6. Omega-3 Fatty Acids

6.1. Metabolism and Functions
Omega-3 fatty acids are a family of polyunsaturated fatty acids (PUFAs) characterized by the presence of a double bond at the omega−3 carbon atom. The simplest omega-3 fatty acid is α-linolenic acid (18:3n-3), which is synthesized from the omega-6 fatty acid linoleic acid (18:2n-6) by desaturation, catalysed by delta-15 desaturase.
Linoleic acid (18:2n-6) and α-linolenic acid (18:3n-3) are essential fatty acids (EFAs), meaning that they must be obtained from the diet. Indeed, they are synthesized by plants and cannot be synthesized sufficiently by the human organism [190]. However, animals can metabolize α-linolenic acid by further desaturation and elongation to yield eicosapentaenoic acid (20:5n-3; known as EPA) and docosahexaenoic acid (22:6n-3; known as DHA). It is important to note that the same enzymes are employed by omega-6 fatty acids for their metabolic pathways, which leads to the production of arachidonic acid. This means that α-linolenic acid is a competitive inhibitor of linoleic acid metabolism and vice versa [191]. However, it has been demonstrated that the conversion to EPA and DHA is generally poor in humans, with reported rates of less than 15%. Therefore, these fatty acids must be supplied with food [192]. Alfa-linolenic acid is present in plant oils, DHA and EPA are present in fish, fish oils, and krill oils.
Omega-3 fatty acids play important roles in the body as components of the phospholipids that form the structures of cell membranes. Furthermore, they provide energy for the body and are used to form eicosanoids, exercising several functions in the body’s cardiovascular, pulmonary, immune, and endocrine systems [189]. Both omega-3 and omega-6-derived metabolites have important immune-regulatory functions [193]. PUFAs represent substrates for the enzymatically production of molecules that play an important role in the resolution of inflammation, named specialized pro-resolving mediators (SPMs) [194,195]. These molecules are distinct from immunosuppressive agents because they contribute to the inflammatory response resolution but also display antimicrobial action promoting host defence [196]. SPMs derived from omega-3 fatty acid (EPA and DHA) are classified as resolvins, protectins, and maresins. These pro-resolving mediators are important in supporting immune cell functions to neutralize and eliminate pathogens and play a crucial role in promoting the resolution of inflammation [197].
Omega-3 fatty acids metabolites resolvins are effective in inhibiting neutrophil migration, reducing further neutrophil entry in the inflammation site [198,199]. Furthermore, SPMs exercise a potent anti-inflammatory action, also reducing tissue neutrophil activation and preventing tissue damage [197,200]. In order to obtain tissue resolution of inflammation, it is essential the clearance of apoptotic neutrophils and protectins stimulate phagocytosis of apoptotic cells mediated by macrophages [201,202,203,204,205]. Furthermore, SPMs stimulate natural killer cells to trigger granulocyte apoptosis, accelerating the clearance of apoptotic polymorphonuclear leukocytes [206]. The anti-inflammatory response is promoted by SPMs also by dampening cytokine production. A study of Ariel et al. suggests that pro-resolving mediators upregulate CCR5 expression on apoptotic, activated T cells, thus sequestering pro-inflammatory cytokines, and promoting the resolution of the inflammation [207].

6.2. Omega-3 Fatty Acids Status
Plasma and serum fatty acid values can vary significantly based on an individual’s most recent meal, so they do not reflect long-term dietary intake. However, omega-3 status can be valued by calculating the percentage of the total serum phospholipid fatty acids. Although a normal range is not established, mean values for serum phospholipid EPA plus DHA are about 3–4% [206]. Omega-3 status could also be assessed analysing erythrocyte fatty acids. Harris and von Schacky proposed the “omega-3 index”, which represents the content of EPA plus DHA in red blood cells membranes, expressed as a percentage of total erythrocyte fatty acids, and reflects better long-term intake of EPA and DHA [207,208]. EPA and DHA are about 3–5% of erythrocyte fatty acids in Western populations with low fish intakes [209]. Moreover, the recent discovery of novel dietary omega-3 and omega-6 lipid-derived metabolites-such as resolvin, protectin, maresin, 17,18-epoxy-eicosatetraenoic acid, and microbe-dependent 10-hydroxy-cis-12-octadecenoic acid, and their potent biologic effects on the regulation of inflammation, have initiated a new era of nutritional immunology [210]. It has been shown that a synergy between omega-3 fatty acids and gut microbiota enhances the efficacy of immune checkpoint inhibitors [211].

6.3. Recommended Daily Allowance and Supplementation
Since insufficient data are available to establish an estimated average requirement (EAR), the EFSA panel on Dietetic Products, Nutrition, and Allergies (NDA) indicated adequate intake (AI) for adults of 250 mg for eicosapentaenoic acid plus docosahexaenoic acid based on considerations of cardiovascular health. For older infants (>6 months of age) and young children, below the age of 24 months, was proposed an adequate intake of 100 mg docosahexaenoic acid. For the age period 2 to 18 years, the AI proposed for the adult population should be considered suitable [212].

6.4. Omega-3 Fatty Acids Supplementation against Viral Infection
As mentioned above, the omega-3 fatty acids play a crucial role in the resolution of inflammation induced by infections, including in the respiratory tract [196]. Table 7 summarizes the main studies in which were investigated the link between the omega-3 fatty acids supplementation and respiratory infections/illness, and the potential role in improving the acute lung injury and acute respiratory distress syndrome (ARDS) [213,214,215,216,217,218,219,220,221,222,223].
Some studies investigated the effects of the omega-3 fatty acids supplementation on infant morbidity, particularly caused by respiratory tract infections, wheezing, and asthma. Imhoff et al. showed that DHA supplementation during pregnancy decreased the occurrence of colds in children at 1 month and influenced illness symptom duration [213]. Pastor et al. in a multicenter, prospective, open-label observational study, which included 1342 infants, showed a higher incidence of bronchiolitis in control versus groups who received omega-3-supplemented formula [214]. In contrast, in another study aimed to valuate the effect of neonatal DHA supplementation, the hospitalisation for lower respiratory tract problems in the first 18 months for preterm infants was not reduced [215]. A randomized controlled, trial which included 736 pregnant women and a total of 695 children, showed that the risk of persistent wheeze or asthma was reduced by approximately 7% in the first 5 years of life among children of women who received daily supplementation with omega−3 PUFA (EPA/DHA) during the third trimester of pregnancy. It is notable that this effect was most prominent among children of women with low EPA and DHA blood levels at randomization. Furthermore, supplementation was also associated with a reduced risk of infections of the lower respiratory tract [216].
Some studies have demonstrated the effect of omega-3 supplementation also on children’s morbidity, particularly reducing the episodes of upper respiratory tract infections [217,218]. Malan et al. in a randomized, double-blind, placebo-controlled trial, which included 321 South African children with iron-deficiency, showed that iron supplementation was associated with an increased morbidity, mostly respiratory, but when given in combination with DHA/EPA, this increase in morbidity was prevented. Authors suggested that this effect could be explained by the DHA- and EPA-mediated protection against iron-induced oxidative stress and the improved resolution of inflammation [219].
It has been shown that severe COVID-19 could manifest as a hyperinflammatory syndrome (secondary haemophagocitic lymphohistiocytosis), which is characterized by an important hypercytokinaemia (cytokine storm) with multiorgan failure and ARDS in approximately 50% of patients [220]. Several studies have been conducted to determinate if omega-3 fatty acids DHA and EPA could modulate systemic inflammatory response and affect plasma cytokine production. Thienprasert et al., in a randomized controlled trial, demonstrated that consumption of omega-3 PUFAs was associated with fewer episodes and shorter duration of illness (mainly upper respiratory tract) and with a significantly lower concentration of TGF-beta1 concentration compared with the placebo group [221]. Two randomized controlled trials, aimed to determinate if omega-3 fatty acids could modulate the systemic inflammatory response, improving the outcomes in patients with acute lung injury, have shown that in the intervention groups there was not a reduction of the biomarkers of systemic inflammation and pulmonary outcomes did not improve [222,223]. In a recent systematic review, Dushianthan et al. have reported a significant improvement in blood oxygenation and in the duration of ventilator days and ICU length of stay in patients with ARDS who received nutrition containing antioxidants and rich in EPA and DHA, although there was a low quality of evidence [224].
These findings supported also by results of animal studies [225,226,227], may suggest a potential role for EPA and DHA in reducing the lung injury supporting the resolution of inflammation, probably via the production of SPMs [207]. However, further trials are needed to support this hypothesis.