Plasma oxylipin levels may predict Covid-19 patient outcomes. An observational and retrospective study
Authors: Biagini Denise , Franzini Maria , Oliveri Paolo , Lomonaco Tommaso , Ghimenti Silvia , Bonini Andrea , Vivaldi Federico , Macera Lisa , Balas Laurence , Durand Thierry , Oger Camille , Galano Jean-Marie , Maggi Fabrizio , Celi Alessandro , Paolicchi Aldo , Di Francesco Fabio 
Published: July 2021

Background

The key role of inflammation in the progression of COVID-19 was evident right from the beginning of the pandemic. Consequently, many authors studied the onset and evolution of the cytokine storm. In contrast, other inflammatory mediators such as oxylipins have received almost no attention.

Methods

We conducted a monocentric observational and retrospective study (IMPRE-COVID-19) with patients (aged ≥ 18 years) admitted to Pisa University Hospital with COVID-19 related pneumonia. SARS-CoV-2 infection was confirmed by polymerase chain reaction in a nasopharyngeal swab, while pneumonia was demonstrated by CT scan. Oxylipin plasma levels were analysed in a convenient sample of 52 patients randomly selected from those that had a complete set of cytokine values evaluated for clinical purposes. In 12 cases, plasma samples collected on different days were available at the BMS Multispecialistic Biobank of Pisa University Hospital and were analysed to understand the evolution of the oxylipin levels during hospitalization. The two datasets that included oxylipin and cytokine values were analysed by principal component analysis (PCA), computation of Fisher’s canonical variable, and a multivariate receiver operating characteristic (ROC) curve.

Findings

Between March and April 2020, 52 patients were enrolled of which 28 were hospitalised in COVID-19 wards, 20 in ICUs, and 4 who were initially hospitalised in the wards and who were then transferred to the ICUs due to deteriorating health conditions. Plasma samples collected on different days were available from 7 patients in the wards, 1 from an ICU, and 4 from patients who were hospitalised in both. The mean age of participants was 61 years (SD 16), 11 were females (21%), and 41 were males (79%), without significant differences between groups in terms of age and gender. PCA of oxylipin data led to a clear differentiation of samples collected in COVID-19 wards and ICUs. This differentiation had not been obtained with cytokine data. In addition, borderline samples were from patients hospitalised in COVID-19 wards that were about to be transferred to the ICUs, thus suggesting that differentiation is not a consequence of a different treatment, but somehow related to a diverse evolution of the pathology. Computation of Fisher’s canonical variable identified the original input variables that were the most effective in discriminating between the two classes. The combination of the two datasets did not improve the discrimination, thus suggesting that oxylipins are more informative than cytokines for this purpose. A multivariate class model built using the four lowest-order principal components as the input variables, and COVID-19 ward samples as the target class, produced a ROC curve with a resulting area under the curve (AUC) equal to 0·92 – which is much higher than most AUC outcomes obtained for individual oxylipins.

Interpretation

After analysing the metabolic pathways of the most informative oxylipins, we speculate that more severe COVID-19 is associated with a selective deficiency of pro-resolving oxylipins leading to ineffective resolutive mechanisms of inflammation, likely worsened by endothelial damage. We believe that our oxylipin data suggest the possibility to predict the evolution of COVID-19 in individual patients at an early stage.

Funding

Institutional funds from the University of Pisa supported the study.