The therapeutic, preventive, and immune-boosting effects of some minerals and vitamins in COVID-19: A narrative review

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), which produces COVID-19, is the most deadly coronavirus ever identified. Essential treatments and nutrition are crucial for improving the immune system against viral infection. As studies recommended checking the nutritional state of COVID-19-infected individuals before treatment, we aimed to review the therapeutic, preventive, and immune-boosting effects of some minerals and vitamins on COVID-19. This review emphasizes the possible therapeutic, preventive, and immune-boosting effects of some minerals such as zinc, selenium, iron, calcium, phosphorus, potassium, and magnesium and vitamins C, D, and E on COVID-19 patients. Regarding the evidence that shows the preventive effects of vitamins and minerals on serious COVID-19, it seems that clinicians have to consider these factors precisely.


COVID-19
The pneumonia of unknown causes was detected in Wuhan city (China) in December 2019, and it was called coronavirus . This virus spread rapidly and caused a global pandemic in March 2020. Thus, various countries adopted extreme public health measures to control it (4).
The clinical characteristics of COVID-19 are categorized into five distinct types as follows (5)

Implication for health policy/practice/research/ medical education
This review emphasizes the possible therapeutic, preventive, and immune-boosting effects of some minerals such as zinc, selenium, iron, calcium, phosphorus, potassium, and magnesium and vitamins C, D, and E on COVID-19 patients.
• Shortness of breath. 5. Critical illness; septic shock, acute respiratory distress syndrome, mechanical ventilation, necessitates intensive care unit treatment, and multiple organ failure (5). COVID-19 is not independent and can be associated with different underlying diseases. Even comorbidities such as diabetes can be the risk factors for COVID-19. Therefore, understanding the pathophysiology of COVID-19 helps improve comorbidity management (6).
Since it is a severe contagious disease that can quickly spread, new care methods are required to reduce the likelihood of face-to-face contact between patients and healthcare providers. Thus, the telemedicine application can be an alternative method for in-person visits to stop the virus spread (7). The previous studies highlighted the importance of nutritional supplements. Indeed, these studies helped COVID-19 patients by possibly lowering the viral load and preventing hospitalizations (8). In the next section, the authors investigated the effects of minerals and vitamins on COVID-19.

Zinc and COVID-19
Zinc is a component of various enzymes, and the growth and improvement of immunological and other cells depend significantly on zinc. The deficiency of zinc makes people more vulnerable to viral infectious diseases by impairing cellular and humoral immunity (9). Moreover, it has antiviral effects and is a substantial component of the immune defense against viral infections such as H1N1 influenza (10). Since zinc deficiency decreases cellmediated immunity, its supplementation is suggested for improving several viral infections. in addition, zinc intake impacts many cellular immune processes, including releasing interferon-γ (IFN-alpha) and interleukin-2 (11).
The previous studies demonstrated that older people taking zinc supplements produced more IFN-alpha from their leukocytes in vitro than others. This situation can be beneficial for preventing and treating viral infections such as COVID-19. However, long-term zinc therapy raises the possibility of immune system suppression. Maywald et al revealed that excessive zinc supplementation could decrease the IFN-alpha production and some essential cytokines for the immune system (12). Furthermore, they reported that raising intracellular zinc levels could effectively prevent coronaviruses (13). Therefore, its potential impact cannot be ignored on COVID-19.

Selenium and COVID-19
Selenium is the most trustworthy trace element. This issue is due to its anti-inflammatory and antiviral capabilities. The immune system, made up of selenocysteine, is generally regulated by several sets of selenoproteins. Besides, selenium deficiency created significant viral infection risk factors (14). It affects pathogens, especially viruses, and the immunological response. A viral genome changes by dietary selenium deficit, and a mild virus becomes more severe and virulent under oxidative stress (14).
The selenium deficiency not only dysfunctions the host immune system but also transforms coronaviruses from benign to virulent forms. Moreover, it helps collect enzymes that inhibit the production of free radicals and prevent oxidative damage to cells and tissues (15).
An overactive inflammatory response accompanies a compromised antioxidant defense even without active infection. Besides, its efficient operation needs at least 100 µg of selenium per day (16). The previous studies demonstrated that Selenium was in charge of the antiviral properties of glutathione peroxidase. In addition, glutathione peroxidase counterbalances the inflammation induced by COVID-19 (17).
The obtained data demonstrated the critical role of Selenium-based mechanisms in coronavirus infection. Consequently, Selenium considerably impacts COVID-19.

Iron and COVID-19
Anemia, iron overload, and perhaps neurodegenerative disorders are a few clinical symptoms of iron metabolism disorders. These are classified as the most widespread diseases affecting people. In the biological system, iron has several different functions. It is an oxidant that contributes to creating hemoglobin and red blood cells (18). The previous studies showed that both the host and virus needed iron. Although iron excess leads to oxidative stress and the spread of dangerous viral mutations, the iron shortage weakens the immune system (19).

Calcium and COVID-19
Calcium helps fight against viral infections. This procedure is performed by cleaning them out of the cells. Thus, calcium not only gives protection against the simple common cold but also prevents breast cancer and promotes health by adding calcium to vitamin D as a supplement. The patient's calcium level in the blood is adversely correlated with the disease severity. A combined study showed that patients with severe COVID-19 had lower calcium concentrations than patients with mild and moderate diseases. Hypocalcemia (e.g., decreased plasma potassium and sodium levels) indicates COVID-19 infection (20). This retrospective clinical analysis demonstrated that people with COVID-19 had a relatively high rate of hypocalcemia. The imbalances of 25-hydroxy-vitamin D and parathyroid hormone (PTH) levels are related to hypocalcemia. Besides, the lower serum calcium levels were associated with poorer clinical outcomes, higher rates of septic shock, and death (21). Hence, it is assumed that blood calcium levels are related to the severity and prognosis of individuals with COVID-19.

Phosphorus and COVID-19
The low amounts of phosphorus (hypophosphatemia) are directly correlated with COVID-19 severity, and thus tracking the blood phosphorus level in patients with severe COVID-19 is helpful for prognosis (22). Hypophosphatemia raises the risk of susceptibility to coronavirus infection. Since few minerals are available, phosphorus primarily impairs immune responses, which makes it impossible to repair the harm imposed on cells and tissues and promotes the disease spread. It sheds light on the potential function of phosphorus in reducing COVID-19 causalities (23).

Potassium and COVID-19
Patients with COVID-19 may have potassium problems. The proportion of hypokalemia is higher than hyperkalemia. However, both of them are subject to a poor prognosis and consequences. Serious arrhythmias can be prevented, especially in severely COVID-19 patients. This procedure is conducted through the early diagnosis and control of potassium abnormalities and regular electrocardiogram monitoring (24). A study showed that potassium level in patients with severe COVID-19 was considerably lower than in mild or moderate patients. In this case, potassium variability was significantly less than sodium variability. The decreased plasma potassium and sodium levels are a coronavirus infection sign (25).

Magnesium and COVID-19
Mg supplements may be quite helpful in reducing the stress brought on by post-traumatic stress disorder due to the COVID-19 pandemic that would affect survivors of COVID-19, medical professionals, and the general public. Controlling several processes, including immune cell adhesion, immunoglobulin production, binding of immunoglobulin M lymphocytes, and cytolysis, also play a crucial role in immune function (23).
However, a previous study revealed that blood magnesium levels may be negatively correlated with White blood cells, neutrophil, and lymphocyte cell concentrations and that high magnesium levels may contribute to or be a consequence of infection with COVID-19 (26). Another study discovered an association between magnesium levels and pneumonia. The mortality rate in hospitalized patients with hypermagnesemia and even normomagnesemia were higher than in the hypomagnesemia group (27).

Vitamin C and COVID-19
Vitamin C is recognized as an antioxidant because of its potential effect to eliminate harmful reactive oxygen species. It guards the cells and tissues against oxidative harm and malfunction. The levels of vitamin C could drop during infection regarding the need for vitamin C. Therefore, in severe circumstances, vitamin C should be administered intravenously to reach normal levels in the body (28). Based on established research, people that received vitamin C supplements showed considerably reduced rates of pneumonia, which raises the possibility that, under some circumstances, vitamin C may lessen the risk of lower respiratory tract infections. Therefore, Vitamin C can be beneficial in respiratory tract infections due to COVID-19 and is an effective option for treating COVID-19. Additionally, sepsis due to pneumonia, also observed in COVID-19, is influenced by vitamin C. Evidence shows that people with severe COVID-19 may benefit from high dosage vitamin C treatment. To help prevent and promote immunological responses, vitamin C supplementation makes sense for people who are micronutrient deficient and at risk of contracting COVID-19 (29).

Vitamin D and COVID-19
Vitamin D has antioxidant and anti-inflammatory effects, and calcium-phosphorus metabolism is supported by it. Our body may create vitamin D by using sunlight, which besides functions as a hormone. It helps to accelerate the development of numerous cells, including immune cells. Studies have shown that vitamin D prevents the upregulation of inflammatory cytokines, including tumor necrosis factor-α and Interleukin-1 (30). Xu et al showed that calcitriol (the agonist of vitamin D) protects against acute lung damage. Calcitriol regulates the expression of ACE2 (angiotensin-converting enzyme 2) in lung tissue, which is the pathophysiology of COVID-19. A high dosage of between 250 and 500 thousand IU had notable outcomes in several trials (31). According to the previous meta-analysis, people using vitamin D supplements had a lower chance of developing acute respiratory tract infections than those with low baseline vitamin D levels. Hence, it may be beneficial in COVID-19 patients because it is a common complication of coronavirus infection (32). The prospective cohort study showed the level of vitamin D could be the prognostic tool for coronavirus infections. Furthermore, vitamin D insufficiency might be linked to poorer outcomes from COVID-19 (33). There seems to be a link between nations with a higher prevalence of vitamin D insufficiency and greater COVID-19 incidence and death.

Vitamin E and COVID-19
Vitamin E is crucial in lowering oxidative stress through its ability to bind to free radicals as an antioxidant (34). Vitamin E has a role in the immune system besides having antioxidant and anti-inflammatory effects, and it is said to be critical against COVID-19 (35). Vitamin E levels are inversely associated with the number of oxidative stress metabolites. Vitamin E derivatives' antioxidant capabilities, which enhance cell membrane and the immune system against respiratory tract infections, are considered one of vitamin E's possible mechanisms of action against COVID-19 (36). Folic acid, vitamin E, or a combination of the two, improved blood indices more efficiently. The hemoglobin and hematocrit may considerably increase, especially in acute hemolysis. Therefore, it might be helpful for COVID-19 patients who have acute hemolysis (37).
Taking vitamin E could help COVID-19 patients' neurological damage be partially controlled. In COVID-19 patients, supplemental vitamin E could also act as a therapeutic medicine and reduce damage to several organs, including the heart, lungs, kidneys, liver, gut, and neurological system. According to some research, it causes viral eradication and the elimination of inflammation through modulating T cells (38).

Conclusion
Previous studies showed that vitamin and mineral supplements prevented serious COVID-19 or expedited the recovery rate from COVID-19 complications. Therefore, adding nutritional supplements into the diet is an adopted approach for prevention and treatment processes against infections, especially for those at risk of coronavirus infection.
Clinicians must consider these factors precisely regarding the preventive effects of vitamins and minerals on serious COVID-19.