Association of Altered Plasma Lipidome with Disease Severity in COVID-19 Patients

Author:

Zhang Zhengzheng1,Karu Naama12ORCID,Kindt Alida1ORCID,Singh Madhulika1ORCID,Lamont Lieke1ORCID,van Gammeren Adriaan J.3,Ermens Anton A. M.3,Harms Amy C.1ORCID,Portengen Lutzen4,Vermeulen Roel C. H.4,Dik Willem A.5ORCID,Langerak Anton W.5ORCID,van der Velden Vincent H. J.5ORCID,Hankemeier Thomas1ORCID

Affiliation:

1. Metabolomics and Analytics Centre, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands

2. Tasmanian Independent Metabolomics and Analytical Chemistry Solutions (TIMACS), Hobart, TAS 7008, Australia

3. Department of Clinical Chemistry and Hematology, Amphia Hospital, 4818 CK Breda, The Netherlands

4. Department of Population Health Sciences, Institute for Risk Assessment Sciences, University Utrecht, 3584 CK Utrecht, The Netherlands

5. Laboratory Medical Immunology, Department of Immunology, Erasmus MC University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands

Abstract

The severity of COVID-19 is linked to an imbalanced immune response. The dysregulated metabolism of small molecules and bioactive lipids has also been associated with disease severity. To promote understanding of the disease biochemistry and provide targets for intervention, we applied a range of LC-MS platforms to analyze over 100 plasma samples from patients with varying COVID-19 severity and with detailed clinical information on inflammatory responses (>30 immune markers). This is the third publication in a series, and it reports the results of comprehensive lipidome profiling using targeted LC-MS/MS. We identified 1076 lipid features across 25 subclasses, including glycerophospholipids, sterols, glycerolipids, and sphingolipids, among which 531 lipid features were dramatically changed in the plasma of intensive care unit (ICU) patients compared to patients in the ward. Patients in the ICU showed 1.3–57-fold increases in ceramides, (lyso-)glycerophospholipids, diglycerides, triglycerides, and plasmagen phosphoethanolamines, and 1.3–2-fold lower levels of a cyclic lysophosphatidic acid, sphingosine-1-phosphates, sphingomyelins, arachidonic acid-containing phospholipids, lactosylceramide, and cholesterol esters compared to patients in the ward. Specifically, phosphatidylinositols (PIs) showed strong fatty acid saturation-dependent behavior, with saturated fatty acid (SFA)- and monosaturated fatty acid (MUFA)-derived PI decreasing and polystaturated (PUFA)-derived PI increasing. We also found ~4000 significant Spearman correlations between lipids and multiple clinical markers of immune response with |R| ≥ 0.35 and FDR corrected Q < 0.05. Except for lysophosphatidic acid, lysophospholipids were positively associated with the CD4 fraction of T cells, and the cytokines IL-8 and IL-18. In contrast, sphingosine-1-phosphates were negatively correlated with innate immune markers such as CRP and IL-6. Further indications of metabolic changes in moderate COVID-19 disease were demonstrated in recovering ward patients compared to those at the start of hospitalization, where 99 lipid species were altered (6 increased by 30–62%; 93 decreased by 1.3–2.8-fold). Overall, these findings support and expand on early reports that dysregulated lipid metabolism is involved in COVID-19.

Funder

TKI-LSH project ‘METACOVID’

NWA project ‘Measuring and detection of health’

NWO

European Funds for Regional Development

Publisher

MDPI AG

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