1. Introduction

COVID-19, the illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been diagnosed in over 80 million people worldwide as of the end of 2020, and over 1.8 million have died [1]. Although 81% of symptomatic individuals have relatively mild disease, 14% will develop severe disease characterized by dyspnea, hypoxia, or >50 percent lung involvement by imaging, with the remaining 5% developing critical disease characterized by respiratory failure, shock, and/or multiorgan dysfunction [2]. Severe and critical disease from COVID-19 is associated with advancing age (especially over 65 years), male gender, chronic lung disease, obesity, cardiovascular disease including hypertension, diabetes, and other chronic medical conditions.

Severe COVID-19 disease and death is, in part, mediated by rapid elevations of inflammatory cytokines including TNF-alpha, IL-1β, and IL-6 leading to a cytokine release syndrome or “cytokine storm.” [3] Accordingly, an attractive preventative approach to COVID-19 infection is to minimize cytokine release. Very long-chain omega-3 s (DHA and EPA) found in fish oils have a plethora of biological activities including directly and indirectly modulating inflammatory responses and cytokine release [4], [5], [6]. In non-COVID-19 ettings, higher intakes [7], [8] and blood levels [9], [10] of these omega-3 s are associated with lower levels of circulating inflammatory cytokines, and intervention with fish oils reduces levels [11], [12]. EPA and DHA are precursors to a suite of inflammation-resolving mediators (IRMs; resolvins, maresins and protectins [13]) that actively regulate the resolution of acute inflammation. IRMs down-regulate cytokine production and promote a return to homeostasis via monocyte/macrophage-mediated uptake of debris, apoptosis of neutrophils, and clearing of microbes. Accordingly, higher intakes of EPA and DHA (which result in higher RBC EPA+DHA levels, hereafter called the Omega-3 Index, O3I [14], [15]) have been proposed to lower the risk for adverse outcomes from COVID-19 [16], [17], [18], [19], [20], [21], [22], and case reports suggesting benefit have been published [23], [24].

Given the profound public health concerns related to the current COVID-19 pandemic, modifiable risk factors for developing severe and critical complications are urgently needed, especially ones that may be easily implemented and nutritionally based. Despite the known mechanisms by which IRMs and omega-3 fatty acids support the active, endogenous resolution of inflammatory mechanisms, to our knowledge no study has explored the relationship between omega-3 tissue levels and COVID-19 outcomes. The primary objective of this pilot study was to define the relationship between O3I and death from COVID-19. We hypothesize that a higher O3I is associated with lower risk for death in these patients.

2. Methods

3. Results

4. Discussion

The 2020 COVID-19 pandemic has had devasting effects on morbidity and mortality worldwide. While vaccines may soon slow the spread and drugs may help diminish the adverse effects of infection, preventative measures – ideally ones that are cheap, safe, and readily accessed by large numbers of people – that modulate the most severe disease outcomes are desperately needed. Some evidence is accumulating for a potential benefit of vitamin D [27], and here we examined another nutrient, omega-3 fatty acids, which like vitamin D, have multiple anti-inflammatory effects and may also reduce risk for adverse COVID-19 outcomes.

In this pilot study we compared the associations between the O3I and risk for death from COVID-19 in 100 patients. We found (in age and sex-adjusted models) that those patients with an O3I at 5.7% or greater were at about 75% lower risk for death compared with those below that value (p = 0.071). Although not meeting the criteria for classical statistical significance, this strong trend suggests that a relationship may indeed exist, but more well-powered studies are clearly needed.

The OR for death was higher in Q3 than in the other quartiles including Q4. Part of the reason for this was the mean age (and the percent of patients with DNR orders) was the highest in Q3. Accordingly, in the age-adjusted model the OR in Q3 dropped by a third. The comparison of Q4 to Q1–3 has historical precents. For example, in the Framingham Heart Study, significantly larger brain volumes and better cognitive function were observed in Q4 vs Q1–3 [28], and 10-year risk for dementia was 47% lower in subjects with omega-3 levels in Q4 vs Q1-Q3 [29]. More generally, higher omega-3 FA blood levels have been associated with the better clinical outcomes for cardiovascular disease [30,31], post-MI cardiac remodeling [32], telomere attrition [33], attempted suicide [34] and total mortality [35]. These data suggest that in some settings there may be threshold effects of the O3I.

This study used the O3I as a biomarker of omega-3 FA status. This RBC-based metric has advantages, particularly in the acute hospitalization setting. This is because, much like a hemoglobin A1C versus plasma glucose, the O3I is a better long-term reflection of tissue omega-3 levels versus plasma omega-3 levels [36], and it would thus be less affected by an acute change in omega-3 intake, as might happen with hospitalization for an acute illness [37]. The O3I has been validated [25] and used in several interventional [14] and prospective cohort studies such as the Framingham Heart Study [31] and the Women's Health Initiative Memory Study [38]. The O3I is also easily modified by increasing the intake of oily fish (e.g., salmon, herring, mackerel, albacore tuna, etc.) which are rich in EPA and DHA, and dietary supplements of omega-3 will also raise levels [15]. The average O3I in this study was 5.1% which is similar to that seen other US-based studies [39], [40]. We also examined the associations between risk for death and EPA and DHA individually and with the omega-6:omega-3 ratio. We found the same directional relationships as with the O3I but they were not as statistically strong (data not shown).

Multiple randomized clinical trials (RCTs) are currently (as of January 2021) underway testing the hypothesis that treatment with omega-3 fatty acids (EPA and DHA) will have beneficial effects on a variety of aspects of COVID-19 infection. Although their outcomes are not yet known, there are compelling scientific reasons to expect that these studies will be positive (and these same reasons formed the foundation for the present study). The data supporting a possible beneficial role for omega-3 fatty acids in COVID-19 infection come from past epidemiological, interventional, therapeutic, and basic science studies. For example, in the Framingham Offspring study [41], the O3I was inversely associated with 10 separate inflammatory biomarkers (e.g., CRP, IL-6, ICAM-1, LpPLA2, TNF receptor 2, and osteoprotegerin). In intervention studies [11], EPA supplementation alone (3 g/d for 10 weeks) significantly reduced the expression of TNFα from LPS-stimulated monocytes as did a similar dose of DHA which, in addition, lowered IL-6 and MCP-1. EPA+DHA supplements had similar effects [42]. Meta-analyses of multiple RCTs confirmed that treatment with omega-3 fatty acids routinely lowers cytokine levels [43], [44], [45]. More important than studies of effects on intermediate markers are clinical findings from RCTs. Langlois et al. [5] summarized the results of 12 RCTs of omega-3 treatment in 1280 intensive-care-unit patients with acute respiratory distress syndrome. There was a significant improvement in measures of blood oxygenation in the treated patients and strong trends (p ≤ 0.08) for reduced ICU length of stay and duration of mechanical ventilation. Overall mortality, hospital length of stay and infectious complications were unaffected.

As noted earlier, the potential mechanisms underlying these actions are multiple. EPA/DHA are substrates for the production of IRMs which cannot be made if the parent compounds are not present. Examples of some of the functions of IRMs were summarized by Calder as, “Resolvin E1, resolvin D1 and protectin D1 all inhibit trans-endothelial migration of neutrophils, so preventing the infiltration of neutrophils into sites of inflammation; resolvin D1 inhibits IL-1β production and protectin D1 inhibits TNF-α and IL-1β production.” [46] Higher EPA/DHA levels reduce arachidonic acid (the omega-6 cousin of EPA) membrane levels [47] for the production of some pro-inflammatory oxylipins (certain prostaglandins and leukotrienes). Quite independently of the synthesis of these mediators, the presence of EPA/DHA in inflammatory cells blocks the activation of the key pro-inflammatory transcription factor, nuclear factor kappa B thus retarding the entire intracellular inflammatory cascade [48,49]. This effect is downstream from the action of these fatty acids on membrane G-protein coupled receptors GPR40 and GPR120 and nuclear peroxisome proliferator-activated receptors (reviewed in [50]). Finally, EPA/DHA insert into cell membrane phospholipids and disrupts lipid rafts so as to disassemble surface receptors thereby blocking incoming inflammatory signals [51]. All of these actions together result in a muted “cytokine storm” which, in alveolar macrophages and elsewhere, can result in death from COVID-19 [3].

Author disclosure statements

WSH holds an interest in OmegaQuant Analytics, LLC; and is a member of the Schiff Science and Innovation Advisory Board. The other authors have no conflicts of interest to disclose.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Funding statement

This study was supported in part by Cedars-Sinai Medical Center (through the Cancer Clinical Trials Office), by the Fatty Acid Research Institute (for biostatistical support), and by a donation from Michael Myers (for blood analysis).

CRediT authorship contribution statement

Arash Asher: Conceptualization, Investigation, Methodology, Project administration, Supervision, Writing - original draft. Nathan L. Tintle: Formal analysis, Writing - review & editing. Michael Myers: Conceptualization, Resources, Methodology, Writing - review & editing. Laura Lockshon: Project administration, Writing - review & editing. Heribert Bacareza: Project administration, Writing - review & editing. William S. Harris: Conceptualization, Methodology, Resources, Writing - original draft.