Copyright Claims: This review is an intellectual property of the authors and of the Institute of Clinical Epidemiology, National Institutes of Health-UP Manila and Asia-Pacific Center for Evidence Based Healthcare Inc.

INTRODUCTION

With the COVID-19 pandemic, the role of nutritional supplements, including fatty acids, are being explored for possible prevention of SARS-CoV-2 infection in vulnerable individuals at high risk of exposure or as adjunct therapy for those with the infection. Hyperinflammation leading to cytokine storm and multiorgan failure is an important cause of disease progression in critically ill patients with COVID-19.1

A recent narrative review on bioactive lipids recommended supplementation with micronutrients and omega-3 fatty acids as a safe, effective, and low-cost strategy to support optimal immune function and reduce infection in light of COVID-19.2 Eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) are two types of omega-3 fatty acids. The review noted that the US Food and Agri- culture Organization, World Health Organization, European Food Safety Authority (EFSA) and Chinese Nutrition Society, recommend the intake of 250 mg EPA + DHA per day in normal adults.3–5

Omega-3 or n-3 polyunsaturated fatty acids (PUFAs), found in fish oil and flaxseed oil, are a popular food supplement and has recently been found to be beneficial in rheumatoid arthritis, atherosclerosis, and hypertriglyceridemia.6

Long-chain PUFAs mediate inflammation and adaptive immune responses.7 Omega-3 fatty acids promote anti‐ inflammatory effects and reduce influenza virus replication.8 Adiponectin, a cytokine produced in adipose tissue, has an anti-inflammatory effect in lung tissue and helps maintain vascular integrity in chronic lung diseases such as chronic obstructive pulmonary disease.9 Between the two omega-3 fatty acids, DHA applied to mouse adipocytes led to higher adiponectin secretion compared to EPA.10 In addition, EPA and DHA have been shown to be converted to specialized pro- resolving mediators (SPMs) known as resolvins, protectins, and maresins, which mediate resolution of inflammation and healing of injured lung tissue.11 In vitro studies on lung epithelial cells infected with influenza A virus stain A/Puerto Rico/8/34 (H1N1) (PR8 virus) showed decreased viral titers after incubation with PUFA-derived metabolites such as PD1,17-HDoHE, 12-HETE, and 15-HETE.8

However, the omega-3-fatty acid arm of a pre-COVID, large multicenter randomized controlled trial (EDEN study) in mechanically ventilated patients with acute lung injury was terminated in 2011 due to futility. The authors concluded that twice-daily enteral supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants did not improve the primary end point of ventilator-free days or other clinical outcomes compared to isocaloric control and resulted in significantly more days with diarrhea.12

Omega-3-fatty acids usually produce only mild side effects, such as heartburn, nausea and diarrhea. It may cause allergy in those allergic to fish or shellfish and may affect blood clotting if taking other medicines that affect clotting. It is uncertain on whether omega-3s may increase the risk of prostate cancer.13

OBJECTIVE

Tis rapid review summarizes the available evidence on the efficacy of fatty acid supplementation in the prevention of SARS-COV-2 infection and/or treatment of patients with COVID-19.

METHODS

As of May 15, 2020, we searched two electronic databases (MEDLINE, CENTRAL) and two trial registries. (ClinicalTrials.gov; Chinese Clinical Trial Registry) using the following key words: Fatty acids OR Omega‐3 fatty acids OR n‐3 fatty acids OR Long?chain polyunsaturated fatty acids OR Linoleic acid OR Linolenic acid OR Lauric acid OR Palmitic acid OR Choline OR unsaturated fatty acids OR Arachidonic acid OR Eicosapentaenoic OR

Docosahexaenoic acid. We also searched grey literature (medRXIV; BioRXIV).

Specific details about the literature search is given in Appendix 1.

Articles were selected based on the following inclusion criteria:

•Population: COVID-19 patients of any age, with any comorbidities, any severity

•Intervention: any oral fatty acid supplements, any dose, any duration; used as prevention or as adjunctive therapy to active drug or standard care

•Comparator: placebo, any active control, no intervention

•Outcomes: any clinical outcome

•Study designs: randomized controlled trials (RCTs), non-randomized studies, observational studies (e.g. cohort, case-control, cross-sectional, case report, case series)

RESULTS

As of May 15, 2020, we found no studies on the use of oral fatty acid supplements as prevention and adjunctive therapy for COVID-19.

We found indirect evidence in one systematic review on acute respiratory distress syndrome (ARDS),14 and two longitudinal cohort studies that studied the risk of community-acquired pneumonia among men15 and women.16 The systematic review (7 RCTs, N=955 patients with ARDS) showed that enteral supplementation of omega-3 FA did not significantly reduce all-cause 28-day mortality (RR 0.90; 95 % CI 0.68–1.18; p = 0.44), VFD (WMD,

2.47days; 95 % CI, -2.85 to 7.79; p = 0.36) or ICU-free days (WMD, 2.31 days; 95 % CI, -2.34 to 6.97; p = 0.33), compared to a control or placebo group. The authors concluded that routine use of enteral omega-3 FA cannot be recommended based on the available evidence.14

The 1st longitudinal cohort study (N=51,529 male US health professionals aged 40–75 y from the Health Professionals Follow-up Study) showed that higher intakes of α-linolenic (RR 0.68; 95% CI: 0.50, 0.93; P for trend=0.01) and linoleic acids (RR 0.70; 95% CI:

0.51, 0.96; P for trend=0.01) and possibly of fish oil may reduce the risk of pneumonia. On the other hand, taking eicosapentaenoic acid and docosahexaenoic acid were not significantly related to pneumonia risk.15

The 2nd longitudinal cohort study (N= 83,165 young and middle-aged women from the Nurses’ Health Study II cohort) showed there may be increased risk of community- acquired pneumonia from higher dietary intake of palmitic acid (RR 1.54, 95% CI 1.12–2.12) and possibly docosahexanoic and eicosapentaenoic acids (RR 1.24, 95% CI 1.00–1.55). There was a trend towards reduction of pneumonia risk with higher oleic acid intake (RR 0.75, 95% CI 0.55–1.04), but this was inconclusive. Intake of linoleic acid, α-linolenic acid, or docosahexanoic acid alone did not

show significant associations16 There are 2 registered clinical trials at clinicaltrials.gov (not yet recruiting as of May 15, 2020) investigating oral supplementation with omega-3-fatty acid or eicosapentaenoic fatty acids (Appendix 2).

Recommendations from other guidelines

WHO Interim guidelines, CDC interim guidelines, Infectious Diseases Society of America COVID-19 treatment guidelines, American Thoracic Society did not give any recommendation on the use of nutritional supplements in patients with COVID-19.17–20

CONCLUSIONS

There is lack of clinical evidence supporting the use of oral fatty acid supplements as prevention and adjunctive treatment for COVID-19.

Declaration of conflict of interest

No conflict of interest

REFERENCES

1.Mehta P, Mcauley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar; 395(10229):1033-4. doi:10.1016/S0140-6736(20)30628-0

2.Calder PC, Carr AC, Gombart AF. Optimal nutritional status for a well-functioning immune system is an important factor to protect against viral infections. Nutrients. 2020 Apr; 12(4):1181. doi: 10.3390/ nu12041181.

3.EFSA Panel on Dietetic Products. Scientific opinion on dietary reference values for fats, including saturated fatty acids, polyunsaturated fatty acids, monounsaturated fatty acids, trans fatty acids, and cholesterol. EFSA J. 2010;8(3):1461. doi: 10.2903/j.efsa.2010.1461

4.From the Joint FAO/WHO Expert Consultation on Fats and Fatty Acids in Human Nutrition. Interim Summary of Conclusions and Dietary Recommendations on Total Fat & Fatty Acids Summary of Total Fat and Fatty Acid Requirements for Adults, Infants (0-24 Months) and Children (2-18 Years). 2008.

5.Chinese Nutrition Society. Chinese Dietary Reference Intakes Summary (2013). People’s Medical Publishing House: Beijing, China, 2013; p. 16.

6.Jones GJB, Roper RL. The effects of diets enriched in omega-3 polyunsaturated fatty acids on systemic vaccinia virus infection. Sci Rep. 2017 Nov; 7(1):15999. doi:10.1038/s41598-017-16098-7

7.Cai C, Koch B, Morikawa K, Suda G, Sakamoto N, Rueschenbaum S, et al. Macrophage-derived extracellular vesicles induce long-lasting immunity against hepatitis C virus which is blunted by polyunsaturated fatty acids. Front Immunol. 2018 Apr; 9:723. doi:10.3389/ fimmu.2018.00723

8.Morita M, Kuba K, Ichikawa A, Nakayama M, Katahira J, Iwamoto R, et al. The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza. Cell. 2013 Mar; 153(1): 112-25. doi:10.1016/j.cell.2013.02.027

9.Messina G, Polito R, Monda V, Cipolloni L, Di Nunno N, Di Mizio G, et al. Functional role of dietary intervention to improve the outcome of COVID-19: A hypothesis of work. Int J Mol Sci. 2020 Apr; 21(9):3104. doi: 10.3390/ijms21093104.

10.Song J, Li C, Lv Y, Zhang Y, Amakye WK, Mao L. DHA increases adiponectin expression more effectively than EPA at relative low concentrations by regulating PPAR γ and its phosphorylation at Ser273 in 3T3-L1 adipocytes. Nutr Metab (Lond). 2017 Aug; 14:52. doi:10.1186/s12986-017-0209-z

11.Basil MC, Levy BD. Specialized pro-resolving mediators: Endogenous regulators of infection and inflammation. Nat Rev Immunol. 2016 Jan; 16(1):51-67. doi:10.1038/nri.2015.4

12.Rice TW, Wheeler AP, Taylor Thompson B, deBoisblanc BP, Steingrub J, Rock P. Enteral omega-3 fatty acid, γ-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA. 2011 Oct; 306(14):1574-81. doi:10.1001/jama.2011.1435.

13.National Center for Complementary Integrative Health Care.Omega-3 Supplements: In Depth [Internet]. [cited 2020 Jun 15]. Available from: https://www.nccih.nih.gov/health/omega3-supplements-in-depth.

14.Zhu D, Zhang Y, Li S, Gan L, Feng H, Nie W. Enteral omega-3 fatty acid supplementation in adult patients with acute respiratory distress syndrome: A systematic review of randomized controlled trials with meta-analysis and trial sequential analysis. Intensive Care Med. 2014 Apr; 40(4):504-12. doi:10.1007/s00134-014-3244-5

15.Merchant AT, Curhan GC, Rimm EB, Willett WC, Fawzi WW. Intake of n-6 and n-3 fatty acids and fish and risk of community- acquired pneumonia in US men. Am J Clin Nutr. 2005 Sep; 82(3): 668-74. doi: 10.1093/ajcn.82.3.668.

16.Alperovich M, A B, Neuman MI, Willett WC, Curhan GC. Fatty acid intake and the risk of community-acquired pneumonia in U.S. women. Nutrition. 2007 Mar; 23(3):196-202. doi:10.1016/j.nut.2006.11.007

17.WHO Interim Guidelines Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. [Internet]. March 13, 2020. [cited 2020 May 13]. Available from: https://www.who.int/publications-detail/clinical-management-of- severe.

18.CDC. Information for Clinicians on Investigational Therapeutics for Patients with COVID-19 [Internet]. [cited 2020 Jun 10]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic- options.html.

19.Bhimraj A, Morgan RL, Shumaker AH, Lavergne V, Baden L, Cheng VCC, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. Clin Infect Dis. 2020 Apr; ciaa478. doi: 10.1093/cid/ciaa478.

20.Wilson KC, Chotirmall SH, Bai C, Rello J, Force IT. COVID‐19: Interim Guidance on Management Pending Empirical Evidence . From an American Thoracic Society ‐ led International Task Force [Internet]. [cited 2020 Jun 15]. Available from: https://www.thoracic. org/covid/covid-19-guidance.pdf. Published 2020.

Database	Search strategy / search terms
Medline (COVID 19/MERS)	(Fatty acids OR Omega‐3 fatty acids OR n‐3 fatty acids OR Long?chain
	polyunsaturated fatty acids OR Linoleic acid OR Linolenic acid OR
	Lauric acid OR Palmitic acid OR Choline OR unsaturated fatty acids OR
	Arachidonic acid OR Eicosapentaenoic OR Docosahexaenoic acid)
	AND ((("Coronavirus Infections"[Mesh] OR "Coronavirus"[Mesh]
	OR coronavirus OR novel coronavirus OR NCOV OR "COVID-19"
	[Supplementary Concept] OR covid19 OR covid 19 OR covid-19 OR
	"severe acute respiratory syndrome coronavirus 2" [Supplementary
	Concept] OR severe acute respiratory syndrome coronavirus 2 OR
	SARS2 OR SARS 2 OR SARS COV2 OR SARS COV 2 OR SARS-COV-2
	OR Human coronavirus 229E OR HCoV-229E OR Human coronavirus
	NL63 OR HCoV-NL63 OR human coronavirus OC43 OR HCoV-OC43
	OR Human coronavirus HKU1 OR HCoV-HKU1 OR Swine Flu OR Camel
	Flu OR Severe acute respiratory syndrome coronavirus OR “Middle
	East Respiratory Syndrome Coronavirus” OR MERS#COV OR MERS
	Coronavirus OR MERS OR SARS)))

Date and time	Results
of search	Yield	Eligible
May 15, 2020	117	0
17:00 GMT+8