In December 2019, an outbreak of pneumonia of unknown cause took place in Wuhan, China. Chinese health authorities took action to determine the cause and to control the infection, including isolation of people suspected of having the disease, close observation of contacts, collection of epidemiological and clinical information from patients, and improvement of diagnosis and control . Studies found that there is a new beta coronavirus (β CoV) called critical acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due to its phylogenetic similarity with SARS-CoV. Infections spread to the rest of the world, leading to the WHO announcement of a pandemic and a Public Health Emergency of International Importance (PHEIC) [2, 3, 4]. COVID-19 is reported to be more severe and higher in mortality in older patients with conditions such as diabetes and hypertension, and in people with impaired immune systems [3, 5].
The number of Covid-19 cases was determined to be 30,000,000 worldwide in September 2020, and the number of deaths on the same date was reported to be over 940,000 . As of February 7, 2021, a total of 106,404,126 laboratory-confirmed cases and 2,321,761 deaths had been documented globally .
In studies, vitamins (B12, C, D, E) and trace elements (zinc, selenium, magnesium, and copper) to support the immune system were determined to be important [8, 9, 10]. Inadequate intake of these nutrients is common. Malnutrition causes suppression of the immune system, a decrease in resistance to infections, and an increase in disease burden .
In research, some nutrients that may be useful in the treatment of COVID-19 have been reported: zinc, resveratrol, hydroxytyrosol, curcumin, quercetin, vitamin C, and vitamin D . In diabetic people who were hospitalized with COVID-19, inadequate long-term glucose control was positively and independently related with tracheal intubation and/or death within 7 days . One study examined the relationship between dietary diversity of countries and COVID-19 mortality rate. When Germany was examined, consumption of a higher fat diet was reported in the southern states. It has been stated that the diet pattern differs according to the regions. The southern states traditionally have a higher-fat diet. Regional dietary differences and mortality rates are also different, suggesting that they are related. Therefore, differences in nutrition between countries with low and high mortality rates have been investigated. It has been determined that foods with high antioxidant or anti-ACE activity (raw or fermented foods) are consumed more in low-mortality European countries, and Korea and Taiwan. Cabbage is widely consumed in Romania and fermented milk in Bulgaria and Greece: it has been reported that lower mortality rates can be associated with these diets. Turkey is another country with low mortality rates, where fermented cabbage is widely consumed. Information like this shows that although diet has an effect on prevention of the COVID-19 outbreak, further studies are needed to know its importance . It is reported that individuals aged 60 and over are most affected by COVID-19 all over the world. It was determined that mortality rate increased with increasing age due to comorbid diseases .
All these results showed that nutrition is a very important subject in COVID-19 disease. Nutritional supplements, recommendations, and researches have been explored in the pandemic.
Vitamin B12 deficiency is a common condition in both elderly and diabetic patients. The importance of folate, homocysteine, and B12 in single carbon metabolism is known. In a study examining the effect of COVID-19 on the elderly and diabetic patients, the role of vitamin B12 deficiency was investigated. It has been shown in a study that areas where the negative effects of B12 deficiency and incidence of COVID-19 coincide. There is also evidence that COVID-19, which causes problems in immunological, microbiological, hematological, and endothelial cell functions, can add a potential therapeutic dimension by interfering with its replication with B12 supplements. For this reason, it is stated that B12 deficiency is a modifiable and absolutely preventable risk factor in the fight against COVID-19. As a result, researchers have found that the folate, homocysteine, and B12 levels of COVID-19 patients should be optimized .
Studies have found [16, 17, 18] that high serum vitamin B12 is associated with increased mortality in critically ill patients. It has been suggested that vitamin B12 levels should be determined, especially in intensive care patients with chronic disease and increasing disease severity .
The antiviral property of vitamin C has been found in researches with patients affected by various types of herpes or influenza viruses. In addition, people who have acute infectious diseases have been reported to have low serum vitamin C levels. Ascorbate has been shown to have the capacity to increase interferon production and reduce the production of different cytokines. Vitamin C also provides positive effects in terms of immunomodulation in patients affected by different viral infections .
In a different study, methemoglobin, nitrite, nitrate, and prooxidant-antioxidant levels were determined in 25 healthy individuals and 25 patients hospitalized in the COVID-19 intensive care unit. It was determined that methemoglobin, nitrite, nitrate, and oxidative stress were importantly enlarged in COVID-19 positive patients compared to healthy individuals. Methylene blue-vitamin C-N acetyl Cysteine (MCN) was administered to 5 patients as the last treatment option. It was determined that four out of five patients responded well to treatment. As a result, it has been determined that nitric oxide, methemoglobin, and oxidative stress may play a central role in the pathogenesis of critical COVID-19 disease; moreover, MCN therapy can increase the survival rate of patients .
A review study established that the use of high doses of oral vitamin C provided protection against viral infections. It has been stated that antioxidants such as vitamin C can be used in high doses for treatment of early-stage COVID-19 patients. Intravenous or oral administration of high doses of vitamin C has been shown to be safe. Therefore, including vitamin C in COVID-19 treatment is recommended .
Vitamin D is one of the fat-soluble vitamins. In the form of vitamin D2 (ergocalciferol), it can be taken by consuming dairy products, fish, and eggs. Under the influence of the sun, vitamin D3 (cholecalciferol) can be converted into 1,25-dihydroxycholecalciferol (calcitriol), which is the active form of vitamin D in the skin. It plays a role in the absorption of vitamin D, calcium, magnesium, and phosphate .
Vitamin D plays an important role by interfering with most of the macrophages, B and T lymphocytes, neutrophils, and dendritic cells in the immune system . Additionally, vitamin D deficiency been found to be involved in various diseases such as diabetes, changes in regulation of immune system, cardiovascular diseases, cancer, inflammation, hypertension, cognitive changes, and osteoporosis . During the pandemic, the level of exposure to sunlight decreases as time spent by individuals in the open air decreases [24, 25, 26]. Lower serum vitamin D levels are reported to be associated with psychiatric illnesses, including autism and major depressive disorders (MDD) [27, 28]. Different amino acids and vitamin D are known to be precursors and regulators of mental well-being .
Low serum vitamin D is common in Europe, with the exception of the Nordic countries. It is reported that 12 European countries show a significant (P = 0.046) inverse correlation with the COVID-19 mortality rate, plasma 25 (OH) D concentration .
If vitamin D deficiency is accompanied by comorbidities such as hypertension, diabetes, cardiovascular diseases, and metabolic syndrome, closer follow-up of COVID-19 patients is recommended. It has been determined that the natural vitamin D synthesis of the skin is reduced, especially as the exposure time of people to the sun decreases due to the pandemic. It is recommended that individuals consume vitamin D–fortified foods if they have access to them. It is emphasized that the vitamin D level of COVID-19 patients staying in hospital must be measured and supplemented with supplements if low .
The possible role of vitamin D in providing immune response in viral infection becomes even more important in the pandemic. In addition, dexamethasone is used as an anti-inflammatory drug in COVID-19 patients with critical disease. It has been emphasized that large-scale studies should be carried out on whether vitamin D can be used in combination with dexamethasone or alone in reducing the effects of viral infection .
Another descriptive retrospective study was conducted in a health center with COVID-19 patients in Tehran, Iran, between March and April 2020. In this study, in which a total of 205 patients were examined, no statistical difference was found between the serum vitamin D levels of COVID-19 patients who died in hospital and those who recovered. When the patients were grouped according to disease level, it was determined that there was a significant difference in serum vitamin D level in patients with severe disease, healing, and death (P value: 0.021). In addition, it was emphasized that the mortality rate was higher in patients with very low vitamin D levels. It was concluded that vitamin D deficiency may affect the control of the disease and mortality in individuals, especially if there is an accompanying disease or the individual is elderly .
In a study conducted in Italy, serum 25 (OH) vitamin D levels of 129 adult COVID-19 patients hospitalized in the health center between March and April 2020 were evaluated. No correlation was found between COVID-19 and serum 25 (OH) vitamin D deficiency (< 20 ng/mL) in the research. Contrary to expectations, a significant positive association was observed between increased serum 25 (OH) vitamin D level and mortality .
Another retrospective study was conducted in medical centers in Boston and New York. Serum 25 (OH) D levels of COVID-19 positive patients are inversely correlated with mortality and the need for invasive mechanical ventilation. It was emphasized that randomized clinical studies are needed to evaluate the effects of vitamin D in reducing morbidity and mortality of COVID-19 .
In a study examining the relationship between vitamin D status and disease severity and mortality, 185 patients diagnosed with COVID-19 and treated in the center where the study was conducted were examined. In this observational study, it was determined that there is a relationship between vitamin D status and the severity and mortality of COVID-19. It has been emphasized that prospective, randomized controlled trials on vitamin D supplementation in COVID-19 patients are highly warranted .
A retrospective, observational study conducted in the United States was conducted between March and June 2020. In this study, which included 191,779 patients from all 50 states, an inverse relationship was observed between SARS-CoV-2 positivity and circulating 25 (OH) D levels. According to the results, vitamin D supplementation has been reported to be required to reduce the risk of COVID-19 infection .
Vitamin E, one of the fat-soluble vitamins, shows an important role in decreasing oxidative stress . Vitamin E deficiency increases the symptoms of diseases and causes critical conditions. An inverse correlation was found between vitamin E and viral infection. Therefore, improving vitamin E status is suggested to decrease the harmful effect of oxidative stress in patients with COVID-19 disease .
Vitamin K is a biochemically single functional nutrient, because its only defined function is γ-carboxylation. However, it has been determined to activate proteins with yet not fully resolved functions . In a study, it was reported that vitamin K decreased in COVID-19 patients and this decrease was related to poor prognosis. This study states that new studies are required to determine the effect of vitamin K administration on patients with COVID-19 . In another study, it is reported that small intestine involvement and/or decreased dietary intake due to COVID-19 may be among the causes of decreased vitamin K status in COVID-19 patients. Among other potential reasons, decreased access to green leafy vegetables is cited as a possible cause, as was increased alcohol consumption and increased use of paracetamol .
Zinc is an essential mineral that serves as a cofactor in most intracellular processes. Additionally, it plays a role in cell functions. It can be related to metabolism and immune system function. It is estimated that about 20% of the world's population has low blood zinc levels. It is also reported that blood zinc level is more important for the elderly. It has been determined that zinc deficiency causes a decrease in antibody production. In zinc deficiency, the activity of natural killer cells decreases and the innate immune system changes .
Selenium is an essential trace element. Along with vitamin E, selenium prevents free radical formation and oxidative damage in cells and tissues. It has been found to have an effect on immune response . It has been reported that selenium deficiency may be responsible for lung damage and may be associated with mutation of viral genomes . Inadequate intake of selenium, an antioxidant nutrient, with nutrition causes diseases or death by leading to immune system impairments and RNA viral mutations .
In the observational cohort study, 43 COVID-19 patients 50 years old were identified and 17 patients were given vitamin D3 1000 IU OD, magnesium 150mg OD and vitamin B12 500mcg OD (DMB). Supplements were not given to the remaining 26 patients. DMB supplementation administered to COVID-19 patients depending on age has been related to a significant decrease in the proportion of patients needing oxygen and/or intensive care support. Studies in larger groups have been suggested to confirm the benefit of DMB .
Prebiotics are substances used by microorganisms living in the body which positively affect health. Consumption of prebiotics promotes the growth of
Probiotics colonize mainly in the intestine. However, these enities have been determined to have a fundamental effect on the immune system. They also play a role in the emergence of immune responses in the lung and other mucosal areas . Studies have found that prebiotic consumption is as important as probiotic consumption for immunity. A healthy diet rich in prebiotics, such as fibers, fruits, vegetables, and whole grains, is essential for properly nurturing probiotics and for the proper functioning of the immune system .
Prebiotics are derived from plants such as Jerusalem artichoke, chicory root, yacon (source of inulin), onions, whole grains, garlic, and bananas. Dietary fiber that is water-soluble and digested by intestinal bacteria, and those that are fermented in the large intestine, such as water-insoluble but resistant starches, have been termed
Probiotics taken with the consumption of dairy products have many functions in intestinal health, such as strengthening the immune system and increasing the bioavailability of foods . Probiotics are known to help protect the gut microbiome. They aid the immune system in the formation of the response to diseases .
Fecal samples of COVID-19 patients have been studied. SARS-CoV-2 viral RNA appears in the gut of patients. Therefore, gut health is thought to be important for COVID-19 . Probiotics are recommended against COVID-19 because they regulate the intestinal-lung axis, have positive effects on innate/developable immunity, and they are required in regeneration of damaged tissues and organs [47, 50, 52].
In addition to
Although good vaccines for COVID-19 are now available, an immune-boosting diet containing prebiotics and probiotics is recommended .
In another review study, it was stated that the use of probiotics in COVID-19 should not be recommended until its effect on SARS-CoV-2 pathogenesis and intestinal microbiota is determined. With this work to be done, it is thought that new suggestions will be presented for the change of intestinal microbiota against COVID-19 and accompanying diseases .
In a case-control study conducted with 505 participants (226 controls and 279 subjects with clinical symptoms of COVID-19) in Iran, the eating habits of the control group and the patient group were examined. The consumption of doogh drink and yogurt was found to have a protective role in the occurrence of COVID-19. Individuals at high risk for COVID-19 have been advised to consume adequate amounts of yogurt and doogh drink during the pandemic .
The use of fermented foods, probiotics, and/or prebiotics is recommended to protect intestinal health and increase immunity. Consumption of probiotics and prebiotics is thought to help reduce intestinal inflammation and strengthen immunity. Fermented foods and probiotics contain live microorganisms with the potential to boost (intestinal or systemic) immunity. It is reported that prebiotics can increase intestinal immunity by selectively stimulating microorganisms in the intestine. For this reason, it is reported that beneficial microorganisms may be important in the prevention of COVID-19 and other infectious diseases that may occur in the future .
It has been determined that the content of all onion species is rich in flavonols such as quercetin, tannins, kaempferol, allyl propyl disulfide and diallyl disulfide . Onion has been used as a traditional medicine for thousands of years .
According to the results of a study, onion consumption may have an antithrombotic, anti-inflammatory and possibly anti-viral effect in the primary treatment of COVID-19 patients. The study noted that further researches are needed to determine the useful effects on COVID-19 .
It has been determined that kaempferol and quercetin contained in onions reduce the growth of various viruses. In addition, virucidal activities of quercetin and kaempferol against herpes simplex type I virus, rabies virus, mengo virus, polio virus, sindbis virüs, pseudorabies virus and parainfluenza type 3 virus were determined in studies. Numerous previous studies have noted the antiviral effect of onion and garlic . In another study based on these results, onion and garlic consumption is recommended to prevent COVID-19 disease .
Research was conducted to determine the resistance of compounds in garlic essential oil to SARS-CoV-2. The strongest anticoronavirus effect has been found in allyl disulfide and allyl trisulfide compounds. Allyl disulfide and allyl trisulfide are the most dominant compounds in garlic essential oil .
Quercetin is one of the flavonols and six subfamilies of flavonoids. It is the most dominant flavonoid molecule found in various vegetables and fruits such as apple, onion, dill, strawberry, and coriander. It is a yellow compound that can be soluble in lipids and alcohol. Many useful pharmacological activities of quercetin have been reported. Among them, anticancer capacity and ability to fight viruses can be highlighted. In addition, it has been reported that it has positive impacts in the treatment of allergic diseases, cardiovascular disorders, metabolic diseases and inflammation .
Quercetin can inhibit the entry and replication of influenza virus, Dang virus, and enterovirus into host cells [63, 70]. According to the data of another study, it was determined that quercetin can inhibit the replication of different respiratory viruses [71, 72]. It was theoretically determined that quercetin would interfere with the replication of SARS-CoV-2 .
While it is thought that the use of quercetin may have a positive effect on the incidence and duration of respiratory tract infections, in another study, it is emphasized that more research is needed to determine its use in the treatment of COVID-19 .
Resveratrol is in the the polyphenol family and is found in grapes, strawberries, nuts, red wine, chocolate, and similar foods. Resveratrol is known to protect against a range of diseases, including respiratory, malignant, and cardiovascular diseases . In the cellular stage, resveratrol shows as an cytostatic, anti-oxidant, antiviral, anti-inflammatory, and it extends the lifespan of cells .
Antiviral properties of resveratrol against various viral pathogens have been established. Positive results have been determined in in vitro and in vivo studies on diseases such as Middle East Respiratory Syndrome Coronavirus (MERS-CoV) , duck enteritis virus , and pseudorabies virus [79, 80]. In a study, it was emphasized that resveratrol, which is naturally found in many fruits, is expected to decrease mortality caused by COVID-19 with its anti-inflammatory and anti-thrombotic properties .
A study was conducted with 230 severe COVID-19 patients between April and May 2020 at a hospital in Mumbai. Thirty patients were given resveratrol and copper in addition to care. According to the results of the study, the use of resveratrol-copper combination resulted in a twofold reduction in mortality. It was stated that new randomized controlled studies should be conducted in addition to this study .
Curcumin is found in the turmeric plant, and has long been used in food. Due to its proven antiviral properties, use of it has become widespread . It has been established that it can affect the cell metabolism and organisms in different ways, including anti-oxidant, anti-inflammatory and anti-proliferative properties . Previous studies have established antiviral properties against many viruses, including HIV , dengue , herpes simplex , and hepatitis C virus [84, 88]. Another study found its antiviral effect on mosquito-borne Zika and Chikungunya viruses .
Curcumin, zinc, and zinc-ionophores were also investigated in studies. Antiviral effects against viral infections have been determined. Curcumin can form ionophore complexes with polyphenols such as zinc. It has been reported that zinc, curcumin, and zinc-ionophores can be used in immune support and in the treatment of COVID-19 using various mechanisms [89, 90].
A study was conducted on isolated probiotics derived from traditional Indian (turmeric) pickles used in the process of the COVID-19 outbreak. The study found that the turmeric in fermented pickles is a good probiotic candidate and is recommended as a very beneficial product for health .
Homocysteine is an amino acid that contains a sulfhydryl group. It is found during the metabolism of the amino acids methionine and cysteine. Hyperhomocysteinemia is used as a predictive risk indicator in screening congenital methionine metabolism, in the detection of cardiovascular diseases and vitamin B12 deficiency. Homocysteine shows the most negative effects in the cardiovascular system and nervous system .
Previous studies have shown that hyperhomocysteinemia has adverse effects on many viral infections, including human hepatitis virus, human papilloma virus , and human immunodeficiency virus . In addition, the emergence of hyperhomocysteinemia not only in COVID-19 patients but also in many other diseases may have a negative effect, but the results have not been determined .
In a study of 40 individuals with COVID-19, routine detection of plasma homocysteine as a potential indicator for disease was performed, and found to be useful. Sharing first observations about the potential biomarkers for serious diseases during the pandemic will provide important benefits for patients and rapid development of available information . It has been reported that if COVID-19 is present with harmful hyperhomocysteinemia in patients, it is thought that the use of vitamin B9 and other B vitamins is positive and safe in lowering the homocysteine level. B vitamins may be temporarily preferred for treatment. However, in the same report, it was stated that more studies are needed on this subject .
Propolis is widely used in health promotion and strengthening the immune system. Propolis produced by bees has antiviral activity . Propolis is an auxiliary ingredient in traditional Chinese medicine . It has also been identified as an immunostimulating and powerful vaccine adjuvant .
It has been observed in studies that propolis has antiviral and anti-inflammatory [99, 100] properties. In other researches, it was determined that propolis has an inhibition effect on influenza [100, 101] and herpes simplex virus type 1 . It is found that propolis may also have an antiviral effect against SARS-CoV-2 .
In a study, the antiviral activities of theaflavins in black tea and epigallocatechin-3-gallate (EGCG) polyphenols in green tea were examined. The antiviral activity of epigallocatechin-3-gallate (EGCG) against several viruses has been established. It has been found to be an important treatment option compared to chemical drugs . Apart from antiviral effects, antibacterial, antitumorigenic, antioxidant, anti-inflammatory, and antiproliferative properties have been observed . Theaflavins (TF) are found in black tea. The anti-inflammatory, anti-tumor, anti-bacterial, anti-oxidative and anti-viral properties of theaflavins have been determined. Both green tea and black tea polyphenols have anti-viral activities against various viruses, especially single-stranded RNA viruses. When studies are reviewed, the use of tea polyphenols is recommended in the treatment of COVID-19 .
In a review article, it was stated that in countries where large amounts of green tea is consumed, such as China, Indonesia, and Japan, the mortality rates are lower than in Europe, Africa and the USA .
Various effects of natural micronutrients and bioactive substances
|Anti-inflammatory||Vitamin D, Curcumin, Quercetin, Propolis||[99, 100, 105, 106, 107]|
|Antioxidant||Vitamin C, Vitamin E, Curcumin, Selenium||[37, 106, 108, 109]|
|Antiviral||Selenium, Curcumin, Quercetin, Riboflavin, Vitamin C, Green Tea, Propolis, Resveratrol, Zinc||[99, 100, 103, 109, 110, 111, 112, 113]|
|Immune response||Vitamin A, Vitamin C, Vitamin D, Vitamin B12, Folate, Pyridoxine, Zinc, Nicotinamide, Selenium||[38, 109, 113]|
|Interferon production||Vitamin C|||
|Virus-ACE2 interaction reduction||Quercetin, Curcumin|||
It was stated that among the nutritional recommendations published by the World Health Organization (WHO) for adults during the COVID-19 pandemic process, unprocessed foods and fresh vegetables and fruits should be consumed daily. It was emphasized that 8–10 glasses of water should be consumed every day, less salt and sugar should be consumed, and fat and oil consumption should be moderate. In addition, it has been suggested that meals should be consumed at home to reduce exposure to COVID-19 .
Nutritional recommendations of ASPEN for COVID-19 patients are 3 liters of fluid consumption per day, a diet containing 2000–2500 calories and 75–100 grams of protein. It was emphasized that even if the patient is not hungry, food should be consumed every 2–3 hours .
According to the ASPEN recommendation, patients receiving enteral nutrition should be targeted to meet 70% to 80% of their daily energy needs (15 to 20 kcal/kg actual weight) and 1.2 to 2 grams of protein/kg per actual weight .
It has been reported by ESPEN that energy intake should be 27–30 kcal/day during the COVID-19 period (determined according to nutritional status, weakness, polymorbid status). Protein intake has been suggested to be 1 g/kg/day. It has been stated that fat and carbohydrate consumption should be 30–70% or 50–50% in patients with respiratory problems. It has been reported that adequate intake of vitamins A, E, B6 and B12 and micronutrients such as Zn and Se should be considered .
The prevalence of obesity and type 2 diabetes is high, as diets high in saturated fat, refined carbohydrates, and sugar are common worldwide. Individuals with comorbidities are reported to have a higher mortality rate from COVID-19.
Elderly patients and patients with concomitant illnesses mostly had impaired nutritional status and sarcopenia, independent of body mass index. Increased body mass index appears to be associated with poor prognosis in the presence of comorbidity in COVID-19 patients. As a result, the importance of nutrition has been observed in studies on COVID-19 patients. It was stated that the nutritional therapies and the treatment to be applied should be improved in order to overcome the new global crisis.
Adequate and balanced diet, avoidance of processed foods, and consumption of healthy foods are very important in COVID-19, as in many diseases. In the long run, new studies should be conducted with more people to determine the safest and most effective dietary supplements for COVID-19.
Various effects of natural micronutrients and bioactive substances
|Anti-inflammatory||Vitamin D, Curcumin, Quercetin, Propolis||[
|Antioxidant||Vitamin C, Vitamin E, Curcumin, Selenium||[
|Antiviral||Selenium, Curcumin, Quercetin, Riboflavin, Vitamin C, Green Tea, Propolis, Resveratrol, Zinc||[
|Immune response||Vitamin A, Vitamin C, Vitamin D, Vitamin B12, Folate, Pyridoxine, Zinc, Nicotinamide, Selenium||[
|Interferon production||Vitamin C||[
|Virus-ACE2 interaction reduction||Quercetin, Curcumin||[