High plasma concentration of non-esterified polyunsaturated fatty acids is a specific feature of severe COVID-19 pneumonia

Maxime Nguyen, Abderrahmane Bourredjem, Lionel Piroth, Bélaïd Bouhemad, Antoine Jalil, Gaetan Pallot, Naig Le Guern, Charles Thomas, Thomas Pilot, Victoria Bergas, Hélène Choubley, Jean-Pierre Quenot, Pierre-Emmanuel Charles, Laurent Lagrost, Valerie Deckert, Jean-Paul Pais de Barros, Pierre-Grégoire Guinot, David Masson, Christine Binquet, Thomas Gautier, Mathieu Blot, Lymphonie study group, Pascal Andreu, François Aptel, Jeremy Barben, Guillaume Beltramo, Philip Bielefeld, Philippe Bonniaud, Bernard Bonnotte, Jean-Baptiste Bour, Marielle Buisson, Pascal Chavanet, Auguste Dargent, Marjolaine Georges, Alexandre Guilhem, Julien Guy, Marie Labruyère, Serge Monier, Suzanne Mouries-Martin, Sébastien Prin, Alain Putot, Maxime Nguyen, Abderrahmane Bourredjem, Lionel Piroth, Bélaïd Bouhemad, Antoine Jalil, Gaetan Pallot, Naig Le Guern, Charles Thomas, Thomas Pilot, Victoria Bergas, Hélène Choubley, Jean-Pierre Quenot, Pierre-Emmanuel Charles, Laurent Lagrost, Valerie Deckert, Jean-Paul Pais de Barros, Pierre-Grégoire Guinot, David Masson, Christine Binquet, Thomas Gautier, Mathieu Blot, Lymphonie study group, Pascal Andreu, François Aptel, Jeremy Barben, Guillaume Beltramo, Philip Bielefeld, Philippe Bonniaud, Bernard Bonnotte, Jean-Baptiste Bour, Marielle Buisson, Pascal Chavanet, Auguste Dargent, Marjolaine Georges, Alexandre Guilhem, Julien Guy, Marie Labruyère, Serge Monier, Suzanne Mouries-Martin, Sébastien Prin, Alain Putot

Abstract

COVID-19 pneumonia has specific features and outcomes that suggests a unique immunopathogenesis. Severe forms of COVID-19 appear to be more frequent in obese patients, but an association with metabolic disorders is not established. Here, we focused on lipoprotein metabolism in patients hospitalized for severe pneumonia, depending on COVID-19 status. Thirty-four non-COVID-19 and 27 COVID-19 patients with severe pneumonia were enrolled. Most of them required intensive care. Plasma lipid levels, lipoprotein metabolism, and clinical and biological (including plasma cytokines) features were assessed. Despite similar initial metabolic comorbidities and respiratory severity, COVID-19 patients displayed a lower acute phase response but higher plasmatic concentrations of non-esterified fatty acids (NEFAs). NEFA profiling was characterised by higher level of polyunsaturated NEFAs (mainly linoleic and arachidonic acids) in COVID-19 patients. Multivariable analysis showed that among severe pneumonia, COVID-19-associated pneumonia was associated with higher NEFAs, lower apolipoprotein E and lower high-density lipoprotein cholesterol concentrations, independently of body mass index, sequential organ failure (SOFA) score, and C-reactive protein levels. NEFAs and PUFAs concentrations were negatively correlated with the number of ventilator-free days. Among hospitalized patients with severe pneumonia, COVID-19 is independently associated with higher NEFAs (mainly linoleic and arachidonic acids) and lower apolipoprotein E and HDL concentrations. These features might act as mediators in COVID-19 pathogenesis and emerge as new therapeutic targets. Further investigations are required to define the role of NEFAs in the pathogenesis and the dysregulated immune response associated with COVID-19.Trial registration: NCT04435223.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Boxplot representing selected lipid parameters depending on the COVID-19 status. Plasma concentration and lipoprotein diameter were measured in 34 non-COVID-19 and 27 COVID-19 patients with severe pneumonia. COVID-19 patients had significantly higher plasma concentrations of apolipoprotein B and NEFA and lower concentrations of Apolipoprotein E and phospholipid transfer protein. High density lipoprotein diameter was higher in COVID patients. HDL: High density lipoprotein; LDL: low density lipoprotein; PLTP: phospholipid transfer protein.
Figure 2
Figure 2
Factorial map for the primary component analysis. Patients are located according to their representation on each axis. Factor 1 appears to separate bacterial and viral pneumonia whereas factor 2 appears to separate COVID-19 and non-COVID pneumonia.
Figure 3
Figure 3
Heatmap of non-esterified fatty acid (NEFA) representation (as percentage normalized to the mean percentage in non-COVID-19 patients) according to COVID-19 status. Plasma concentration of NEFAs was measured in 34 non-COVID-19 and 27 COVID-19 patients with severe pneumonia. Rows represent patients. Colours represent the ratio between the percentage of NEFAs in the patient and the mean percentage of NEFAs in non-COVID-19 patients. In COVID-19 patients, linoleic acid appeared in red, reflecting a higher representation. *significant between-group differences (p < 0.05).
Figure 4
Figure 4
Correlations between NEFAs, PUFAs proportion, inflammation, and outcomes. Heatmap of the Spearman correlation (r) between lipids parameters, clinical severity and outcome, plasma cytokine concentrations. Spearman correlations:p < 0.05, *p < 0.01, **p < 0.001, ***between each variable. CRP: C-reactive protein; GMCSF: granulocyte–macrophage colony-stimulating factor; HDL: High density lipoprotein; IL: interleukin; SOFA: sequential organ failure assessment; TNF-α: tumor-necrosis factor alpha.

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