key: cord-1054932-g71h5nbi
authors: Mazidimoradi, Afrooz; Alemzadeh, Esmat; Alemzadeh, Effat; Salehiniya, Hamid
title: The effect of polyunsaturated fatty acids on the severity and mortality of COVID patients: A systematic review
date: 2022-03-28
journal: Life Sci
DOI: 10.1016/j.lfs.2022.120489
sha: a416539bf5df667b40598cd7d8b8299753352528
doc_id: 1054932
cord_uid: g71h5nbi

BACKGROUND: Covid-19 mortality is largely associated with a severe increase in inflammatory cytokines and polyunsaturated fatty acids (PUFAs) play an important role in modulating immune pathways and inflammatory responses; so this study was done to evaluate the effect of polyunsaturated fatty acids on the prognosis of Covid-19 disease. METHODS AND MATERIALS: A comprehensive search was conducted in PubMed, Scopus and Web of Science. For systematic identification, the search was performed based on the following keywords COVID-19, SARS-CoV-2, COVID, Coronavirus Disease 19, SARS COV- 2 Infection, SARS-CoV-2, COVID19, Coronavirus Disease, Fatty Acids, Omega-3, Omega-3 Fatty Acid, Omega-6, n 3 Fatty and Omega-9 in the mentioned databases, using OR, and AND. All searched articles were included in the study and retrieved, and End-Note X7 software was used to manage the studies. RESULTS: Findings on the relationship between omega-3 and omega-6 fatty acids and the risk of Covid-19 are various, but omega-3 supplements have been found to be 12 to 21% effective in reducing the risk of Covid-19. Most studies emphasized the increasing severity of the disease and the need for mechanical ventilation and hospitalization due to polyunsaturated fatty acid deficiency. It is also demonstrated that omega-3 fatty acid deficiency increased mortality in patients with Covid-19. However, there is also a warning that in critical cases, elevated levels of fatty acids in patients' lungs and a cytokine storm are the main reasons for mortality in Covid-19 patients. CONCLUSION: Polyunsaturated fatty acids can reduce the risk of covid-19 which could be considered as a preventative, inexpensive and safe method. However, the risk of taking high-dose omega-3 supplements before or during SARS-COV-2 infection needs to be investigated.

Covid-19 is an acute respiratory syndrome disease caused by SARS-COV-2, which was introduced as a pandemic in early 2020 and has been diagnosed in more than 230 million people worldwide by September 2021 (1, 2). The disease worsens with age (especially over 60 years), male sex, and underlying diseases and its mortality is largely associated with rapidly increasing inflammatory cytokines, including interleukin-6 (IL-6) (3). In SARS-CoV-2 infection, excessive and uncontrolled production of pro-inflammatory cytokines by innate immune cells, intensify secretion of other pro-inflammatory chemical agents such as vascular endothelial growth factor (VEGF), MCP-1, interleukin-8 (IL-8) while reduce the expression of E-cadherin in endothelial cells (4) . VEGF and decreased E-cadherin expression contribute to permeability and vascular leakage, leading to pulmonary dysfunction (ALI), acute respiratory syndrome (ARDS) and ultimately systemic inflammation and multiple organ failure in individuals infected with covid-19 (4) (5) (6) . Thus, cytokine storms are considered as a key factor in disease control, which can exacerbate COVID-19 and even cause mortality.

Accordingly, a prophylactic approach to prevent the covid-19 infection is to minimize the release of inflammatory cytokines (3) . Poly unsaturated fatty acids (PUFAs) are an integral component of cell membrane and play an important role in the structural integrity and fluidity of membrane phospholipids. In addition to PUFAs antioxidant function, they play an importanr role in modulating immune pathways and inflammatory responses which can be helpful in the treatment of viral diseases with a tendency to increase inflammatory cytokines (7) (8) (9) .

PUFAs include omega-3 PUFA and omega-6 PUFA which the former acids originate from natural sources and include alpha linoleic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (2, 3) and the latter one, mainly contain linoleic acid (LA) and arachidonic acid (AA) (10) .

Up to 25% of the fatty acids in the phospholipids of skeletal muscles, brain, liver, platelets, and immune cells can be attributed to AA (11) . The interaction of AA with molecular oxygen produces mediators known as eicosanoids, which include prostaglandins (PGs), thromboxanes (TXs), and leukotrienes (LTs) (12, 13) . In the presence of certain stimuli such as inflammatory stimuli, enough AA is released to cause significant increases in eicosanoid production. In this situation eicosanoids such as PGD2 and E2, as well as 4-series LTs, are produced in greater quantities and serve as mediators and regulators of the inflammatory response (12) .

Recent studies has revealed that omega-3 PUFAs are significant mediators of inflammation that can amplify anti-inflammatory responses, block hyper inflammatory reactions, reduce the incidence of systemic inflammatory response syndrome (SIRS), and complications of infection (14, 15) . One of the anti-inflammatory effects of EPA and DHA is reduced activation of the NF-κB pro-inflammatory transcription factor in response to inflammatory stimuli. This effect has been linked to EPA and DHA's membrane-mediated actions, which block the early phases of inflammatory signaling (16, 17) .

However, it appears that EPA and DHA can reduce inflammatory responses by acting directly on inflammatory cells via membrane receptors. For instance binding long-chain fatty acids, especially DHA to GPR120 receptor in macrophages reduce NF_κB activation and decrease the production of inflammatory cytokines. This mechanism of action suggests that EPA and DHA can have anti-inflammatory effects without having to be incorporated into cell membranes or affecting lipid mediator production (18) . Also, Omega-3 fatty acids are thought to give rise to mediators referred to as specialized pro-resolving mediators (SPMs).

SPMs including resolvins, protectins and maresins activate the resolution of inflammation in various diseases (9, (19) (20) (21) (22) . In addition, omga-3 fatty acids are involved in regulating the activation of immune cells, including macrophages, neutrophils, basophils, eosinophils, T and B cells. Studies have shown that omega-3 fatty acids are present in neutrophil cell membrane phospholipids, and by secreting cytokines and chemokines improve macrophage function and increase phagocytic ability, thereby enhancing immune function (23) . These findings show that omega-3 fatty acids might be effective as a pharmaconutrient in lowering the impact of inflammation produced by COVID-19 (24) .

Given the public health concerns the current covid-19 epidemic and its mortality, it is necessary to investigate modifiable risk factors for severe complications of inflammatory storm. One of the possible preventives and relatively cost-effective methods for high-risk patients can be the use of diets and supplements rich in unsaturated fatty acids, especially omega-3 PUFA. According to the contradictory results obtained from various studies, the present study has been reviewed the studies to find out the possible role of polyunsaturated fatty acids in the severity of Covid-19 disease.

Search Strategy J o u r n a l P r e -p r o o f For systematic identification, the search was performed based on the following keywords   COVID-19, SARS-CoV-2, COVID, Coronavirus Disease 19, SARS COV-2 Infection, SARS-CoV-2, COVID19, Coronavirus Disease, Fatty Acids, Omega-3, Omega-3 Fatty Acid, Omega-6, n 3 Fatty and Omega-9 in the mentioned databases, using OR, AND. The search was conducted in Aug 17th, 2021; all searched articles were included in the study and retrieved, and End-Note X7 software was used to manage the studies. Also, to increase the validity of the search, the list of references used in all final articles selected for meta-analysis was manually.

Inclusion criteria included the following: evaluation the effect of polyunsaturated fatty acids on mortality, severity, admission to ICU and hospital admission among COVID Patients, articles in English and all original research articles.

Exclusion criteria were as follows: articles written in languages other than English, case report articles, reviews and letters to the editor.

After completing the search and entering articles in Endnote software 7, duplicate articles were found by EndNote and removed, then all articles were evaluated by title and abstract, by reading the abstracts, articles related to the effect of polyunsaturated fatty acids on COVID-19 were entered in this review. PRISMA flow diagram was used for study selection ( Figure 1 ). comparison, and conclusion. Studies were scored based on overall scores and divided into 3 categories: good, fair, and poor.

The search result in the databases based on the intended keywords included 862 articles.

After removing duplicates, the articles (570) were screened based on the title and abstract information and 36 articles were assessed for eligibility. Afterward, a thorough review of the remaining articles was performed; then, 18 other articles were excluded due to publication in a language other than English [4 articles], a letter to the editor [3 articles], etc. Subsequently, the full text of the articles was reviewed and 3 articles were deleted due to lack of access to the full text or inconsistency with the objectives of the study. Finally, 18 articles were analyzed in this systematic review ( Figure. 1).

According to the goals of this study, included articles was divided in 4 groups; PUFAs and risk of Covid-19 (26) (27) (28) (29) (30) (31) , PUFAs and severity of Covid-19 (27, (32) (33) (34) (35) (36) (37) , PUFAs and Risk of Death Due to Covid-19 (3, 26, 29, 32, (38) (39) (40) and Covid-19 and receiving PUFAs (26, 41) . J o u r n a l P r e -p r o o f

In terms of PUFAs and the risk of Covid-19, Hamulka et al. examined the trend of omega-3 PUFA intake worldwide and Covid-19 incidence and found that the correlation coefficient between Covid-19 incidence and omega-3 PUFA intake in the world was 0.06 and in Poland was 0.21 (26) . the USA and Sweden respectively (30) . In Sweden, no relationship was found between omega-3 PUFA intake and positive covid-19 test in women (30) .

In a study, Thomas et al. found that the mean serum levels of omega-3, omega-6 and omega-9 fatty acids were significantly different in healthy individuals and Covid-19 patients (p <0.05) (31).

In terms of PUFAs and severity of Covid-19 disease, the mean omega-3 PUFA Index (consistent with insufficient fish and Omega-3 supplement consumption) was 4.15% ± 0.69% in patients with severe Covid-19 and markedly lower than the healthy control subjects (mean:

7.84%; range: 4.65-10.71%) (32) .

The results of a study in China showed that the levels of omega-3 fatty acids, including oleic acid (FA 18: 1) and omega-3 PUFA (FA 20: 0) in patients with asymptomatic Covid-19

decreased. Also, the ratio of omega-3 fatty acids in asymptomatic Covid-19 patients decreased by 35% compared to healthy individuals (33) .

A study conducted in Belgium found increased serum levels of PUFA with lower disease severity and increased serum levels of monounsaturated fatty acids (MUFA) were associated with higher disease severity (34) . This prospective study of a population showed that the median ratio of omega-6 fatty acids to total fatty acids as well as ratio of PUFA by MUFA fatty acids (P = 0.022) decreased in patients with severe Covid-19 and who dies compared to patients with lower severity of the disease (P = 0.002). It was also shown that the serum concentration of linoleic acid and omega-6 fatty acids was lower in patients with severe

Covid-19 (34) .

In terms of requirement to mechanical ventilation, Zapata et (35) .

The results of a study in France showed that the ratio of linoleic acid has a negative correlation with the number of days without ventilator (r = -0.404, p = 0.001) (27) .

In terms of necessity to be hospitalized, in a study by Archambault 

Regarding PUFAs and risk of death due to Covid-19, in a study in Chile, the risk of death for patients with low omega-3 PUFA (lowest O3I quartile <3.57%) was more than tripled (OR = 3% (n = 2); p= 0.003) (38) .

In Poland, a study of the trend of omega-3 PUFA consumption worldwide and death due to

Covid-19 has shown that the correlation coefficient between Covid-19 incidence and omega-3 PUFA consumption in the world is 0.06 and in Poland is 0.21 (26) . The results of an ecological study showed that omega-3 PUFA intake through food sources varies with the mortality rate in Covid-19 patients in different regions; so that the countries of the Eastern Mediterranean region which have the lowest omega-3 PUFA intake from marine sources (45.14 mg/day) have the highest mortality in patients with Covid-19 (3.52%). While in Southeast Asian countries with the highest omega-3 PUFA intake (634.00 mg/day), the mortality in Covid-19 patients (1.01%) was the lowest in the world. Also, a positive correlation was observed between receiving omega-3 PUFA from plants and mortality rate (r = 165) (p> 0.05) (29) .

In a study that evaluated the relationship between mortality from Covid-19 and the consumption of unsaturated fatty acids (UFA% intake) in 61 countries with more than 1,000 deaths from Covid-19, positive correlation was observed between the intake of unsaturated fatty acids and mortality in patients with Covid-19 (40) .

Regarding Covid-19 and receiving PUFAs, considering food intake and supplementation are important.

The results of a study in Slovenia showed that the mean of fatty acids intake ratio 

In a study conducted in Poland, omega-3 PUFA supplements were found to increase from 2.8% in the pre-Covid-19 period to 8.2% in the epidemic period (26) .

The covid-19 pandemic has had devastating effects on mortality worldwide (43) . Although (49) (50) (51) (52) . Given that COVID-19 is a viral infection that causes considerable inflammation, PUFA supplementation may be beneficial (9, (53) (54) (55) .

The results of studies on the relationship between omega-3 fatty acids and disease severity in

China showed that the proportion of omega-3 fatty acids in asymptomatic Covid-19 patients was 35% lower than in healthy individuals. A study in Belgium showed that in different parts of the country, increased serum levels of multiple PUFA related with lower disease severity J o u r n a l P r e -p r o o f and increased serum levels of monounsaturated fatty acids (MUFA) were related with higher disease severity (34) . Also, in this prospective study of a population showed that the median ratio of omega-6 fatty acids to total fatty acids decreased in patients with severe Covid-19

and patients who died compared to patients with less severity (P = 0.002) (34) .

In addition, evidence has shown that omega polyunsaturated fatty acid deficiency increases the likelihood of hospitalization rate and ICU admission. Furthermore, the results of a study in the UK showed that a lack of omega-3 PUFA and omega-6 PUFA biomarkers increased the risk of hospitalization by 2.9 times (36, 37, 42) . Also, in a study conducted in Italy, it was observed that the average amount of arachidonic acid in patients admitted to the ICU was higher than patients admitted to other wards and healthy patients (37) .

Numerous studies have also shown an increase in mortality with a decrease in omega polyunsaturated fatty acids (3, 26, 29, 32, (38) (39) (40) . As an illustration, Zapata et al. showed that the mortality rate of patients with covid-19 increased to 3 times in patients with low omega-3

PUFA levels (32) .

The synthesis of polyunsaturated fatty acids (PUFAs) and their metabolites (termed as bioactive lipid mediators) is one of the underappreciated mechanisms by which the human 

Kawasaki Disease-Like Features in 10 Pediatric COVID-19 Cases: A Retrospective Study

Role of OMEGA-3 Fatty Acid Supplementation in COVID-19 Patients: A Narrative Review

Blood omega-3 fatty acids and death from COVID-19: A pilot study

Cytokine release syndrome in severe COVID-19

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Cytokines in Inflammatory Disease

StatPearls. Treasure Island (FL): StatPearls Publishing Copyright © 2021

The antiinflammatory and antioxidant properties of n-3 PUFAs: Their role in cardiovascular protection

Beneficial outcomes of omega-6 and omega-3 polyunsaturated fatty acids on human health: An update for 2021

Omega-3 and omega-6 polyunsaturated fatty acids: Dietary sources, metabolism, and significance -A review

Dietary arachidonic acid: harmful, harmless or helpful?

Oxidation of polyunsaturated fatty acids to produce lipid mediators

Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques

Effect of ω-3 polyunsaturated fatty acid-supplemented parenteral nutrition on inflammatory and immune function in postoperative patients with gastrointestinal malignancy: A meta-analysis of randomized control trials in China

Saturated and polyunsaturated fatty acids reciprocally modulate dendritic cell functions mediated through TLR4

Fatty acids modulate Tolllike receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts in a reactive oxygen species-dependent manner

GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects

The resolution code of acute inflammation: Novel proresolving lipid mediators in resolution

Proresolving mediators produced from EPA and DHA: Overview of the pathways involved and their mechanisms in metabolic syndrome and related liver diseases

Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators

Discovery of specialized pro-resolving mediators marks the dawn of resolution physiology and pharmacology. Molecular aspects of medicine

Effects of Omega-3 Fatty Acids on Immune Cells

The Role of an Anti-Inflammatory Diet in Conjunction to COVID-19

The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses 2021

Dietary Supplements during COVID-19 Outbreak. Results of Google Trends Analysis Supported by PLifeCOVID-19 Online Studies

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

Alteration in the Lipid Profile and the Desaturases Activity in Patients With Severe Pneumonia by SARS-CoV-2

Silico Study of Polyunsaturated Fatty Acids as Potential SARS-CoV

Spike Protein Closed Conformation Stabilizers: Epidemiological and Computational Approaches

Modest effects of dietary supplements during the COVID-19 pandemic: Insights from 445 850 users of the COVID-19

Symptom Study app

COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status

Index and Clinical Outcomes of Severe COVID-19: Preliminary Results of a Cross-Sectional Study

Distinct Lipid Metabolic Dysregulation in Asymptomatic

The metabolic fingerprint of COVID-19 severity

High levels of eicosanoids and docosanoids in the lungs of intubated COVID-19 patients-CAN NOT EXTRACTED DATA

DrugWAS: Leveraging drug-wide association studies to facilitate drug repurposing for COVID-19

Large-Scale Plasma Analysis Revealed New Mechanisms and Molecules Associated with the Host Response to SARS-CoV-2

The effect of omega-3 fatty acid supplementation on clinical and biochemical parameters of critically ill patients with COVID-19: a randomized clinical trial

Survival Factors and Metabolic Pathogenesis in Elderly Patients (>= 65) With COVID-19: A Multi-Center Study

Mortality From Coronavirus Disease 2019 Increases With Unsaturated Fat and May Be Reduced by Early Calcium and Albumin Supplementation

The Impact of COVID-19-Related Lockdown on Diet and Serum Markers in Healthy Adults

Metabolic biomarker profiling for identification of susceptibility to severe pneumonia and COVID-19 in the general population

Quantifying impacts of the COVID-19 pandemic through life-expectancy losses: a population-level study of 29 countries

Strengthening the immune system and reducing inflammation and oxidative stress through diet and nutrition: considerations during the COVID-19 crisis

May omega-3 fatty acid dietary supplementation help reduce severe complications in Covid-19 patients?

Omega-3 polyunsaturated fatty acids and their health benefits. Annual review of food science and technology

Therapeutic potential of ω-3 polyunsaturated fatty acids in human autoimmune diseases

Polyunsaturated fatty acids and their derivatives: therapeutic value for inflammatory, functional gastrointestinal disorders, and colorectal cancer

EPA and DHA differentially modulate monocyte inflammatory response in subjects with chronic inflammation in part via plasma specialized pro-resolving lipid mediators: A randomized, double-blind, crossover study

Red blood cell fatty acids and biomarkers of inflammation: a cross-sectional study in a community-based cohort

Supplementation with eicosapentaenoic acid and docosahexaenoic acid reduces high levels of circulating proinflammatory cytokines in aging adults: A randomized, controlled study. Prostaglandins, leukotrienes, and essential fatty acids

Eicosapentaenoic acid and docosahexaenoic acid containing supplements modulate risk factors for cardiovascular disease: a meta-analysis of randomised placebo-control human clinical trials

Role of specialized pro-resolving lipid mediators and their receptors in virus infection: a promising therapeutic strategy for SARS-CoV-2 cytokine storm

The effect of omega-3 fatty acid supplementation on clinical and biochemical parameters of critically ill patients with COVID-19: a randomized clinical trial

Omega 3 fatty acids and COVID-19: a comprehensive review

Bioactive lipids-based therapeutic approach to COVID-19 and other similar infections. Archives of Medical Science

Pro resolving inflammatory effects of the lipid mediators of omega 3 fatty acids and its implication in SARS COVID-19

Resolution phase lipid mediators of inflammation: agonists of resolution. Current opinion in pharmacology

Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms

Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways

Assessment of Polyunsaturated Fatty Acids on COVID-19-Associated Risk Reduction

DHA-and EPA-derived resolvins, protectins, and maresins in airway inflammation

Resolvins D1, D2, and other mediators of selflimited resolution of inflammation in human blood following n-3 fatty acid supplementation

Can N-3 polyunsaturated fatty acids be considered a potential adjuvant therapy for COVID-19-associated cardiovascular complications?

Novel functional sets of lipidderived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing

Resolvin D3 and aspirin-triggered resolvin D3 are potent immunoresolvents

Resolvin D4 stereoassignment and its novel actions in host protection and bacterial clearance

Pro-resolving lipid mediators are leads for resolution physiology

Apoptotic neutrophils and T cells sequester chemokines during immune response resolution through modulation of CCR5 expression

Resolvin E1 and protectin D1 activate inflammation-resolution programmes

Resolvin D1 and D2 reduce SARS-Cov-2-induced inflammation in cystic fibrosis macrophages

Stimulating the resolution of inflammation through omega-3 polyunsaturated fatty acids in COVID-19: rationale for the COVID-Omega-F Trial

Specialized proresolving lipid mediators in patients with coronary artery disease and their potential for clot remodeling

Parenteral nutrition with fish oil modulates cytokine response in patients with sepsis. American journal of respiratory and critical care medicine

Omega-3 polyunsaturated fatty acids in critically ill patients with acute respiratory distress syndrome: A systematic review and metaanalysis

Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions

The role of pro-resolution lipid mediators in infectious disease

Arachidonic acid and other unsaturated fatty acids and some of their metabolites function as endogenous antimicrobial molecules: A review

Can bioactive lipids augment anti-cancer action of immunotherapy and prevent cytokine storm? Archives of Medical Research

Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses

Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2

COVID-19, ACE2, and the cardiovascular consequences

Polyunsaturated ω-3 fatty acids inhibit ACE2-controlled SARS-CoV-2 binding and cellular entry

The lysosome: A potential juncture between SARS-CoV-2 infectivity and Niemann-Pick disease type C, with therapeutic implications

Afrooz Mazidimoradi: Conceptualization, Methodology, data extraction

Esmat Alemzadeh : Data extraction, Writing-Original draft preparation

Effat Alemzadeh: Visualization, Investigation, Data extraction, Writing-Original draft preparation

Hamid Salehiniya : Conceptualization, searching, Validation, Writing-Reviewing and Editing