4. Vitamin C

4.1. Metabolism and Functions
Vitamin C (ascorbic acid) is a water-soluble vitamin and an essential micronutrient for humans. The main sources of vitamin C are citrus fruit, tomatoes, potatoes, and green leafy vegetables. The provision of dietary vitamin C is dependent on food preparation because it is easily destroyed by prolonged storage, overcooking, and processing of foods. Breast milk represents an adequate source of vitamin C for newborns and infants.
Ascorbic acid is an antioxidant (electron donor) and is involved in several biological processes: synthesis of collagen, neurotransmitter metabolism, cholesterol metabolism, fatty acid transport (synthesis of carnitine), maintaining the iron and copper atoms, and is a cofactor of the metalloenzymes, in a reduced active state. Furthermore, vitamin C affects the cellular and immunologic functions of the hematopoietic system, due to its role in enhancing nonheme iron absorption, the transfer of iron from transferrin to ferritin, and the formation of tetrahydrofolic acid [44].
Vitamin C is an essential nutrient that influences several aspects of the immune system, particularly barrier integrity and leukocyte function [45]. The fact that vitamin C is actively accumulated into the epidermal and dermal cells and into leukocytes, via sodium-dependent transporter, suggests that the vitamin plays a crucial role within the skin and the leukocytes [46]. Vitamin C is a potent water-soluble antioxidant and plays an important role in maintaining redox homeostasis within cells and in protecting host cells against the actions of reactive oxygen species (ROS) [45], released by phagocytes in order to lead to the deactivation of viruses and the killing of bacteria. Thus, acid ascorbic as scavenger of ROS may both protect crucial cell structural components and modulate the pro-inflammatory signaling pathway activated by the oxidative burst [46,47]. Vitamin C influences innate immunity also by regulating several aspects of neutrophil function [48], particularly the chemotactic ability, as shown in several in vitro and in vivo animal studies [49,50]. Severe septic syndromes are associated with impaired neutrophil chemotactic ability [51], and studies conducted in children and neonates may suggest that it could be due also by a severe infection-induced status of vitamin C deficiency [52,53]. Furthermore, studies have shown that, in patients with recurrent infections or affected by genetic conditions such as Chediak–Higashi syndrome (CHS), supplementation with vitamin C improved significantly the antibacterial activity of neutrophils [54,55]. Ascorbic acid may also influence the apoptotic process of neutrophils, thus promoting resolution of inflammation and reducing extensive tissue damage [46]. Lastly, promising in vitro and preclinical data suggest that vitamin C supplementation could play a role on more recently discovered functions of neutrophils, such as the formation of neutrophil extracellular traps (NETs), resulting by the release of toxic intracellular components following the necrotic death of neutrophils [56]. Ascorbic acid may attenuate tissue damage reducing the formation of NETs [48].
Furthermore, vitamin C is effective in supporting both the humoral response and the cell-mediated immunity [46]. Vitamin C accumulates in phagocytic cells, such as neutrophils, and can enhance chemotaxis, phagocytosis, generation of ROS, and ultimately microbial killing [57]. It is also needed for apoptosis and clearance of the spent neutrophils from sites of infection by macrophages, thereby decreasing necrosis/NETosis and potential tissue damage. The role of vitamin C in lymphocytes is less clear, but it has been shown to enhance differentiation and proliferation of B- and T-cells, likely due to its gene-regulating effects. The effect of vitamin C on cytokine generation appears to depend on the cell type and/or the inflammatory stimulant. Recent research has indicated that vitamin C treatment attenuates synthesis of the pro-inflammatory cytokines TNF, IL-6, and IL-1β [57]. In vitro studies suggest that ascorbic acid operates as potent immunostimulator of antibody production (IgM and IgG) in humans and that the intracellular ascorbic acid content is a key parameter for establishing the immune response of peripheral blood lymphocytes [58]. Other in vitro studies have shown the role of vitamin C in promoting T-cell maturation [59]. Recent research indicates the possible role of vitamin C in regulating T-cell maturation via epigenetic mechanisms involving in the ten-eleven translocations (TETs) and histone demethylation [60,61].

4.2. Vitamin C Status
Normal plasma vitamin C concentration is 50 µmol/L. Plasma ascorbate concentrations above 10 µmol/L but below 50 µmol/L represent a status with an increased risk of insufficiency. Scurvy appears when the plasma concentration falls below 10 µmol/L, which corresponds to an intake of less than 10 mg vitamin C/day and a body pool less than 300 mg [60]. It is acknowledged that vitamin C concentration declines during stress and infection, particularly in leukocytes, as it is used to protect host cells against the oxidative stress [46]. For the same reason, children exposed to smoking or environmental tobacco smoke require increased intake of vitamin C [44].

4.3. Recommended Daily Allowance and Supplementation
In adults, the average requirement of vitamin C is considered to be the amount that compensates for the metabolic losses of vitamin C and ensures a fasting ascorbate plasma level of 50 µmol/L [62,63] (Table 1).
In infants and children, no data for deriving the average requirement are available. The European Food Safety Authority (EFSA) extrapolated the vitamin C requirement in this age group from the vitamin C requirement in adult [62].

4.4. Vitamin C Supplementation against Viral Infection
Vitamin C deficiency status is correlated with an increased susceptibility to severe respiratory infections such as pneumonia [46,47,64,65,66,67,68,69,70,71,72] (Table 3).
In a recent meta-analysis, Hemilä and Louhiala analyzed the effect of vitamin C in preventing and treating pneumonia regardless of the etiology [65]. They reported three studies that show a >80% lower incidence of pneumonia in the vitamin C groups, supporting the potential role of vitamin C in reducing the risk of pneumonia, particularly in individuals with low plasma vitamin C levels [66]. Furthermore, regarding the effect of vitamin C in treating pneumonia, in older patients, lower mortality and reduced severity of disease was found in the vitamin C group, particularly in the most ill patients. However, the authors concluded that the current evidence is too weak to advocate widespread prophylactic use of vitamin C to prevent pneumonia in the general population, and further studies are needed to clarify the population that could have a benefit from vitamin C use. The effect of vitamin C on upper respiratory tract infections, such as the common cold, has also been studied in several trials. Vitamin C supplementation significantly decreases the incidence and the severity of the common cold in people under heavy physical stress [67,68]. In a randomised controlled pilot study, Garaiova et al. have shown a significant reduction in the incidence and duration of upper respiratory tract infection, but no significant differences were observed in the incidence rate ratio or duration of lower respiratory tract infection [69]. A recent meta-analysis comparing vitamin C with placebo demonstrated that administration of extra doses of vitamin C at the onset of a common cold could help reduce the duration by about half a day, shorten the time confined indoors, and relieve the symptoms of a common cold [70].
With the COVID-19 outbreak, vitamin C could play a role in preventing and treating the severe respiratory viral infection caused by SARS-CoV-2. The potential beneficial effect of vitamin C supplementation could be expected also from the depleted vitamin C levels that are present during a severe infection and in critically ill patients [71]. A recent randomised clinical trial (CITRIS-ALI) demonstrated that 96 hours’ infusion of vitamin C compared with placebo in patients with sepsis and ARDS did not improve the primary outcome of organ dysfunction scores, but significantly reduced mortality and significantly increased ICU-free days to 28 and hospital-free days to 60 [72].
Recently, Diao et al. retrospectively reviewed the numbers of total T cells, CD4+, CD8+ T cell subsets in a total of 499 COVID-19 patients and found a significantly reduction of T cells counts. Furthermore, they demonstrated a state of T cell dysfunction (T cell exhaustion) following SARS-CoV-2 infection [73]. Thus, the possibility that vitamin C affects viral respiratory tract infections, also supporting the viral clearance mediated by T cells, could encourage further studies aimed to investigate the role of vitamin C for prevention and treatment of COVID-19 disease.