Fatty Acyl Lipidomic Changes Converge Towards Increased Inflammation with Severity of COVID-19

Background: COVID19 is a heterogeneous disease;while some patients experience mild or asymptomatic disease, others develop respiratory failure and death. Although there is increased understanding of clinical factors associated with severe disease, studies investigating biomarkers to predict severity and uncover treatment targets are still needed. Polyunsaturated fatty acid-derived lipid mediators (PUFA-LM) can promote inflammation or resolution of inflammation. Previous research showed differences in PUFA-LM expression in septic patients that developed ARDS. Here we evaluate the plasma PUFA-LM profile at admission in 20 patients with COVID-19 and correlate our findings with disease severity. Methods: Blood was collected at admission from 41 patients with COVID-19 at Virginia Commonwealth University between April and July, 2020. Platelet poor plasma from 20 patients were selected;10 with nonsevere COVID19 (NSC) defined by <4L O2 need and 10 severe COVID-19 subjects (SC) defined as requiring admission to the intensive care unit, for PUFA-LM analysis by liquid chromatography mass spectrometry. Patients with active malignancy were excluded. Results: Demographic data and comorbidities are similar between the two groups. Both cohorts were predominately African American (80%) and male (60%). The SC cohort exhibited higher levels of lipoxygenase metabolites, hydroxyeicosatetraenoic acids (HETEs), hydroxyeicosapentaenoic acids (HEPEs) and hydroxydocosahexaenoic acids (HDoHEs), which serve as intermediates in the synthesis of both pro-inflammatory and pro-resolving mediators. Epoxygenase metabolites were also higher in the SC cohort and were mostly diols indicating elevated epoxide hydrolase activity. Conversely PGE1 and 15-OxoETE were elevated in the NSC cohort compared to SC. Discussion: In this predominantly African-American patient cohort, admission PUFA-LM profiles differed in subjects who developed mild vs. severe COVID19. Higher levels of lipoxygenase activity in the SC cohort is of unclear significance since this pathway promotes synthesis of both pro-inflammatory and pro-resolving mediators. Given sample collection early in the disease course it may signify incomplete synthesis of resolution mediators or increased inflammation. The higher levels of diols from epoxides are intriguing. PUFA epoxides are anti-inflammatory and prevent prostaglandins from eliciting an inflammatory response. Hence, higher levels of epoxide hydrolysis in SC cohort suggests an exacerbation of inflammation by prostaglandins. Higher levels of PGE1 (a known pulmonary vasodilator) and 15-OxoETE (an anti-inflammatory mediator which inhibits NFκB activation) in the NSC group may contribute to a dampening of inflammatory response in NSC cohort. Overall, this data suggests a complex interplay of dysfunctional homeostatic and inflammatory mechanisms early in disease which may contribute to development of severe COVID-19.