoprotein Supramolecular Phospholipids Using Statistical Heterospectroscopy in n-Dimensions (SHY-n): Identification of Potential Cardiovascular Risk Biomarkers Related to SARS-CoV-2 Infection

“…DIRE NMR experiments when applied to the plasma of SARS-CoV-2 positive and negative and control patients revealed a strong diagnostic pattern involving lipoprotein-bound phospholipid and glycoprotein signals . Additionally, we and others have shown that NMR-generated lipoprotein signals are profoundly altered in SARS-CoV-2 infection − and that some of these lipoproteins give further information on cardiovascular disease risk factors that can then be statistically linked to novel disease biomarkers.…”