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. 2022 Mar 28;299:120489. doi: 10.1016/j.lfs.2022.120489

Table 1.

The characteristics of articles included in a systematic review of omega-3 and omega-6 fatty acids and COVID-19.

First Author; (year) Place (Country) Sample size Type of study Age Review period or Comparison date Quality Assessment Examined indicators
Zapata B et al. (2021) [32] Chile 74:
Male: 39
Female: 35
(74 patients (39 m and 35 f) with severe COVID-19 and 10 healthy quality-control)
Cross sectional Patients: 21–82 (59.68 ± 13.6) November 2020 and April 2021 Good - Omega-3 Index in patients with severe COVID-19: 4.15% ± 0.69%
- Risk of mechanical ventilation for the lowest O3I quartile (<3.57%) compared to higher quartiles: OR = 1.348, 95%CI: 0.925–1.964; P = 0.183
- Risk of death for the lowest O3I quartile (<3.57%) compared to higher quartiles: OR = 3.111, 95%CI:1.261–7.676; P = 0.032
- Reduction in the risk of mechanical ventilation for the highest O3I quartile (>4.51%) compared to the lo west quartile: OR = 0.257, 95%CI: 0.083–0.791; P = 0.026
- Reduction in the risk of death for the highest O3I quartile of (>4.51%) compared to the lowest quartile: OR = 0.195 95%CI: 0.024–1.605; P = 0.165
Archambault et al. (2021) [35] Canada 25 healthy subjects and 33 COVID-19 patients healthy subjects:26 ± 1
COVID-19 patients: 58 ± 3
between May and
June 2020, before COVID-19
Poor - Higher in bronchoalveolar lavage of COVID-19 patients compared with healthy subjects Mean ± SD of:
- arachidonic acid, 89.3 ± 6.4 vs. 16 ± 9 nmol/ml
- docosahexaenoic acid, 290 ± 35 vs. 35 ± 20 nmol/ml
- eicosapentaenoic acid, 8.9 ± 0.9 vs. 8.6 ± 0 nmol/ml
Asher et al. (2021) [3] USA 100:
59 male, 41 female (86 alive, 14 dead)
pilot study 72.5 (16.5; 25,100) from March 1, 2020 onwards Good - patients with an O3 index at 5.7% or greater: 75% lower risk for death compared with those below that value (p = 0.071)
- Q4: O3I ≥ 5.7% omega-3 index with death adjusted for age and sex: 32.0% (8/25); OR = 0.25, 95% CI: 0.03–1.11; p = 0.071
- Omega-3 Index and death: Q3 (4.7 < O3I < 5.7%) vs other quartiles: OR = 3.13, 95% CI: 0.82–14.30; p = 0.1
Doaei et al. (2021) [38] Iran 101 patients infected with
COVID-19:
28 fortified formula with n3-PUFA and 73 controls; 60 male, 41 female.
Interventions: 15 m, 13 f; controls: 45 m, 28 f
A double-blind, randomized clinical trial between 35 and 85 years
(Interventions: 66 (14.58); Controls:64 (14.25))
from May to July 2020 Good Effects of omega-3 supplementation(one capsule of 1000 mg omega-3 daily (Vita Pharmed, Switzerland) containing 400 mg EPAs
and 200 mg DHAs for 14 days) in intervention group vs. control group:
- On 1-month survival rate: significantly higher, 21% (n = 6) vs. 3% (n = 2); P = 0.003
- On kidney function: levels of BUN (35.17 vs 43.19, F = 4.76, P = 0.03) and Cr (1.29 vs 1.68, F = 5.90, P = 0.02), significantly lower and the amount of urine excreted (2101 vs 1877.02, F = 12.26, p = 0.01), significantly higher.
- On arterial blood gas (ABG) parameters:
levels of arterial pH (7.30 vs 7.26, F = 19.11, P = 0.01), HCO3 (22.00 vs 18.17, F = 10.83, P = 0.01), and Be (−4.97 vs −3.59, F = 23.01, P = 0.01), significantly higher.
- On the mean of Glasgow coma scale (GCS): at admission time8.37 vs. 7.90, P > 0.05, significantly lower; after 14 days 7.90 vs 7.49, F = 6.07, P = 0.05.
No significant difference in APACHE II score (15.54 ± 1.73 vs 15.42 ± 1.92, P = 0.78).
- On serum electrolytes:
The level of K, significantly reduced (4.00 vs 4.14, F = 10.15, P = 0.01) after 14 days.
No significant differences between the levels of serum electrolytes including Na, Ca, and P.
- On blood clotting function and cell blood count (CBC):
The lymphocyte count increased, marginally significant (11.59 vs 11.80, F = 4.08, P = 0.05). no significant differences in levels of PTT, hematocrit, neutrophil, monocyte, hemoglobin, and Plt
- On the other blood factors:
No significant differences in blood glucose, albumin, MAP, and O2 sat.
Hamulka et al. (2021) [26] Worldwide and Poland First wave: 2296
Second wave: 978
Online cross-sectional ≥18 (1) in April and May 2020
(2) in November 2020 during the second wave
Good Spearman rank's coefficients Omega-3 fatty acids and Worldwide:
COVID-19 cases: 0.06; Deaths: 0.06
Coronavirus relative search value (RSV): 0.74; p ≤ 0.01
Poland:
COVID-19 cases: 0.21; Deaths: 0.21, coronavirus relative search value (RSV): 0.26
- Omega-3 fatty acids supplement consumption: increase from 2.8% to 8.2%
Jontez et al. (2021) [41] Slovenia 38 (14 m
, 24 f)
web
survey
36.3 ± 10.1 December 2019 Fair Mean ± SD fatty acids intake ratio (PUFA+MUFA)/SFA) in healthy Adults: Baseline 1.98 ± 1.34, During Lockdown 1.77 ± 1.20 and Post-Lockdown 1.54 ± 0.78
Julkunen et al. (2021) [42] UK Pneumonia participants:
n = 105,142; 102,639 controls, 2507 severe incident cases
COVID-19 Participants: n = 92,725; 92,073 control, 653 severe incident cases
Retrospective cohort 49–84 blood samples collected 2007–2010 Good - multi-biomarker score for fatty acids and susceptibility to severe COVID-19: odds ratio 2.9 [95%CI 2.1–3.8] for highest vs lowest quintile; p-value<0.001
Mei et al. (2021) [39] China 223: 91 discharged and 132 deceased multi-center study ≥65 years old Between January and March 2020 Good - Fatty acid: lower flux in the survivors vs. the deceased subgroup, AOR = 15.61 [95% CI: 6.66–36.6], p < 0.001.
Nguyen et al. (2021) [27] France 61:
34 non-COVID-19,27 COVID-19
prospective non-COVID-19:
69 (± 12)
COVID-19:
62 (± 11)
Good In COVID-19 patients vs. non-COVID-19 patients:
- Linoleic acid (C18:2 n-6): significantly increased 207 ± 109 vs. 113 ± 67 nmol/ml; p < 0.01.
- Arachidonic acid (C20:4 n-6): significantly increased 16 ± 6 vs 12 ± 5 nmol/ml p < 0.01
- Relative proportion of linoleic acid:
significantly higher 12.8 ± 3.6 vs. 8.3 ± 2.3%; p < 0.01
- Linoleic acid proportion and ventilator-free days: r = − 0.404, p = 0.001)
Perez-Torres et al. (2021) [28] Mexico COVID-19 patients n = 42: 31 m, 11 f
(healthy subjects
n = 22)
over 18 years
62 ± 13 years
Good - Increased in COVID-19 patients: oleic (OA), p = 0.001; linoleic (LA), p = 0.03 and arachidonic acid (AA), p = 0.02.
- Mean ± SE of Fatty acids in Healthy subjects vs. COVID-19 patients
- Monounsaturated fatty acids (MUFA): 23.82 ± 0.70 vs. 32.09 ± 0.61; p = 0.001
- Omega 3 polyunsaturated fatty acids (PUFA (n-3)): 0.91 ± 0.11 vs. 0.31 ± 0.05; p = 0.001
- Omega 6 polyunsaturated fatty acids (PUFA (n-6)): 25.94 ± 0.53 vs. 28.19 ± 0.82; p = 0.02
Vivar-Sierra et al. (2021) [29] worldwide Web based Fair - Eastern Mediterranean region: higher mean fatality rate (3.52%) and the lowest omega −3 intake from marine sources (45.14 mg/day)
- South-East Asia: lowest fatality rate (1.01%) and the highest average consumption (634.00 mg/day) from marine sources
- In nations with a consumption <250 mg/day from marine products, differences among regions were observed (chi2 = 59.361; p = 0.000), as well as a trend for higher fatality rates, >2.5 and 4% (chi2 = 10.432; p = 0.064) and (chi2 = 10.367; p = 0.066),
- Omega −3 intake from plants and cumulative cases: rSpearman = 0.321;
p < 0.001
- Omega −3 intake from plants and total cumulative cases per 1 million population: rSpearman = 0.329; p < 0.001
- Omega −3 intake from plants and fatality rates: rSpearman = 165; p > 0.05
Bejan. (2021) [36] USA 7768 COVID-19 patients, 509 (6.55%) hospitalized,
82 (1.06%) admitted to ICU, 64 (0.82%) mechanical ventilation, and 90 (1.16%)
died
retrospective cohort Median = 42 Patient exposure to a drug during 1-year prior to the pandemic and COVID-19
diagnosis
Good - Hospitalized-mild, cumulative severity: supplement of Omega-3 fatty acids:
Total exposed: 475
Total unexposed: 7293
Severity rate exposed: 10.7
Severity rate unexposed: 15.7
OR = 0.60, 95% CI: 0.39–0.94
- Hospitalized-mild, exclusive severity supplement of Omega-3 fatty acids:
Total exposed: 456
Total unexposed: 7168
Severity rate exposed: 7.2
Severity rate unexposed: 11.5
OR = 0.56, 95% CI: 0.33–0.95(Lower risk for COVID-19 outcomes)
Hao et al. (2021) [33] China 89 asymptomatic COVID-19 patients and 178 healthy controls 19 to 91
Mean ± SD:
Asymptomatic:
45 ± 13;
healthy controls: 45 ± 13

-
Good - FAs (including FA 18:1 and FA 20:0) decreased in asymptomatic COVID-19 patients.
-Z-scored log 2-scaled peak area value for relative intensity of FA 18:1: 0.42, (95%CI: −0.31 to 1.09) in healthy controls and − 0.73, (95%CI: −1.1 to −0.14) in COVID-19 patients; adjusted p-value = 1.23e-12
- FA 18:1 (asymptomatic/healthy): 0.44
-Z-scored log 2-scaled peak area value for relative intensity of FA 20:0:0.068, (95%CI: −0.34 to 0.89) in healthy controls and − 0.50, (95%CI: −0.99 to −0.17) in COVID-19 patients; adjusted p-value = 8.74e-10
- FA 20:0 (asymptomatic/healthy): 0.65
Louca et al. (2021) [30] UK,
USA, Sweden
UK: n = 372,720: 39263 supplement
users and 333,457 non-users.
USA: n = 45,757, 8663 supplement
users and 37,094 non-users
Sweden: n = 27,373, 3039 supplement
users and 24,334 non-users
App-based community survey aged 16–90 years in the first
waves of the pandemic up to 31 July 2020
Fair - SARS-CoV-2 positive, n (%):
UK: 10508 (6%)
USA: 2002 (6.2%)
Sweden: 1806 (13.5%)
- UK cohort: users regularly supplementing their diet with omega-3 fatty acids had a lower risk of testing positive for SARS-CoV-2 by 12% (OR = 0.88, (95%CI: 0.84 to 0.92), p = 5.8 × 10−8) after adjusting for age, sex, BMI, sign-up health status and multiple testing
- omega-3 supplement use was not associated with testing positive in Swedish females
- Swedish men taking probiotics, omega-3 fatty acids had a decreased risk of infection
- protective effect in omega-3 fatty acid supplements users with a 12% reduction in risk of testing positive for SARS-CoV-2 in the overall UK cohort, 21% in the US cohort and 16% in the SE cohort.
- women taking multivitamins, omega-3 fatty acids have a slightly lower risk of SARS-CoV-2 infection in the UK, US and SE cohorts
El-Kurdi et al. (2020) [40] 61 countries
With >1000 COVID-19 death
1,476,418 patients Web survey between 3/25/2020 and 04/08/2020 Good - %UFA intake was positively associated with mortality: Rate Ratio = 1.02, 95% CI: 1.01–1.03; (p < 0.001)
- Multivariate analysis showed only %UFA as significantly associated with mortality (p < 0.0001).
Barberis et al. (2020) [37] Italy Non-COVID-19 Patients:26 Healthy Control,
32 non-COVID-19 with symptom
COVID-19 Patients:103
(Mean ± SD) Healthy Control: 50.1 ± 5.3
non-COVID-19 with symptoms: 68.6 ± 8.9
COVID-19 Patients: 67.3 ± 18.0
Good - Free fatty acids, especially arachidonic acid (AUC = 0.99) and oleic acid (AUC = 0.98), were well correlated to the severity of the disease; p value <0.0001.
- By using ROC curves, the quantification in the negative mode identified AUC values of 0.99 (SE: 93%, SP: 100%) for arachidonic acid (FA 20:4) and 0.98 (SE: 96%, SP: 88%) for oleic acid (FA 18:1).
- Mean ± SD of oleic acid (FA 18:1) in covid-19 patients vs. controls: 2355 ± 1305 vs 0.567 ± 326 pmol/ml plasma
- Mean ± SD of arachidonic acid (FA 20:4) in covid-19 patients vs. controls: 415 ± 237 vs. 49.5 ± 24.75.6 pmol/ml plasma
- Oleic acid and arachidonic acid levels are directly correlated to the severity of the disease
Thomas et al. (2020) [31] USA COVID-19: n = 33
Controls: n = 16
(Mean ± SD) COVID-19: 56.5 ± 18.1
Controls: 37.8 ± 11.6
Fair - Serum levels of free fatty acids (c18:0–3 and c 20:4–5) were significantly different when comparing COVID-19–positive patients and controls; P < 0.05
Dierckx et al. (2020) [34] Belgium 581 samples from 480 patients in three different cohorts:
UZL, n = 219 and JESSA, n = 164, subset of plasma
samples
retrospective >18 years old between
March 2020 and September 2020
Good - Increased poly-unsaturated FA (PUFA) content was associated with less severe disease
- Increased mono-unsaturated FA (MUFA) content was associated to more severe disease
- Linoleic acid (LA) and total Omega-6 FA: stronger and more consistent associations opposite associations with COVID-19 severity than Omega-3 FA.
- Opposite associations with COVID-19 severity:
- Linoleic acid (LA): OR = 0.55, percentile2.5 = 0.42, percentile97.5 = 0.71; p = 0.000 in UZL and OR = 0.72, percentile2.5 = 0.54, percentile97.5 = 0.96; p = 0.025 in Jessa
- total Omega-3 FA: OR = 0.69, percentile2.5 = 0.54, percentile97.5 = 0.89; p = 0.003 in UZL and OR = 1.05, percentile2.5 = 0.75, percentile97.5 = 1.47; p = 0.77 in Jessa
- Omega-6 fatty acids: OR = 0.59, percentile2.5 = 0.45, percentile97.5 = 0.75; p < 0.001 in UZL and OR = 0.66, percentile2.5 = 0.47, percentile97.5 = 0.92; p = 0.014 in Jessa
- Docosahexaenoic acid (DHA) OR = 0.74, percentile2.5 = 0.57, percentile97.5 = 0.94; p = 0.015 in UZL, OR = 1.1, percentile2.5 = 0.84, percentile97.5 = 1.46; p = 0.48 in Jessa.
(n = 198, from 97 patients) taken for the CONTAGIOUS observational clinical trial

69 in analyze
prospective >18 years old Samples were taken at the time of admission (within
maximum 48 h), at day 7, at the time of hospital discharge and 30 days after hospital
discharge (if available).
Good - Ratio of omega-6 fatty acids to total fatty acids: median = 35.16; IQR = 34–36.6 in sv3: and median = 32.34; IQR = 30.2–34.7 in sv4; p = 0.002
- Ratio of polyunsaturated fatty acids to monounsaturated fatty acids(PUFA by MUFA): median = 1.4; IQR = 1.26–1.47 in sv3: and median = 1.27; IQR = 1.02–1.37 in sv4; p = 0.022
- Ratio of polyunsaturated fatty acids to total fatty acids (PUFA pct): median = 38.45; IQR = 36.9–40.2 in sv3: and median = 37.05; IQR = 34–38.6 in sv4; p = 0.008
- Higher relative PUFA content and PUFA to MUFA ratio were consistently associated with lower severity, in contrast to increased MUFA levels
- Linoleic Acid concentration and total omega-6 fatty acid content (absolute concentration and relative to total FAcontent) were lower in severe COVID-19 cases.