Figure 1 shows the preferred reporting items for systematic reviews and meta-analysis flow-diagram outlining the process to retain 27 papers. After evaluation of 74 papers, only 27 papers were relevant to the objective of this study which was used in this review. Twenty studies emphasize adequate intakes of nutrients for strengthening the immune system, of which 16 studies highlighted vitamin D for protection against respiratory infections. Eight papers discuss food items (fruit and vegetables, refined or whole grains, sea foods, garlic, ginger, cabbage, fermented milk), herbs or spices, phytochemicals, polyphenols; six papers explain optimal dietary patterns for supporting the immune system (Table 1).
The flow diagram through the different phases of systematic review
Due to heterogeneity in the contents of papers, the narrative synthesis approach was chosen as the papers revealed the founding of the same nutrients or phytochemicals discussed in the same unit.
Nutrients for strengthening the immune system and prevention of COVID-19
Energy intake
Scientific studies have shown that both energy restriction and diet-induced obesity have adverse effects on the immune system’s response to influenza infection in mouse models through impaired natural killer cell function and altered inflammation. Both types of these conditions have also been shown to be associated with an increased risk of mortality from influenza infection in experimental models. The effects of energy restriction are more marked during innate responses to influenza infection. People who are malnourished or losing weight through a self-administered or non-scientific low-calorie diet are more likely to be exposed to, corona virus due to immunosuppression [13,14,15,16], whereas the effects of diet-induced obesity are demonstrated to diminish immune function through innate and adaptive responses to both primary and secondary infection. Some reports have proposed that obese subjects carry risk factors for complications appearing from a COVID-19 infection like a higher prevalence of heart or pulmonary problems relative to their healthy counterparts. Previous retrospective studies reported that obesity is a risk factor for symptom severity and mortality of the 2009 influenza A virus H1N1 pandemic [17]. Moreover, confinement increases sedentary behaviors performed mainly in a sitting position. Low physical activity levels, irregular eating patterns and frequent snacking, are associated with higher calorie intake and an increased risk of obesity [18].
These patterns endorsed recommendations for proper energy intake and demonstrate approaches for under- or overweight populations to be at risk for an infection such as influenza and other viral diseases [16, 19].
Water or fluids
Drinking enough water is an effective step in preventing disease risk. Liquids help to dilute the secretion and excretion of toxins and deliver essential nutrients in foods to cells and play a fundamental role in the removal of toxins and waste from the body. Drinking enough safe beverages is also very effective in enhancing one’s performance and physical strength; therefore, it is recommended to drink enough water, natural juices, teas and soups. One of the simple indicators to determine the adequacy of fluid intake is diluted and colorless urine [20].
The unhealthy diet
The unhealthy dietary pattern is characterized by high amounts of saturated fat, refined carbohydrates and sugars, and low levels of fiber, unsaturated fats, and antioxidants; this pattern is linked with inflammation, hyperglycemia, hyperlipidemia, obesity and chronic disease. Markedly, hyperglycemia is a risk factor related to high mortality in patients with severe COVID-19 infection [21, 22] (Table 1). The unhealthy dietary pattern which is high in saturated fatty acids increases angiotensin-converting enzyme (ACE); ACE converts angiotensin I to angiotensin II which is the main entry point for coronavirus 2 into cells [5]. Furthermore, this pattern induces chronic activation of the innate immune system, produces pro-inflammatory mediators, increases oxidative stress and impairs T and B cell function in the adaptive immune system; while T and B cell counts were significantly lower in patients with severe COVID-19 patients [21]; also, it was reported that high fat diets, rich in saturated fat, reduce the levels of adiponectin, while diets high in poly-unsaturated fatty acids increase adiponectin levels and reducing pro-inflammatory cytokines [23].
Healthy dietary pattern
A healthy, diverse diet with proper energy intake provides sufficient macro- and micro-nutrients, prebiotics, probiotics that can maintain immune cell function with anti-inflammatory effects and prevent potential infections [19, 24] (Table 1). It has long-term benefits in disease prevention even in the presence of obesity by increasing the efficacy of vaccines [21]. Maintaining a healthy diet is important in elderly people, as they are at increased risk of malnourishment due to multifactorial issues which can impair immune function [25].
Regarding that COVID-19 infection can generate a mild or highly acute respiratory syndrome along with high pro-inflammatory cytokines, including interleukin (IL)-6 and tumor necrosis factor (TNF)- α, a diet modification for improving the levels of adiponectin could be very useful to prevent the infection. The Mediterranean diet with anti-inflammatory properties was associated with an increase in adiponectin levels, improving the function of the cardiovascular system, particularly in elderly people [23, 26]. This diet with anti-inflammatory and immunomodulatory compounds is characterized by a relatively high dietary intake of fruit, vegetables, legumes, olive oil, whole grains, nuts, and monounsaturated fats, and low-to-moderate consumption of fermented dairy products, fish, poultry, wine, and processed meats. These foods contain vitamins, minerals and bioactive compounds like polar lipids and peptides with potent anti-inflammatory, antithrombotic and antioxidant properties; therefore, healthy dietary patterns such as the Mediterranean diet or similar are beneficial against COVID-19 infection due to their effects on immune function.
Increased levels of TNF-α and IL-6 have been related to high glycemic index/glycemic load carbohydrate intakes. In contrast, low-glycemic load foods, such as vegetables, fruit, nuts, seeds, and whole grains, do not trigger such adverse post-prandial inflammatory effects [27].
Fruit and vegetables contain vitamins, minerals, fiber, antioxidants and phytochemicals and phenolic compounds, which have potential benefits in association with respiratory and inflammatory conditions. Fruit and vegetables in the diet, such as those rich in flavonoids (like catechins found in tea, dark chocolate, and onions) have reduced serum inflammatory markers. Quercetin from onion and garlic decreased viral infectivity dependent on its concentration and inhibited intracellular viral replication. Previous reports confirm dietary recommendations to consume 3–5 servings of fruit and vegetables per day [19, 27].
Resveratrol, present in purple grape, is an inhibitor of Middle East respiratory syndrome -Coronavirus infection [5]. Foods with potent antioxidant or anti ACE activity like uncooked or fermented cabbage or fermented milk are largely consumed in low-death rate European countries, Korea and Taiwan [5].
Several studies have proposed favorable effects of garlic on the immune cells and on immunity in general, which might be due to its various bioactive sulfur-containing compounds, including sulfoxide, proteins and polyphenols. Moreover, garlic extract, garlic oil and aged garlic showed modulatory effects on macrophages and T-lymphocyte functions. Aged garlic extract inhibits the production of pro-inflammatory cytokines such as TNF-α and IL-6, while it decreases IL-12 production, which could further down-regulate pro-inflammatory cytokines such as interferon gamma and IL-2 produced by T-cells [28, 29]. High doses of garlic induce several complications (diarrhea, dizziness, nausea, vomiting, headache, flatulence), especially when ingested on an empty stomach.
Black and green tea has immune-stimulatory properties due to the presence of epigallocatechin- gallate, quercetin and gallic acid in the leaves [23, 28].
Fava beans contain chemical compounds like quinine-based antimalarial medications, some of which are being used in COVID-19 infected persons, such as hydroxychloroquine [30].
Protein foods
One of the important points in the diet of people with the aim of preventing and strengthening the immune system is to consider getting enough dietary protein. Protein is one of the main building blocks of cells and also the main constituent of internal secretions like an antibody [9, 27] (Table 1). Low protein status due to low protein intake has been recognized to increase the risk of infection through the decreased amount of functional active immunoglobulins and gut-associated lymphoid tissue, which play a role in gut mucosal defense against infection. Protein malnutrition increased susceptibility to Zika and influenza viruses [27].
The acceptable macronutrient distribution range of protein for an adult > 19 years is 10–35% of energy intake or 50 gr/day in a 2000 kcal diet [31]. A healthy eating pattern includes a variety of high biological value protein foods, including seafood, lean meats and poultry, eggs, legumes (beans and peas), nuts, seeds, soy products and dairy [32]. Various protein sources, like red and processed meats, are high in calories and saturated fats, which irritate lipogenesis and increase inflammation. In this regard, it has been acknowledged to reduce animal protein intakes and increase plant derived protein intakes due to their anti-inflammatory properties and egg white [27].
Dietary fiber
Increased fiber intake was associated with a significant reduction in high-sensitivity C-reactive protein concentrations (Table 1). Even small increases of only 5 g additional fiber per day can be beneficial for their immunomodulatory function. Dietary fibers increase the diversity of the gut microbiota and promote health associated bacteria which has been related to lower systemic inflammation. The advantageous effects of intestinal microbiota against viral infections, including influenza, have been known. An increase in dietary fiber per day was associated with a decrease in mortality-relative risk from infectious and respiratory diseases and chronic obstructive pulmonary disease. Also, the importance of both prebiotics and probiotics for prevention of infection has recently been emphasized. Fiber of whole-grain intake has also a favorable effect on the gut microbiome composition, which lowers both gut and systemic inflammation due to its fermentation and short-chain fatty acid production. Short-chain fatty acids might regulate the migration of immune cells toward inflammatory sites and modulate their activation state, enabling accelerated pathogen clearance through reactive oxygen species activation [27, 33].
The intake of 25 g and 38 g of fiber from whole grains, fruit, vegetables, legumes and nuts is recommended for women and men, respectively, to modulate the gut microbiome in the context of the COVID-19 crisis.
Fatty acids
The cholesterol-rich diet, often provided in unhealthy dietary patterns, affects markers of immune inflammation and cellular cholesterol metabolism, modulating lipoprotein profiles and functional properties of high density lipoprotein cholesterol. A high cholesterol diet may irritate and increase the risk of bacterial pulmonary infection in animal models and human populations, respectively while cholesterol intake during active infection may promote tissue-specific pathogen clearance and clinical outcomes. Furthermore, studies in animals and humans found that dietary cholesterol may irritate viral infections [34].
The omega-3 fatty acids, including alpha-linolenic acid from various plant sources, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish and sea-food exist at the site of inflammation is enzymatically converted for specialized pro-resolving mediators. These functions resolve inflammation, reduce the replication of influenza and potentially affect the inflammatory signs of respiratory viral diseases. It was found that SARS corona virus could bind with the cyclooxygenase promotor, increasing its expression; while it was reported that n-3 fatty acids can beneficially interact with the cyclooxygenase enzymes [19, 23, 35]. Also, EPA + DHA are responsible for a decrease in the production of pro-inflammatory cytokines through activation of peroxisome proliferator-activated receptors (PPAR)-γ which leads to the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells, a key transcription of pro-inflammatory cytokine production [36].
Nutritional deficiencies of these essential fatty acids induce delayed or suboptimal resolution of inflammation. A global survey of EPA + DHA status in the blood, from 298 studies, found “low” or “very low” status of these essential fatty acids. Indeed, the supplementation of EPA and DHA increases the level of these fatty acids in the phospholipids of cells involved in inflammation in a time and dose-dependent manner at the expense of Arachidonic acid (Omega-6 fatty acid).
It is recommended to balance fatty acid intake, such as saturated/unsaturated fatty acids, and omega-6/omega-3 fatty acids for immune system homeostasis. A healthy balance between omega-6 and omega-3 is 1:1–4:1, which has been reported to be in the range of 10:1 in individuals adhering to unhealthy diets [27]. The intake of omega-3 poly-unsaturated fatty acid, in the range of 0.5% and 2% of total calories (250 mg/day) is recommended to protect against excessive inflammatory conditions [23].
Furthermore, other lipid molecules in fish, including polar lipids, exhibit anti-inflammatory effects by modulating the activities and metabolism of the potent pro-inflammatory and pro-thrombotic mediator platelet-activating factor. The platelet-activating factor and its receptor are known to be involved in several non-communicable diseases and viral infections. Other bioactive compounds in fish, like peptides, may also prevent thrombosis, the generation of reactive oxygen species, and hypertension. Increasing fish consumption could be very important in the context of severe COVID-19 with uncontrolled inflammation and thrombosis that is linked with acute respiratory distress syndrome [19, 37].
Trans-fatty acid intake of hydrogenated vegetable oils and processed foods such as French fries and chips, has effects of a pro-inflammatory effect and associated with increased tumor necrosis factor-α, IL-6, and high-sensitivity C-reactive protein levels (Table 1).
Vitamin A
Vitamin A (Retinoic acids) regulates the differentiation, maturation, and function of the innate immune system and cells, as a front line of defense against pathogens. Vitamin A has an important role in the formation of healthy mucus layers, such as those of the respiratory tract and the intestine, which is required for mucin secretion and enhancing antigen non-specific immunity functions. Vitamin A deficiency has commonly been associated with an increased risk of infection [9, 24, 27, 33]. To ensure adequate vitamin A intake, it is recommended to consume 700-900 µg per day from animal sources like liver, milk, cheese and egg, and from vegetable sources like carotenoids in fruits and vegetables (Table 1).
Vitamin C
Vitamin C can be found in various fruit and vegetables such as citrus fruits, berries, brassicas, leafy greens and tomatoes. The dietary reference intake (DRI) of vitamin C for healthy adults is 75–90 mg/d. Regular vitamin C consumption reduces cold severity and duration. Previous studies reported that doses of 1–2 g/d were beneficial in preventing upper respiratory infections. As those levels are not attainable through dietary sources, supplementation may be advised for those at a higher risk of respiratory infections [19, 33] (Table 1).
Vitamin D
Vitamin D is found in eggs, mushrooms, fatty fish such as salmon, milk and dairy products, or foods fortified with vitamin D. Also, vitamin D3 is produced in the skin through sunshine radiation on the 7-dehydrocholesterol in the skin. Recent research has proposed that increasing vitamin D intake may reduce the risk of infections, including influenza, corona virus and pneumonia especially in vitamin D deficient subjects [33, 38]. Vitamin D interferes with viral replication and exhibits antiviral effects through its immunomodulatory and anti-inflammatory properties [39, 40]. A retrospective investigation in Switzerland showed that 25-hydroxyvitamin D (25(OH)D) concentration levels in plasma were significantly lower in polymerase chain reaction-positive for SARS corona virus (median value 11.1 ng/mL) patients compared with negative patients (24.6 ng/ml); this was also confirmed by stratifying patients according to age > 70 years [9, 41] (Table 1).
The DRI of vitamin D for healthy adults is 15–20 µg/day. Higher doses of vitamin D are recommended for vulnerable individuals who may be beneficial against COVID-19. Vitamin D supplementation is required for many individuals to reach 25(OH)D concentrations above 30 ng/ml [19, 42]. Supplementation of vitamin D3, at daily doses of 1000–4000 IU, is suggested [43]. Preventive doses of vitamin D3 of 10,000 IU/day for 4 weeks and then 5000 IU/day to gain a target 25(OH)D level of 100–150 nmol/L and treatment doses > 6000 IU/day in deficient subjects to gain a similar level and decrease disease development are recommended [40].
Vitamin E
Vitamin E in the form of α-tocopherol is recognized to meet human requirements. Various foods including nuts, seeds, vegetable oils, green leafy vegetables provide vitamin E. This vitamin enhances the immunity and anti-inflammatory effects through scavenging oxygen species to reduce oxidative stress. Vitamin E can also protect poly-unsaturated fatty acids in the cell membranes from oxidation.
Increasing vitamin E intake in the elderly may be beneficial for their immune function, increasing resistance to infection, and reducing morbidity due to infections. The DRI of vitamin E for healthy adults is 15 mg/d. Vitamin E has been recommended as a potentially beneficial nutrient against COVID-19 infection; however, there are currently no estimates of a beneficial dosage [19] (Table 1).
Zinc
Zinc can be found in various foods, including meat, dairy, and legumes. It is a trace element that is critical to the development of immune cells and an important cofactor for many enzymes.
It has certainly been proposed that increasing zinc intakes may be potentially useful against COVID-19 infections through reducing viral replication and reducing the effects of gastrointestinal and lower respiratory symptoms. The DRI of zinc is 8–11 mg/d of zinc for healthy adults (Table 1) [44].
Copper
Copper is an essential trace-element found in organ meats, nuts, cereals and some fruits. Copper deficiency has been related to change immune responses and increase frequency of infections. The DRI of copper is 900 µg/d for healthy adults. A copper intake of 7.8 mg/d has been reported to decrease oxidative stress and alter immune function [19].
Selenium
The relationship of selenium with influenza and hepatitis C viruses has been reported. Selenium deficiency has been related to viral infections such as influenza, influencing adaptive and innate immunity responses and causing a high level of virus-related pathogenicity. Selenium is required for the synthesis of selenoproteins, including several antioxidant enzymes. Therefore, selenium has a primary role as an antioxidant to quench reactive oxygen species. However, selenium supplementation may be related to elevation incidence of type 2 diabetes [27, 33] (Table 1).
Herbs and spices
Herbs and spices serve as an integrative method to augment the immune system, not the therapeutic efficacy of these foods.
Curcumin, the phytochemical component of turmeric, induces an anti-inflammatory effect through the up-regulation of PPAR-γ and the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells, a pro-inflammatory mediator [36]. The cytokine suppression by curcumin can be related to clinical improvement in conditions associated with cytokine storms in viral infections. Regarding inhibition of blood coagulation of curcumin through inhibiting platelet aggregation, cyclooxagenase pathway and blocking of calcium signaling, it can be an effective agent against intravascular coagulopathy conditions in COVID-19 [45] (Table 1).
Thyme and oregano have a culinary use as aromatic herbs that contain carvacrol, used as a food flavoring. In vitro and in vivo studies show that carvacrol has antioxidant, antibacterial, and anti-inflammatory properties. Hot pepper is the most widespread spice in the world. It contains capsaicin, the most present compound in hot pepper. Capsaicin has anti-inflammatory properties by activating PPAR-γ. Rosemary and sage are herbs which are used in the kitchen as aromatic plants. In the past, they have also been used for their antiseptic, antioxidant, and anti-inflammatory properties through activating PPAR-γ. Pomegranate seed oil contains punicic acid, a conjugated alpha-linoleic acid with anti-inflammatory and immunomodulatory properties. Punicic acid inhibits the expression of pro-inflammatory cytokines [36].
Food safety
Safe supply of food
Based on current epidemiological data, Coronavirus is not transmitted through food, so Corona virus infection is not considered as a food poisoning disease. Cooking significantly decreases the possibility of viral transmission, since the virus is inactivated and reduced to the minimum of 4 logs a 60◦ C for 30◦ min, 65◦ C for 15 min or 80◦ C for 1 min [46]. It is recommended not to consume raw or undercooked animal products. Good hygiene practices must be practiced by everyone in the food industry. Understandable and scientific information about food safety should be provided to all stakeholders in the food chain. Employees who contracted the virus should be able to report their illness and remain at home. At present, the potential presence of the virus in food packaging is not sufficient to cause infection. Food safety should be promoted via reinforcing safe food practices. Also, food systems should change during the pandemic through better use of locally processed foods to recover from difficulties [47].
Safe delivery of food
Social distance in restaurants should be maintained during the pandemic of COVID-19. Promotion of electronic-trade in food delivery services decreases crowds in restaurants. However, this distribution method may still increase the risk of spreading the disease. It has been reported that more than 60% of cases of coronavirus in a public hospital in Vietnam were as a result of food delivery from staff with mild or asymptomatic clinical symptoms [48]. Workers in the food delivery system may have direct contact with asymptomatic infected customers, and subsequently, these asymptomatic infected workers may inadvertently transmit the disease to their healthy customers. In many countries, food delivery workers were suddenly pushed to the front lines of the coronavirus pandemic [49].
Safe purchasing
To have a safe purchase, the following points were mentioned; maintaining a distance of 6 feet between the customer and the shopper, avoiding any physical contact with other customers and vendors, disinfecting the touched surfaces of grocery carts or basket handles, wearing a cloth-mask in the store, using hand sanitizer if available and avoiding shopping in public places if there are any signs such as fever or cough [50].
Virus on the surface of food packing will become inactivated over 24 h, so virus particles on food packaging do not transmit the disease. The inner contents of sealed containers are unlikely to be contaminated. It is necessary to wipe surfaces with household disinfectants and discard disposable grocery bags [50].
The elderly did not pay sufficient attention to food safety or to change or control diet-related risk factors. Limiting shopping and asking a neighbor or friend to shop, online shopping, or setting special hours in the morning for older adults to shop are some of the ways that can reduce the risk of transmitting the disease to this age group [50].