**4.3 Herb/phytochemicals**

Herbal products are consumed in various countries across the globe. Literature suggests immune-boosting properties of these herbal materials which endorse the normal resistance ability of the body against infectious pathogens and to raise health, and as well as to cure and to prohibit diverse infectious diseases [48]. Curcumin, a polyphenolic compound isolated from turmeric, which is a commonly used food colorant and spice [62], can augment the antibody reaction even if it is consumed at reduced doses [63]. Additionally, literature shows that curcumin has a promising affinity for protein binding towards SARS-CoV-2 and thus directly inhibit the invasion of SARS-CoV-2 into target cells [64]. The ability of curcumin in improving various disease conditions is attributed partially to its capability to modulate the immune responses [63]. Numerous reports show that curcumin can alter the proliferation as well as the activation of T cells [65, 66]. Additionally, curcumin has the potential of regulating the response and growth of various immune cells like natural killer (NK) cells, B cells, T cells, dendritic cells (DCs), macrophages and neutrophils [63]. Glycyrrhizin, an active phytochemical moiety found in liquorice was observed to be efficient in comparison to commonly used anti-virals in mitigating the replication of SARS-CoV as well as inhibiting its adsorption and penetration [67]. A recent in-vitro study also showed that glycyrrhizin is a potential inhibitor of SARS-CoV-2 replication by hindering the viral main protease (Mpro) [68]. Molecular docking study showed two phytoconstituents Somniferine and Withanoside V from Ashwagandha (*Withania somnifera*) [69, 70], Tinocordiside [70] and berberine [71] from Giloy (Tinospora cordifolia) and three active ingredients i.e., Vicenin, Ursolic acid and Isorientin 4'-O-glucoside 2″-O-phydroxybenzoagte isolated from Tulsi (*Ocimum sanctum*) [70] may have an antiviral effect against novel coronavirus via potentially inhibiting Mpro of SARS-CoV-2.

#### **4.4 Nutritional supplements**

Recently conducted studies show that suboptimal intake of micronutrients and inadequate nutritional status can lead to poor immunity and consequently affect the severity of infections. Nutritional supplements emerge to reinforce the immune system. Micronutrients consisting of a variety of vitamins (A, D, C, E, B6, B12, folate) and minerals (iron, zinc, selenium and copper) are engaged in various stages of the immune responses against foreign pathogens. A study conducted in the United Arab Emirates (UAE) confirmed the association of low levels of vitamin D3 (25(OH)D3) (<12 ng/mL) with severity and death due to COVID-19 [72]. Another study shows that hospitalized COVID-19 patients receiving vitamin D3 (calcifediol) in contrast with those not consuming vitamin D3, was significantly linked with a lesser rate of mortality during the initial thirty days of hospitalization [73]. Supplementation with vitamin D at high-dose may be well-tolerated, effective, and readily accessible for the management of COVID-19 [74]. One report showed that intake of a high dose of vitamin D has significantly reduced the inflammatory markers (neutrophil/lymphocyte ratio, ferritin, C-reactive protein (CRP), lactate dehydrogenase (LDH), IL-6 associated with COVID-19 without any side effects [75]. A study confirmed that deficiency of vitamin D is correlated with severe lung injury, disease prolongation and risk of mortality, in COVID-19 patients [76]. Another study shows that combination therapy of vitamin D with vitamin B12 and magnesium in geriatric patients with COVID-19 was correlated with a considerable decline in the proportion of patients with clinical deterioration and requiring intensive care support and oxygen support [77]. Vitamin D was found to modulate innate and adaptive immune systems [78, 79]. It augments the innate immune responses while attenuates the adaptive immune responses [78]. Vitamin D metabolites directly target the adaptive immune cells [80] and it is an important part of intricate features that control the immune response against infection [81]. These findings necessitate examining the level of vitamin D in pediatric as well as geriatric persons to maintain it at optimum levels for the prevention of SARS-CoV-2 infection.

In addition to the consumption of higher doses of vitamin D3, previously it was also stated that coronavirus pandemic can be considerably controlled by the utilization of high amounts of vitamin C. Significantly low levels of vitamin C in patients affected with COVID-19 were found and daily supplementation of 100 mg/kg is highly recommended [82]. A high dose of intravenous vitamin C might repress cytokine storms associated with COVID-19, and facilitate improving pulmonary function and lessen the risk of ARDS associated with COVID-19 [83]. As SARS-CoV-2 was found to affect the host immune system, it seems crucial to boost the natural immunity and antioxidant capacity to lessen the effect of any virus infection. Vitamin C is known for its ability to activate the immune system. Therefore it seems promising to administered vitamin C concomitantly with other medications to cure the infection in acute conditions. The ingestion of vitamin C orally up to the daily threshold of bowel tolerance seems to be effective for the majority of persons. However, intravenous administration of vitamin C is suggested for serious cases. On the other side, there are certain reports, claiming that the overstimulation of immune cells in COVID-19 leads to cytokine storm which ultimately causes lung injury following pneumonia. Certain clinical investigations also suggested that intravenous administration of vitamin C in high-dose can be a safe and effective choice for the management of COVID-19 infection in its early stages. Even though previous literature recognized and approved the antiviral activity of vitamin C, but its impact has not been studied widely and, limited information is available on its effect on coronavirus. Moreover, some studies show that adjunctive intravenous administration of vitamin C for the treatment of infection in critically ill COVID-19 patients was unable to reduce the rate of mortality, ventilator settings, the requirement of vasopressor, etc. [84]. Therefore although vitamin C is vital for lessening the inflammatory response and assists in boosting the immune system of the host, there is a lack of substance to support that utilization of vitamin C at a high dose can be successful in the prevention or management of COVID-19. Moreover, as Therapeutic Goods Administration (TGA) [85] declared that more studies are required for any recommendation for utilizing intravenous vitamin C in the management of COVID-19. In addition to vitamin C and vitamin D3, it was reported

*The Role of Complementary and Alternative Medicines in the Treatment and Management... DOI: http://dx.doi.org/10.5772/intechopen.100422*

that vitamin K antagonist regular use was correlated with augmented mortality in hospitalized elderly patients affected with COVID-19 [86].

Studies show that treatment with zinc as adjuvant therapy was appeared to be feasible and safe for the management of COVID-19. However, the infusion of zinc causes limited infusion site irritation on the periphery [87]. Zinc supplement was found to be efficiently clear the SARS-CoV-2 from the nasopharynx in a lesser time than other symptomatic therapy [88]. Zinc cation (Zn2+) coupled with zinc ionophores pyrithione and found to inhibit RNA polymerase of coronavirus and thus block the replication of the virus [89]. Additionally, zinc also mitigates the invasion of the virus by escalating the cell membrane stability as well as stimulate interferonalpha (IFN-α) and IFN-γ formation and attenuate tumor necrosis factor (TNF) and mononuclear cells [90]. Apart from zinc, iron also plays a vital component of enzymes involved in the stimulation of immune cells, lower levels of iron was found to influence severe symptoms associated with COVID-19. Selenium contributes to adaptive immunity by boosting the production and development of antibodies. Lack of selenium can lessen antibody production, compromised cellular immunity, attenuated the cytotoxicity of NK cells, and decreased response to vaccination. Oxidative stresses alter the viral genome from a mildly pathogenic form to a highly virulent form of the virus in the host. Selenium is a known anti-oxidant. Hence selenium with vitamin E and a cluster of certain enzymes scavenges the free radicals and lessens the oxidative stress and thus as a result, the adjuvant therapy of selenium may be considered for the treatment of COVID-19 infection [91].
