The latest COVID-19 epidemic has required emergency treatment for a large number of patients. COVID-19 pandemic is disseminating like a storm, necessitating effective preventive and precautionary measures in addition to the development of a vaccine to fight the disease. Vitamin C is used to treat respiratory infections and is now being increasingly used as a therapeutic agent. It’s main role is that of an antioxidant and it improves the functioning of the immune system, similar to the phagocytes and lymphocytes that improve the response of T lymphocytes by augmenting interferon levels.¹ Dr Fowler and colleagues, in 2014 concluded that administration of intravenous vitamin C to patients with sepsis could decrease the levels of C-reactive protein and thrombomodulin.² The patients with acute respiratory distress syndrome (ARDS) who had sepsis were given intravenous administration of 200 mg/kg/day of vitamin C for 4 days. The results of this randomized controlled trial showed that in 28 days, the mortality was 30% relative to 46% in the placebo group (p = 0.03) and a hazard ratio (HR) of 0.55 (95% CI, 0.33–0.90, p = 0.01) was also found.³ This review concluded that the intervention of vitamin C, which has a high efficacy, low cost, and a potential for rapid healing, can be used to treat severe respiratory infections as seen in COVID-19.⁴ The spectrum of the disease ranges from asymptomatic individuals to severe respiratory tract infection leading to system failure and finally death. This is partially due to a lack of an effective antiviral therapy and therefore there is only symptomatic treatment. Currently, vitamin C has been of interest to the physician to fight against coronavirus as it a play a pivotal role in maintaining immunity and has anti-inflammatory properties.^5-7 When analyzing the current COVID-19 situation in India and worldwide, it seemed quite obvious to address some aspects of the ways to boost up immunity via vitamin C supplementation, which is an effective immune-modulator in severe acute respiratory syndrome associated with coronavirus 2 (SARS-CoV-2) or second wave COVID-19.⁸  Several animal studies conducted on vitamin C and infection, concluded potential protective role of vitamin C in infection.⁹ Various reports available in literature including increase in resistance generation noticed in chick embryo tracheal organ cultures to avian coronavirus infection,^10,11 protection of broiler chicks against the avian coronavirus and vitamin C induced downregulation of proinflammatory genes, enhanced epithelial barrier and increased rate of alveolar fluid clearance among septic mice suffering from acute respiratory distress syndrome(ARDS),¹² etc. An increase in mice lung pathology was also observed due to deficiency of vitamin C. Outcomes of various human trials reported shortening in rate of infection caused by virus with regular administration of nearly 1 gm/day of vitamin C.^9,13 The effect of vitamin C on different new strains of respiratory viruses seems not very specific as the types of viruses varied during trials. It is likely that there may be some impact of the vitamin on various new strains of virus as well.

Biochemistry of Vitamin C
Professor (Dr.) Albert Szent Goyrgi was awarded the Nobel Prize for his work in separating vitamin C molecule from red peppers and declaring its role in the gum disease- Scurvy.⁹ Vitamin C serves as an essential micronutrient in our body, is a potent antioxidant and acts as a coenzyme in various enzyme regulated biochemical reactions.⁶

The plethora of functions performed by vitamin C is due to its ability to donate electrons. Apart from contributing to the enhancement of immune system and support to various cellular activities, it also interferes with the entry of pathogens by destroying the oxidant species on the skin.¹⁴ The proliferation of T and B cells is also enhanced by vitamin C by its gene-regulating effects.¹⁴ It is also involved in phagocytosis, chemotaxis and production of antioxidant species to check the entry of microbes into the body.^15,16

The vitamin is abundantly present in phagocytes such as neutrophils, macrophages and it potentiates their bactericidal role.¹⁵ It is also reported to have a role in apoptosis and removal of dead immune cells and debris from the site of immune response.¹⁴ It is a co-factor in collagen formation and catecholamine synthesis, and is a modulator of the immune system.¹⁵ It has been documented that vitamin C administration improves haemodynamics, organ work, and may also improve endurance in physically sick patients. As stated earlier, apart from its anti-inflammatory properties, vitamin C inhibits nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), which are responsible for the activation of several pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-1), interleukin 6 (IL-6) and interleukin 8 (IL-8).¹⁴ Therefore, vitamin C has a potential anti-inflammatory activity and can be used in conditions like Acne Vulgaris and Rosacea.¹⁷ It can promote wound healing and prevent post-inflammatory hyperpigmentation. As expressed before, vitamin C hinders NFkB, which is responsible for the initiation of the various cytokines, for example, TNF-a, IL-1, IL-6 and IL-8. Therefore, vitamin C has a potential calming action and can be utilized in conditions like skin inflammation and Rosacea. It can advance recuperation of injury and forestall post-fiery hyperpigmentation.^18,19 Excessive production of oxidative stress is the key to severe lung injury among COVID-19 infected patients. Disturbances in the immune system generate huge amount of free radicals responsible for wounding patients.^20,21 Vitamin C being antioxidant works by scavenging free radicals from the site protecting the organ. Vitamin is very abundantly available in white blood cells and are well reported to improve phagocytosis, T cell maturation, cytokine production acting as safeguards against virus menace. While recently Deborah et al using Docking & molecular simulation procedures reported the binding of various other vitamins and steroid ligands to the newly discovered fatty acid binding sites in COVID-19 spike proteins.¹⁸ Simulations studies have depicted that dexamethasone and vitamin D as ligand facilitate the locked conformation of spike proteins thereby inhibiting the ace receptor binding. Docking experiments also suggest fat soluble vitamins (vitamin D, K and A) as very potential ligands for fatty acid binding sites on spike proteins.²² Vitamin D 3 metabolite calcitriol has been found to diminish viral titres in animal models and nasal epithelium cell line of humans. Obesity is one well known risk factors for COVID-19 infection developing the severity to the level of death. Vitamin D level is known to be sequestered in adipose tissue mass among obese subjects leading to deficiency.²² In comparison to these fat soluble vitamins, entirely different approach has been reported by vitamin C as discussed above. Preventive role of vitamin C is less clear, being reported to pose its T and B cell differentiation and proliferation effect through its gene regulatory property.¹⁷

Vitamin C and COVID-19
There is a wealth of literature available showing the role of quality nutrition in maintaining the immune system. The important role played by vitamin C in boosting immunity is well known and more effective in SARS-COV-2 or COVID-19.²³ To minimize infections, correction of nutritional regimen has been of utmost importance. A nutritional focus on the immune system could help minimize the impact of many kinds of infections including COVID-19. The prevailing global situation with COVID-19 and the number of people dying due to the respiratory complications is forcing all the public health officials to develop some strategy focusing on nutrition. In the current pandemic caused by coronavirus, vitamin C has been of interest to the research stalwarts in the fight against the disease. All over the world, several clinical trials are going on vitamin C to assess its impact on COVID-19.^17-19 In one such study conducted in China, COVID-19 critical patients on ventilators were tried with intravenous large doses of vitamin C.²³ The use of high dose of Vitamin C has numerous pharmacological characteristics: antiviral, anti-oxidant, anti-inflammatory and immunomodulatory effects, and potential therapeutically good management of COVID-19. There were no reported adverse reactions with the short-term use of high dose of vitamin C. The current ongoing clinical trials testing the effect of vitamin C in management of COVID-19 show positive results.²⁴

Vitamin C Related to COVID-19 Infections
Researchers around the globe are recommending large doses of this vitamin C in routine lifestyle. An Australian study was done in order to assess the effect of vitamin C in COVID-19 patients, but they did not find any correlation of vitamin C among SARS-COV-2 patients.²⁴ The United States are in the process of trying a combination of various nutrients including vitamin D, zinc and hydroxychloroquine along with vitamin C for COVID-19 prevention.²⁵ Current health strategies include: social distancing, hand washing, other hygienic practices, and vaccination along with a complementary strategy in the form of nutritional supplement to boost immunity. In one non-randomized clinical trials among 252 students, 85% students experienced reduction of influenza like symptoms with high doses of vitamin C.²⁶ Another interventional randomized prospective clinical trial is going on among 140 participants in Wuhan, China to see the effect of vitamin C infusion for treating severe COVID-19 infected pneumonia. Estimated completion time of the study is September 2020 and the results have not been published yet.²⁷ It is reported in the literature that severity and duration of common cold symptoms have been reduced by taking large doses of vitamin C.²⁶ Various studies conducted on critical COVID-19 patients with vitamin c supplementation have given mixed results on the mortality rate, their intensive care unit (ICU) stay and on ventilator stay. Stature of vitamin C as an adjuvant healing agent is still in dilemma therefore large clinical studies are needed to be done in the direction so as to establish its therapeutic role.^28,29 Total 18 clinical trials have used adjuvant therapy of vitamin C in the treatment of COVID-19 that were conducted in New York, Australia, United States, Canada, Italy, Saudi Arabia, Iran and Portland.

Intravenous administration of high doses of vitamin C in sepsis and septic shock acts as a pro-oxidant for immune cells, dependent on glycolysis for bioenergetic function, but as an antioxidant for lung epithelial cells, which produce ATP by oxidative phosphorylation in the mitochondria. Furthermore, vitamin C can inhibit the production of lactate protecting alveolar type II epithelial cells. Intravenous administration of high doses of vitamin C may be beneficial for the patient with COVID-19 if the decision is made at the right time i.e. as early as possible after the report of respiratory distress, based on clinical scores and biomarkers of inflammation and oxidative stress. Activated macrophages lead to an elevated level of lactate, which is moved to alveolar epithelial cells of type II, where it is utilized to produce ATP and inhibits the mitochondrial signaling loci of viral proteins. Macrophage-discharged lactate diminishes the production of type I Interferons (IFN), decreasing viral clearance as shown in Figure 1.

Search Strategy and Selected Criteria
This integrative literature review was conducted in Medical Literature Analysis and Retrieval System, National Library of Medicine (PubMed), Cochrane Library, Elsevier and China National Knowledge Infrastructure (CNKI). The databases were searched from their earliest records through August 2020 using the following keywords: COVID-19 [Coronavirus disease 2019], Second wave COVID-19 [second wave Coronavirus disease 2019], SARS-CoV-2 [severe acute respiratory syndrome coronavirus 2], vitamin C, and ascorbic acid. All the records were selected and screened by two independent reviewers, and a third reviewer was consulted when there was any disagreement. This search included articles published up until 11^th February 2021. The review was conducted according to the guidelines for Preferred Reporting, items for Systematic Reviews and Meta-Analyses (PRISMA).^30,31

Search Results
The 3 Systemic reviews (SRs) and 18 clinical trials (CT) included assessed the effects of therapeutics interventions (vitamin C) for participants with positive COVID-19. After the selection process, CT & SRs were found to fulfil our inclusion criteria and were included in the analysis.

Study Selection
Total 30 articles and 39 clinical trials were retrieved. We identified and screened 18 clinical trials & 25 articles, we excluded 39 unqualified trials on the basis of titles and abstracts, and then 18 trials were excluded because of inappropriate content, while 30 were excluded for the assessment of inappropriate content because it did not match with COVID-19 disease. Finally, 3 articles,^23-25,29 fulfilled our eligibility criteria after manual search and a review of full text manuscripts. The study selection procedure is outlined in [Figure 2].