Supplementation of Micronutrients Against COVID-19

Background and Objectives: There is no pharmacological treatment with proven e�cacy against coronavirus disease-19. Certain micronutrients have roles in the maintenance of an effective immune system. From the point of view of public health, it will be good to adopt a nutrional strategy to enhance the immunity of the general population against viral diseases. Method and Study design: A review was done to now the evidence for the antiviral and immunomodulatory properties of micronutrients. A search was done in Pubmed, Scopus, and Google Scholar for the nutrients with proven effect against viral infection. Experimental studies, clinical studies, reviews, and meta-analyses were studied descripitively. Results: There are experimental studies about the effects of micronutrients against viral infection. Vitamins such as A, B6, B12, C, D, E, and folate, and trace elements such as zinc, selenium, iron, magnesium, and copper boost the immune response. The antioxidants like vitamin C and vitamin E can help in controlling the ‘cytokine storm’, produced by excessive in�ammation. Vitamin D can increase anti-inammatory cytokines. Selenium and zinc can protect the lungs in acute respiratory distress syndrome. There are many meta-analyses on the randomized controlled trials (RCT) about the effect of micronutrients on viral infection. The analyses of the trials supplementing vitamin C, vitamin D, vitamin E, and selenium have shown signi�cance. Conclusions: There is level 2A evidence for the bene�cial effects of vitamins and micronutrients

Vitamins such as A, B6, B12, C, D, E, and folate, and trace elements such as zinc, selenium, iron, magnesium, and copper boost the immune response.The antioxidants like vitamin C and vitamin E can help in controlling the 'cytokine storm', produced by excessive in ammation.Vitamin D can increase antiin ammatory cytokines.Selenium and zinc can protect the lungs in acute respiratory distress syndrome.
There are many meta-analyses on the randomized controlled trials (RCT) about the effect of micronutrients on viral infection.The analyses of the trials supplementing vitamin C, vitamin D, vitamin E, and selenium have shown signi cance.
Conclusions: There is level 2A evidence for the bene cial effects of vitamins and micronutrients in modulating the immunity against viral infections.So a programme for nutritional supplementation of these can help in ghting the pandemic.

Highlights:
From the point of view of public health, it will be good to adopt a nutrional strategy to enhance the immunity of the general population against viral diseases.
Vitamins such as A, B6, B12, C, D, E, and folate, and trace elements such as zinc, selenium, iron, magnesium, and copper boost the immune response.
The antioxidants like vitamin C and vitamin E can help in controlling the 'cytokine storm', produced by excessive in ammation.
Vitamin D can increase anti-in ammatory cytokines.

Selenium and zinc can protect the lungs in acute respiratory distress syndrome.
There is level 2A evidence for the bene cial effects of vitamins and micronutrients in improving the immunity against viral infections.
A programme for nutritional supplementation of these can help in ghting the pandemic.

Introduction:
The pandemic caused by severe acute respiratory syndrome virus-2 (SARS-CoV-2) is not controlled in world.There is no pharmacological treatment with proven e cacy and safety 1 .About 147 million persons are infected worldwide and 3.11 million died.Although vaccination has started, now many countries are facing the second wave of the pandemic.So from the point of view of public health, it will be good to adopt a nutrional strategy to enhance the immunity of the general population against viral diseases.Undernutrition impairs immune system 2 .Certain micronutrients have roles in the maintenance of an effective immune system.Nutrition is also very important in controlling the crisis of sepsis.Vitamins such as A, B6, B12, C, D, E, and folate, and trace elements such as zinc, selenium, iron, magnesium, and copper boost the immune response against viral infection 3 .

Objective, Materials, And Methods:
A review was done to now the evidence for the antiviral and immunomodulatory properties of micronutrients.A search was done in Pubmed, Scopus, and Google Scholar for the nutrients with proven effect against viral infection.Experimental studies, clinical studies, reviews, and meta-analyses were studied descripitively.

Entry, replication, and immune response:
The spike or S protein of coronavirus binds to angiotensin-converting enzyme 2 (ACE2) receptor of host cell 4 .The viral RNA[ribonucleic acid] enter into the host cell.The proteins are translated.The assembly and budding occur in the endoplasmic reticulum and Golgi compartment.Virions are then released from the infected cell through exocytosis.The antiviral drugs target the steps of this process.The macrophages present coronavirus antigens to T cells 5 .T cell activation produces cytokines.The cytokines amplify immune response.Interferons(IFN) limit virus spread, and promote macrophage phagocytosis of antigens.The CD8 cytotoxic T cells kill the infected cells.The B cells produce antibodies against the virus.The T cells assist the B cells to differentiate into plasma cells, which then produce immunoglobulinM(IgM) and immunoglobulin G(IgG) antibodies speci c to the viral antigens 6,7 .An IgG antibody can block the virus from entering into host cells.The messenger RNA(mRNA) vaccine, adenovirus vaccine, and the whole-virus inactivated vaccine induce response against the S protein 8 .
The immune responses induced by SARS-CoV-2 infection have two phases 9 .During the non-severe stage, strategies to boost adaptive immune response is required to eliminate the virus.The damaged cells induce in ammation in the lungs, mediated by pro-in ammatory macrophages and granulocytes.In the severe stage of 'cytokine storm', in ammation should be suppressed.

Experimental evidence :
Atherton et al exposed chick embryo tracheal organ cultures to ascorbic acid 10 .Increased resistance to infection by coronavirus was observed.An animal study by Jee et al. has shown that a diet high in vitamin A boosted the production of immunoglogulin G(IgG) in calves injected with bovine coronavirus 11 .
Research has shown that vitamin D stimulates genetic expression of antimicrobial peptides such as defensins and cathelicidins in human monocytes, and neutrophils 12 .They have antiviral activity.Animal studies have shown that vitamin E increases lymphocyte proliferation, immunoglobulin levels, natural killer (NK) cell activity, and interleukin (IL)-2 production 13 .A study in healthy individuals showed that repletion of vitamin B6 resulted in decreased lymphocyte and interleukin-2 14 .Folic acid de ciency results in atrophy of thymus and spleen, and decreased circulating T lymphocytes in animals 15 .Vitamin B12 administration increases CD8 and NK cells 16 .
Zinc inhibited the replication of SARS-CoV in cell culture study 17 .Supplementation with selenium has been shown to cause increase in the activity of cytotoxic lymphocytes and NK cells 18 .A study in aged mice has shown that dietary selenium increased the ability of splenic lymphocytes to undergo blastogenesis 19 .Iron de ciency impairs cell-mediated and innate immunity 20 .The T cell proliferation on stimulation is only 40-50% in iron-de cient women, compared to iron-su cient women.A murine cell line study demonstrated that magnesium induced macrophages to produce the cytokines interleukin (IL)-4 and IL-10 21 .Cell culture studies have shown that a decline in copper status decreases IL-2 production by activated human T-cells 22 .

Control of in ammation:
The antioxidants like vitamin C and vitamin E can help in controlling the pro-oxidative state known as a 'cytokine storm', produced by excessive in ammation 15 .Intravenous vitamin C is being investigated as a treatment for cytokine storm syndrome 23 .Selenium has been shown to moderate the in ammatory responses, and restore the antioxidant capacity of the lungs in patients with acute respiratory distress syndrome (ARDS) 24 .Zinc has protective effects on the lungs in patients receiving mechanical ventilation for ARDS 25 .Vitamin D can reduce the expression of pro-in ammatory cytokines and increase antiin ammatory cytokines 26 .
The results of the review are tabulated (table-1).
Table 1 Effect of micronutrients on the immune system.

Vitamin C
Increased resistance to infection by coronavirus.

Has antioxidant effect.
Vitamin A Boosts the production of immunoglobuilin G.
Vitamin D Stimulates the expression of antimicrobial peptides such as defensins and cathelicidin.
Increases the anti-in ammatory cytokines.
Vitamin E Increases lymphocyte proliferation, natural killer cell activity, immunoglobulin level, and interleukin-2 production.
Has antioxidant effect.

Vitamin B6
Needed for lymphocyte and interleukin-2.

Folic acid
Needed for thymus, spleen, and circulating T lymphocytes.

Vitamin B12
Increases CD8 and natural killer cells.

Zinc
Inhibits the replication of SARS-CoVirus.
Has protective effect on the lungs.

Selenium
Increases the activity of cytotoxic lymphocytes and natural killer cells.
Restores the antioxidant cpacity of the lungs.
Iron Necessary for T cell proliferation.

Magnesium
Induces the production of interleukin-4 and interleukin-10.

Copper
Needed for the production of interleukin-2.

Current guidelines:
The European Food Safety Authority (EFSA) has endorsed 10 micronutrients as essential for healthy maintenance of the immune system: vitamin A, vitamin B6, vitamin B12, vitamin C, vitamin D, folate, zinc, iron, copper, and selenium 27 .There are several trials ongoing involving vitamins A, C, D, and E, and micronutrients magnesium, and zinc against coronavirus disease-19 (COVID-19), registered by the world health organization (WHO) 28 .There are many meta-analyses on the randomized controlled trials (RCT) about the effect of micronutrients on viral infection 29 .The analyses of the trials supplementing vitamin C, vitamin D, vitamin E, and selenium have shown signi cance.Han et al did a pilot study of high dose vitamin D administration in ventilated intensive care unit patients 30 .It was found that high-dose vitamin D3 was associated with decreased the length of hospital stay.

Safety of supplementation:
There are concerns about the adverse effects of vitamin and mineral supplementation 31 .It has been found in systematic review that the use of multivitamins and minerals within the range of the dietary reference intake will not result in excess intake 32 .The American and European boards have de ned the Tolerable Upper Intake Levels (UL) of vitamins and minerals to avoid the adverse health effects 33 .There are micronutrient supplementation programmes in developing countries for at-risk groups 34 .Examples are vitamin A supplementation for children and iron and folic acid for pregnant women 35 .

Conclusion:
There is level 2A evidence for the bene cial effects of vitamins and micronutrients in improving the immunity against viral infections and in modulating the immune responses.So a programme for nutritional supplementation of these can help in ghting the pandemic.Since the vaccination has started, an adjuvant programme for nutritional supplementation can help in increasing the immunity of the people.
List Of Abbreviations: RCT-Randomized controlled trials.
mRNA-messenger RNA NK-Natural killer cells.
EFSA-European Food Safety Authority.