Metabolic Signatures Associated with Severity in Hospitalized COVID-19 Patients

Abstract

The clinical evolution of COVID-19 pneumonia is poorly understood. Identifying the metabolic pathways that are altered early with viral infection and their association with disease severity is crucial to understand COVID-19 pathophysiology, and guide clinical decisions. This study aimed at assessing the critical metabolic pathways altered with disease severity in hospitalized COVID-19 patients. Forty-nine hospitalized patients with COVID-19 pneumonia were enrolled in a prospective, observational, single-center study in Barcelona, Spain. Demographic, clinical, and analytical data at admission were registered. Plasma samples were collected within the first 48 h following hospitalization. Patients were stratified based on the severity of their evolution as moderate (N = 13), severe (N = 10), or critical (N = 26). A panel of 221 biomarkers was measured by targeted metabolomics in order to evaluate metabolic changes associated with subsequent disease severity. Our results show that obesity, respiratory rate, blood pressure, and oxygen saturation, as well as some analytical parameters and radiological findings, were all associated with disease severity. Additionally, ceramide metabolism, tryptophan degradation, and reductions in several metabolic reactions involving nicotinamide adenine nucleotide (NAD) at inclusion were significantly associated with respiratory severity and correlated with inflammation. In summary, assessment of the metabolomic profile of COVID-19 patients could assist in disease severity stratification and even in guiding clinical decisions.

Keywords: COVID-19; ceramides; kynurenine; metabolomics; severity.

Figure 1

(a) Distribution of hospitalized COVID-19 patients stratified according to severity; (b) supervised partial least squares discriminant analysis (PLS-DA) showing the discrimination between COVID-19 patients regarding severity.

Figure 2

Plasma metabolic levels of long-chain ceramides (in response), hexosylceramides (in response), and hexosylceramide/ceramide ratios in hospitalized patients with COVID-19. Abbreviations: Cer: ceramides; HexCer: hexosylceramides, resp.: response. * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001.

Figure 3

Metabolic pathway of the tryptophan metabolism via the kynurenine pathway in hospitalized patients with COVID-19 pneumonia. Abbreviations: IDO/TDO: indoleamine dioxygenase; KAT: kynurenine aminotransferase; KMO: kynurenine hydroxylase; KYNU: kynureninase; NAM: nicotinamide; NAD: nicotinamide adenine dinucleotide; NicA: nicotinic acid. * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001.

Figure 4

Metabolic pathways requiring NAD stratified according to the COVID-19 severity are represented by the (a) conversion of cortisol into cortisone via 11βHSD; (b) conversion of α-ketoglutarate to succinate via OGDC; and (c) production of LDH (estimated by the conversion of pyruvate into lactate). Abbreviations: 11βHSD: 11β-hydroxysteroid dehydrogenase; LDH: lactate dehydrogenase; NAD: nicotinamide adenine dinucleotide; OGDC: 2-oxoglutarate decarboxylase; Succ-CoA: succinyl-CoA. * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001.

Figure 5

Clinical and laboratory correlates with metabolomics. Correlation plots illustrate Pearson correlations between plasma biomarkers (after log transformation) and clinical/laboratory parameters. Positive statistical significant correlations are shown in red circles and negative statistical significant correlations are shown in blue circles. The circle size represents the magnitude of the individual correlation. Abbreviations: AA: anthranillic acid; aKA: α-ketoglutarate; BP: blood pressure; Cer: ceramide; CRP: C-reactive protein; E: cortisone; F: cortisol, GAP: days from first symptom until inclusion; HexCer: hexosylceramide; 3OHKyn: 3-hydroxykynurenine; IL6: interleukin 6; KA: kynurenic acid; Kyn: kynurenine; LA: lactate; LDH: lactate dehydrogenase; Leuk: leukocytes; Lymph: lymphocytes; NAM: nicotinamide; NicA: nicotinic acid; PCT: plateletcrit; PyA: pyruvic acid; SA: succinic acid; Trp: tryptophan.