Stimulating the Resolution of Inflammation Through Omega-3 Polyunsaturated Fatty Acids in COVID-19: Rationale for the COVID-Omega-F Trial

Abstract

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). SARS-CoV-2 triggers an immune response with local inflammation in the lung, which may extend to a systemic hyperinflammatory reaction. Excessive inflammation has been reported in severe cases with respiratory failure and cardiovascular complications. In addition to the release of cytokines, referred to as cytokine release syndrome or "cytokine storm," increased pro-inflammatory lipid mediators derived from the omega-6 polyunsaturated fatty acid (PUFA) arachidonic acid may cause an "eicosanoid storm," which contributes to the uncontrolled systemic inflammation. Specialized pro-resolving mediators, which are derived from omega-3 PUFA, limit inflammatory reactions by an active process called resolution of inflammation. Here, the rationale for omega-3 PUFA supplementation in COVID-19 patients is presented along with a brief overview of the study protocol for the trial "Resolving Inflammatory Storm in COVID-19 Patients by Omega-3 Polyunsaturated Fatty Acids - A single-blind, randomized, placebo-controlled feasibility study" (COVID-Omega-F). EudraCT: 2020-002293-28; clinicaltrials.gov: NCT04647604.

Keywords: COVID-19; clinical trial; eicosanoids; omega-3 fatty acids; resolution of inflammation.

FIGURE 1

The metabolism of the omega-6 (n-6) and omega-3 (n-3) polyunstaurated fatty acids (PUFA) arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The pathways depicted in red indicate proinflammatory mediators during the three stages of COVID-19 severity: early infection (stage 1), pulmonary phase (stage 2), and hyperinflammation phase (stage 3); adapted from Siddiqi and Mehra (2020). Intravenous administration of n-3 PUFA is anticipated to decrease n-6 PUFA and, in particular, AA-derived proinflammatory lipid mediators, and increase specialized pro-resolving mediators (including resolvins of the E- and D-series, protectins, and maresins), as well as the monohydroxy intermediates hydroxy-EPA (HEPE) and the cytochrome P450 epoxides epoxyeicosatrienoic (EET), epoxyeicosatetraenoic (EEQ), and epoxydocosapentaenoic (EDT) acids. Mediators potentially inducing the resolution of inflammation at the different stages of COVID-19 infection (green arrows), are depicted in green.

FIGURE 2

Schematic study protocol for the COVID-Omega-F trial, registered in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database with number 2020-002293-28 and at ClinicalTrials.gov (clinicaltrials.gov/ct2/show/NCT04647604). An intravenous omega-3 PUFA emulsion (n-3) is compared with placebo (NaCl) for effects on a panel of inflammatory biomarkers; white blood cells (WBC), C-reactive protein (CRP), cytokines and lipid mediators at the end of the treatment period. Secondary endpoints include changes in specialized proresolving mediators (SPMs), fatty acids, cardiac markers, lactate dehydrogenase (LD), D-dimer, fribronogen (Fg), and infectious load. National Early Warning Score 2 (NEWS2), length of hospital stay, intensive cae unit (ICU) need, and mortality will be monitored for a descriptive analysis. The inclusion criteria for COVID-Omega-F comprise female and male patients ≥18 years of age diagnosed with COVID-19 and presenting with a clinical status requiring hospitalization. Exclusion criteria are defined according to i.v. omega-3 PUFA emulsion contraindications, known hypersensitivity, participation in other clinical research study, pregnancy, and breastfeeding.