Vitamin C IV Therapy

Furthermore, supplementation with vitamin C appears to be able to both prevent and treat respiratory and systemic infections. Prophylactic prevention of infection requires dietary vitamin C intakes that provide at least adequate, if not saturating plasma levels (i.e., 100–200 mg/day), which optimize cell and tissue levels. In contrast, treatment of established infections requires significantly higher (gram) doses of the vitamin to compensate for the increased inflammatory response and metabolic demand.

Due to the low storage capacity of the body for the water-soluble vitamin, a regular and adequate intake is required to prevent hypovitaminosis C. Epidemiological studies have indicated that hypovitaminosis C (plasma vitamin C < 23 μmol/L) is relatively common in Western populations, and vitamin C deficiency (<11 μmol/L) is the fourth leading nutrient deficiency in the United States [13,14].

Vitamin C has a number of activities that could conceivably contribute to its immune-modulating effects. It is a highly effective antioxidant, due to its ability to readily donate electrons, thus protecting important biomolecules (proteins, lipids, carbohydrates, and nucleic acids) from damage by oxidants generated during normal cell metabolism and through exposure to toxins and pollutants (e.g., cigarette smoke) [17].

Leukocytes, such as neutrophils and monocytes, actively accumulate vitamin C against a concentration gradient, resulting in values that are 50- to 100-fold higher than plasma concentrations. These cells accumulate maximal vitamin C concentrations at dietary intakes of ~100 mg/day, although other body tissues likely require higher intakes for saturation. Neutrophils accumulate vitamin C via SVCT2 and typically contain intracellular levels of at least 1 mM. Following stimulation of their oxidative burst neutrophils can further increase their intracellular concentration of vitamin C through the non-specific uptake of the oxidized form, dehydroascorbate (DHA), via glucose transporters (GLUT). DHA is then rapidly reduced to ascorbate intracellularly, to give levels of about 10 mM. It is believed that the accumulation of such high vitamin C concentrations indicates important functions within these cells.

Accumulation of millimolar concentrations of vitamin C into neutrophils, particularly following activation of their oxidative burst, is thought to protect these cells from oxidative damage [119]. Vitamin C is a potent water-soluble antioxidant that can scavenge numerous reactive oxidants and can also regenerate the important cellular and membrane antioxidants glutathione and vitamin E [120]. Upon phagocytosis or activation with soluble stimulants, vitamin C is depleted from neutrophils in an oxidant-dependent manner [50,51,52,53].

Patients with severe infection exhibit compromised neutrophil chemotactic ability [129,130,131,132]. This neutrophil ‘paralysis’ is believed to be partly due to enhanced levels of anti-inflammatory and immune-suppressive mediators (e.g., IL-4 and IL-10) during the compensatory anti-inflammatory response observed following initial hyper-stimulation of the immune system [133]. However, it is also possible that vitamin C depletion, which is prevalent during severe infection [20], may contribute. Studies in the 1980s and 1990s indicated that patients with recurrent infections had impaired leukocyte chemotaxis, which could be restored in response to supplementation with gram doses of vitamin C [57,58,59,60,65,66,67]. Furthermore, supplementation of neonates with suspected sepsis with 400 mg/day vitamin C dramatically improved neutrophil chemotaxis [134].

Preclinical studies using Gluo knockout mice have highlighted the cytokine-modulating effects of vitamin C. Vitamin C-deficient Gulo knockout mice infected with influenza virus showed enhanced synthesis of the pro-inflammatory cytokines TNF-α and IL-1α/β in their lungs, and decreased production of the anti-viral cytokine IFN-α/β [88]. Administration of vitamin C to Gulo mice with polymicrobial peritonitis resulted in decreased synthesis of the pro-inflammatory cytokines TNF-α and IL-1β by isolated neutrophils [75]. Another study in septic Gulo mice administered 200 mg/kg parenteral vitamin C has shown decreased secretion of the inhibitory cytokines TGF-β and IL-10 by Tregs [89]. In this study, attenuated IL-4 secretion and augmented IFN-γ secretion was also observed, suggesting immune-modulating effects of vitamin C in sepsis. Overall, vitamin C appears to normalize cytokine generation, likely through its gene-regulating effects.

Studies using guinea pigs, a vitamin C-requiring animal model, have indicated that vitamin C depletion is associated with enhanced circulating histamine levels, and that supplementation of the animals with vitamin C resulted in decreased histamine levels [56,95,96,97,98]. Enhanced histamine generation was found to increase the utilization of vitamin C in these animals [96]. Consistent with the animal studies, human intervention studies with oral vitamin C (125 mg/day to 2 g/day) and intravenous vitamin C (7.5 g infusion) have reported decreased histamine levels [61,99,100,101], which was more apparent in patients with allergic compared with infectious diseases [101].

Administration of vitamin C to patients with acute respiratory infections returns their plasma vitamin C levels to normal and ameliorates the severity of the respiratory symptoms [246]. Cases of acute lung infections have shown rapid clearance of chest X-rays following administration of intravenous vitamin C [247,248]. This vitamin C-dependent clearance of neutrophils from infected lungs could conceivably be due to enhanced apoptosis and subsequent phagocytosis and clearance of the spent neutrophils by macrophages [73]. Pre-clinical studies of animals with sepsis-induced lung injury have indicated that vitamin C administration can increase alveolar fluid clearance, enhance bronchoalveolar epithelial barrier function, and attenuate sequestration of neutrophils [74], all essential factors for normal lung function.

Meta-analysis has indicated that vitamin C supplementation with doses of 200 mg or more daily is effective in ameliorating the severity and duration of the common cold, and the incidence of the common cold if also exposed to physical stress [249]. Supplementation of individuals who had an inadequate vitamin C status (i.e., <45 μmol/L) also decreased the incidence of the common cold [203].