The first part of 2020 was characterized by the pandemic spread of a novel coronavirus: severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [1]. To date, millions of cases of coronavirus disease 19 (COVID-19) have been reported, and it has caused more than 3.9 million deaths in the world [2]. The population generally is not provided with immunity to SARS-CoV-2 and is susceptible to the new virus disease ^[1][3][4][5][1,3,4,5]. Previous epidemiological and clinical studies featuring COVID-19 have shown that SARS-CoV-2 infection usually results in mild disease, although several patients occasionally develop severe or critical illness ^{[1][3][4][5][6][7][8]}[1,3,4,5,6,7,8]. In particular, asymptomatic individuals are estimated to range from 17.9% to 78% [3], approximately 15% of infected individuals will develop severe illness, and about 5% will eventually develop severe pneumonia and acute respiratory distress syndrome (ARDS) [4]. Some COVID-19 patients will also develop systemic manifestations such as sepsis, cardiovascular complications, thromboembolism, and multi-organ failure ^[4][8][4,8].

Worsening clinical outcomes of COVID-19 have been associated with older age, male gender, and the presence of comorbidities such as hypertension, obesity, and type 2 diabetes mellitus ^[5][6][7][5,6,7].

A recent report shows data from the COVID-19 case fatality rate (CFR) in Italy, highlighting a linear relationship between the CFR and age [9]. In particular, CFRs are less than 0.4% in patients aged 40 or younger, 1% among those aged 50, 3.5% in those aged 60, 12.8% in those aged seventy, at 20.2% in those over eighty; the overall CFR is 7.2% [9]. Recent evidence suggests that the SARS-CoV-2 viral loads are similar in asymptomatic, mild symptomatic, and severe symptomatic patients ^[10][11][10,11], but many other factors influence the progression and severity of the disease.

Currently, no specific data have been reported regarding the immunological response to SARS-CoV-2, but new studies have shown that a cytokine storm overstimulates the body’s immune response to microorganisms as a consequence of increases in the levels of inflammatory factors [12]. Therefore, the inflammatory factors contribute to one of the most important mechanisms underlying disease progression and death. Then, the coexistence of both COVID-19 and chronic diseases should be considered alarming, because it represents the combination of more pandemics [13]. The interaction between nutrition, immune function, inflammation, and infection represents a key tool to reduce the risk of susceptibility and morbidity of viral infectious diseases ^[13][14][15][13,14,15]. Research has shown that greater adherence to the Mediterranean diet (MetDiet) is associated with a reduced risk of major chronic diseases, [16] due to its anti-inflammatory and immune-modulatory properties.

2. The Mediterranean Diet: A Healthy Dietary Pattern for People with SARS-CoV-2 Infection

The MetDiet is a model of eating based on the traditional foods and drinks of the countries surrounding the Mediterranean Sea. Over the last few decades, this nutritional model has been promoted worldwide as one of the healthiest dietary patterns and has been reported to be consistently beneficial with regard to longevity. The MetDiet is characterized by high consumption of unrefined cereals, fruit, vegetables, legumes, and olive oil, moderate consumption of dairy products and wine, and low meat consumption ^[16][17][16,17].

Among other benefits, adhering to the MetDiet has been linked to a lower risk of various chronic conditions ^{[18][19][20][21][22]}[18,19,20,21,22], with lower risk of inflammation as well as increased immunity ^[23][24][23,24]. Its protective properties are thought to be a combination of the high intake of polyunsaturated fatty acids (PUFA) from fish [25], monounsaturated fatty acids (MUFA) and polyphenols from extra virgin olive oil (EVOO) [26], and antioxidants from fruit, vegetables, legumes, and wine ^[20][26][27][20,26,27]. Furthermore, the MetDiet is rich in phytochemicals with antioxidant action, minerals, and vitamins [23].

The first umbrella review meta-analysis of observational studies and randomized trials estimated the association between adherence to the MetDiet and 37 different health outcomes, including overall mortality, cardiovascular and cancer outcomes, neurodegenerative and metabolic disorders, as well as inflammatory markers. This meta-analysis showed that a greater adherence to the MetDiet reduced the risk of overall mortality and cancer incidence, cardiovascular and neurodegenerative diseases, and diabetes [16].

Each component of the MetDiet has its benefits, but it can be assumed that it is the combination of various nutrients that is the basis of the extraordinary health effects of MetDiet ^[16][17][16,17], especially on the immune system ^[28][29][28,29].

Recent research showed that one MetDiet-style meal reduced the expression of pro-inflammatory molecules [29], the overall systemic inflammatory status [30], and several diseases associated with chronic low-grade inflammation. In adult individuals, a MetDiet intervention led to lower glycoxidative impairment [31] and inflammatory response ^[32][33][32,33]. A meta-analysis including 2300 subjects reported a significant reduction in high-sensitivity C-reactive protein (hs-CRP) (−0.98 mg/L, p < 0.0001), intracellular adhesion molecule-1 (−23.73 ng/mL, p = 0.008), and IL-6 (−0.42 pg/mL, p = 0.008) in individuals assigned to MetDiet, compared with those following a control intervention protocol [34].

A potential protection against COVID-19 by a MetDiet was assessed longitudinally in a cohort of 5194 non-health professionals [35]. Participants with the highest adherence to MetDiet had a significantly lower odds of developing SARS-CoV-2 infection compared with those with lowest adherence (multivariable-adjusted OR = 0.36, 95% CI: 0.16–0.84; p for trend < 0.001) [35].

An ecological study, of only European countries, showed a significant negative association between MetDiet and COVID-19-related deaths (r² = 0.771, p = 0.030) [36]. The authors observed that MetDiet adherence was negatively associated with COVID-19 cases as well as related deaths across 17 regions in Spain and that the relationship remained also after adjustment for factors of well-being [36]. The same authors also observed a negative association between Metdiet adherence and COVID-19-related deaths across 23 countries (OECD) after adjustment for physical inactivity and some confounding factors [36].

An observational case control study explored the possible associations among different dietary patterns and COVID-19 events and outcomes. The results showed that the cases had a lower mean of the MedDiet score (p = 0.009) than controls did, demonstrating an inverse association between the MetDiet and COVID-19 risk [37].

The preliminary results of an experimental study aimed to detect the beneficial effects of MetDiet before and after the period of COVID-19 Lockdown in Mediterranean area (Spain) old individuals showed that patients who initiated the MetDiet intervention program before Lockdown increased their level of adherence to the MetDiet by 3.5% and maintained an adequate nutritional status after the Lockdown. In the BMI, there no were statistically significant differences between experimental and control groups before and after Lockdown. These results suggest that adherence to the MetDiet may play an important role in the maintenance of an adequate nutritional status in the confinement situations such as the COVID-19 Lockdown [38].

All these results suggest the important role that nutrition, and, in particular, the MetDiet, could play in the prevention and management of COVID-19 infection (Figure 1).

Figure 1. Mediterranean diet: potential strategy against coronavirus infection.

3. Mediterranean Diet and COVID-19: Plausible Mechanisms of Potential Benefits

COVID-19 is characterized by increased levels of numerous cytokines, mainly of proinflammatory character, including tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and CRP [39]. Therefore, effective treatment strategies pursued could include reducing inflammation in order to prevent the risk of infection or blunt the severity of the COVID-19 disease [12]. In this regard, several studies suggest that MetDiet induces positive effects on both inflammation and oxidative stress. The stimulating effect induced at the level of the immune system is pointed out by the positive results induced by MetDiet on people with inflammatory phenomena impacting the respiratory system [40]. Several micronutrients have been suggested to act as immunomodulatory agents against COVID-19, and they are briefly summarized in Table 1.

Table 1. Possible anti-SARS-CoV-2 effects attributed to MetDiet.

Effects	Components	Food Sources	References
Lower Inflammation (CRP, IL-6, TNF-alpha, ROS, RNS)	PUFA, MUFA, polyphenols, antioxidants, fibers, vitamins, minerals	Fish, EVOO, fruit, vegetables, legumes, wine, whole grains	[16][20][23][24][25][26][27][28][29][30][31][32][33][[41][42]][68][69][70][16,2034][35][36][37][38][39][40][43,23][44,24],25,26,27,28,29[45,30][46,31],32,33,34,35,36,37,38,39,40,41,42,43,44,45,46[47][48][49][50][51][52][53][54][55][56][57,47],48[,49,5658][59][60][61][,5062,51,57],52[63][64][65][66],53[,54,5867,55,59,60,61,62,63,64,65,66,67,68,69,70]
Boost Immune system (anti-thrombotic, anti-PAF effect) and antiviral effects (NF-κB, AP-1)	Vitamin A, C, E, D, selenium, zinc, phytochemicals, and omega-3 PUFA, polifenols, antioxidants, resveratrol,	Legumes, vegetables, fruit, EVOO, seeds, bran, nuts and dried fruit, shellfish, beef, tea, red wine	[14][42][48][51][52][53][57][58][59][74]][88][14,42,4870],51[,5271,53][72][73],57[[75,58][76,59],70,71,72,73,74[77][78][79][80],75[,7681,77][82][83],79[,8084,81,82],83[85][86][,7887,84,85,86,87,88]
Boost Intestinal Barrier Function (gut microbiota)	Prebiotic substances, galactans, fructans, fibers, and inulins	Legumes, vegetables, fruit, nuts, seeds, bran, milk and yogurt	[46][47][48][64][65][72][89][90][91][92][93][94][95][46,47,48,64,65,72,89,90,91,92,93,94,95]
Improvement of the metabolic setting (ACE2, Leptin)	PUFA, MUFA, polyphenols, antioxidants, fibers, vitamins, minerals, prebiotic substances, polifenols, antioxidants, resveratrol	Legumes, vegetables, fruit, EVOO, seeds, bran, nuts and dried fruit, shellfish, beef, tea, red wine	[13][14][15][16]16[17][18][19][20][21][22,17][96][97][98][,18,19,2099][100][101][13,14,15,,21,22,96,97,98,99,100,101]

Abbreviations: CRP, C-reactive protein; IL-6, interleukin-6; TNF-alpha, tumor necrosis factor-alpha; ROS, reactive oxygen species; RNS, reactive nitrogen species; PUFA, polyunsaturated fatty acids; EVOO, extra virgin olive oil.

Fruits, whole grains, vegetables, fish, PUFA, and MUFA have been found to cause less inflammation in the body [41], while foods with high saturated fat content such as processed red meat, cheese, and dairy may induce inflammation [40]. It may be the abundance of beneficial foods (rich in fiber, PUFA, minerals, vitamins, polyphenols, and antioxidants) and lack of fatty foods (rich in starch, refined sugar and trans fatty acids) in the MetDiet that produce its favorable effects [42].

PUFAs include long-chain omega-3 PUFAs, EPA (20:5n–3), and DHA (22:6n–3), derived mainly from fish and seafood [41], as well as α-linolenic acid, derived from various plant sources [43]. Among PUFAs, the omega-3 free fatty acids exert anti-inflammatory effects via specialized pro-resolving mediators, which are the oxylipins, of oxygenated metabolites ^[25][44][25,44].

Dietary fibers are an important factor regarding the influence of complex carbohydrates on inflammation ^[45][46][45,46]. It was demonstrated that an increase in fiber consumption (about 30 g/d) was associated with a significant reduction in hs-CRP concentrations [47]. Another advantage of dietary fiber intake is a more favorable gut microbiome composition, which lowers both gut and systemic inflammation, and even small increases of fiber (5 g/d) can be beneficial ^[89][90][89,90]. Watanabe et al. hypothesized that a rice-eating habit seems to be a factor that explains the reason for low COVID-19 incidence and mortality in rice-eating countries. The authors make a hypothesis that populations who consume rice have a special profile of microbiota that produce butyrate, which stimulates the proliferation of regulatory T cells, prevents a cytokine storm (induced by the infection), and reduces the levels of IL-6 and CRP [91].

Although it is the most consumed food in Asia, rice plays a key role also in the diet of many countries, including those of the Mediterranean area [92].

Modifications in the intestinal barrier contribute to the pathogenesis of many illnesses; viruses may also contribute in disrupting the intestinal epithelium [93]. Sharma clarified that the gastrointestinal structure and the gut barrier may be affected by SARS- CoV-2 virus, and disorder of barrier functions or intestinal microbial dysbiosis may influence the progression and severity of COVID-19 disease [93]. It has been shown that the SARS-CoV-2 virus can impact PALS1, a tight junction-associated protein, present in the intestinal and lung epithelium [71]. For this, it has been proposed that SARS-CoV-2 may increase intestinal permeability, causing damage to enterocytes and the epithelial layer [72].

MetDiet is also very rich in prebiotic substances, such as galactans, fructans, fibers, and inulins. Numerous reports indicate that these compounds are used by host microorganisms, supporting the growth of favorable bacteria and by promoting the production of beneficial metabolites ^[48][49][93][48,49,93].

There is also evidence supporting the protective role of vitamins against viral infections through multiple mechanisms [44]. EVOO is one of the staple foods of the MetDiet, and is the main dietary source of vitamin E. This vitamin is one of the most effective nutrients enhancing immune function and inflammation ^[44][50][44,50]. Several studies have indicated that vitamin E deficiency impairs both humoral and cell-mediated immune functions ^[51][52][51,52]. Vitamin E and vitamin C are well-known antioxidant compounds, able to reduce the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) ^[44][73][44,73]. Moreover, Vitamin A is involved in the production of mucin secretion and enhancing antigen nonspecific immunity functions (healthy mucus stratum), such as those of the bowel and the respiratory tract ^[51][52][51,52].

Many studies have highlighted the ability of vitamin D to reduce infections and to modulate innate and adaptive cellular immunity, and have shown an inverse association between the incidence of airway infections and its serum levels [74].