e frontiers in Immunology OPEN ACCESS ated by: ears Zee, Lnvesty ofan, ror Reviewed by: an Wa, The State University of Now ese Untos State Aetea ©. Cat, erty of O90, New Zt “Correspondance: Massimo Neo massino rerun spuaty to ms wark Speciaty section: ‘Tie arte was eutmitd © Nutanalinmunaty, econ of jour Frente n rmunctoay Received 18h 2020 ‘Accopted: 21 Soisrbar 2020 ‘Publahed: 28 etabe 2020 tation: Coto G Nag M, Parmbat i Peco M, Poms § Lavan endaneCana Hana OArtora (2220) tre Long Hoyos vane C: Treatment of COMD-19, Front mmnal 17:974008 REVIEW bubkeext 29 October 2020 dot: 10.8880 2020874000 a The Long History of Vitamin C: From Prevention of the Common Cold to Potential Aid in the Treatment of COVID-19 Giuseppe Cerullo"", Massimo Negro**", Mauro Parimbelli, Michela Pecoraro*, ‘Simone Perna’, Giorgio Liguori", Mariangela Rondanelli®®, Hellas Cena*” and Giuseppe D’Antona®® Department of Mowarent Scencos and Welbog, Unters of Maps Partbanepa Naps, ta, ® Care dt Acar rtrparimertal le Atti Motori 0 Sportive CRLAMS) Sport Mcine Cai, Univasty of Pav, Vogt, ta 2 Daparnert of Phamacy, Univers of Salo, Féin, ta “Doar of Bog, Colago of Sconce, Unversity fF ‘Barvan, Sain, Baran, °IACCS Mande Fourier, Pava, tay, ® Deparment of Pubic Heath, Expermental ard Forerc Mace, Unersty of Pave, Pav, tly, 7c! Nanton and Deets Serie, Unt of tama Mele and Endoomotay, OS Meuse IRCCS, Unverstyof Pav, Pavia. aly From Pauling’s theories to the present, considerable understanding has been acquired of both the physiological role of vitamin C and of the impact of vitamin C supplementation on the health, Although itis well known that a balanced diet which satisfies the daily intake of vitamin C positively affects the immune system and reduces susceptibility to infections, avaliable data do not support the theory that oral vitamin C supplements boost immunity. No current clinical recommendations support the possibilty of significantly decreasing the risk of respiratory infections by using high-dose supplements of vitamin C in a well nourished general population. Only in restricted subgroups (e.g., athletes or the miftary) and in subjects with a low plasma vitamin C concentration a supplementation may be justfied, Furthermore, in categories at high risk of infection (le, the obese, diabettos, the ‘elderly, etc,), a vitamin C supplementation can modulate inflammation, with potential Positive effects on immune response to infections. The impact of an extra oral intake of vitamin Con the duration of a cold and the prevention or treatment of pneumonia is stil ‘questioned, while, based on critica illness studies, vitamin C infusion has recently been hypothesized as a treatment for COVID-19 hospitalized patients. In this review, we focused on the effects of vitamin C on immune function, summarizing the most relevant studies trom the prevention and treatment of common respiratory diseases to the use of vitamin Cin critical ilness conditions, with the aim of clarifying its potential application uring an acute SARS-CoV? infection, Keywords: vitamin C supplementation, viral infections, COVID-19, pneumonia, immune function, athletes, non ‘communicable disease, fal elder subjects (etober 2000 | Vue 17 | Arce 574029Cont ota INTRODUCTION Vitamin C (ascorbic acid) plays an important role in the normal functioning of the immune system (4) and its use in preventing and/or treating infections has strongly attracted the interest of physicians and investigators for almost a century. A plethora of papers have been published on this topic, but, although it is well known that a deficiency of vitamin C due to a low nutritional intake leads to a greater susceptibility to infections (5), the possibility of reducing the incidence of viral diseases in a well-nourished population through the use of dietary supplements based on vitamin C is not adequately supported in literature. At present, very little evidence supports the benefit of high doses of vitamin C supplementation on immune function in healthy individuals (4,6) and several authors have underlined that this practice is ineffective in preventing the common cold and viral infections in most subjects (7-12). Despite this, the popular belief that an extra intake of vitamin C can boost the immune system is still widespread and every year the market claims that the use of supplements is a winter remedy to prevent infectious disease. ‘While scientists’ current position isnot to recommend the use of vitamin C supplementation to prevent viral invasions in hrealthy subjects, more promising—though questioned—data seem instead to emerge from the intravenous administration (IA) of this vitamin in acute respiratory conditions or critical illnesses. Furthermore a potential pharmacological role during early phases ofthe new coronavirus (SARS-CoV2) infection and its related disease (COVID-19) was recently put forward (13-18). The rapid worldwide spread of SARS-CoV2 and the consequent pandemic emergency recognized by World Health Organization urgently requires a global fort to identify anything that can treat symptoms and reduce deaths, At the beginning of June, more than 6,600,000 cases of infection and 391,000 deaths related to COVID-19 had been reported globally and the number of cases is constantly increasing worldwide (19). Currently, no specific antiviral therapy has been approved for the cure of COVID-19 (20), and this has led researchers to speculate on a possible adjuvant treatment based on indirect evidence from severely il patients and patients with sepsis conditions (21). Sepsis is a life threatening organ dysfunction caused by an impaired host response to infection, characterized by a dramatic fale of the circulatory, metabolic, and immune systems, and recognized as the primary cause of death from infection: patients who develop septic shock can have hospital mortality rates of up to 50% (22). On these clinical conditions literature shows that high doses of vitamin C by intravenous infusion may reduce the inflammatory cylokine-related production and potentially improve important outcomes such as the duration of mechanical ventilation time and mortality rates (13-18). ‘This is of particular importance since acute respiratory distress syndrome (ARDS) is one of the most frequent severe conditions registered in COVID-19 patients (23). ARDS is a serious and, in some cases fatal, syndrome characterized by a strong inflammatory response with massive alveolar damage and multiple organ failure, Fronts in inmundbay | wen torso ‘Yamin Can Perspectives on COMD-19 requiring intensive care unit (ICU) treatment (21). Authors reported @ percentage of ARDS eases of around 15% among hospitalized patients with SARS-CoV2 infection (25). Data on the use of intravenous-administered vitamin C in COVID-19 patients are still unavailable, but clinical trials to explore the efcacy ofthis treatment are currently in progress in several countries (26) and important results will be availble soon. Based on the above, the aim of this review is firstly to summarize the immunological role of vitamin C with @ description ofits potential eects as a dietary supplement, on the mechanisms involved during respiratory vital infections, and in relation to the inflammatory response considering diferent subject categories and clinical conditions: secondly, the manuscript describes the updated literature on the IA of vitamin C in the treatment of severe sepsis and ARDS conditions, with the aim of establishing whether the current clinical background on this topic offers strong enough perspectives to propose vitamin C for a pharmacological application to reduce the dramatic eytokine production and regulate other recognized COVID-19-related immune responses PHYSIOLOGY OF VITAMIN C Bioavailability ‘Vitamin C isan essential nutrient that must be taken through the diet as humans are unable to synthesize it (27). Thus, our body has developed an effective adaptation system which maintains the organic reserves of vitamin C and prevents its deficiency due to a low dietary intake. These adaptations include a higher absorption and recycling capacity of vitamin C compared 10 ‘other animal species (eg, goat and reptiles), which can normally produce it (28, 9). Animal studies have shown that vitamin C is preferentially stored in the brain, adrenal gland, liver and lungs (30-33) but its levels in these organs are rapidly depleted after bout one week of dietary insufficiency (31). In humans, skeletal _muscle represents the major pool of vitamin € (34), Muscle fibers also lose vitamin C content very rapidly under inadequate dietary intake. However, a consumption of half kiwifeuit per day seems to be enough to saturate the muscle tissue’s vitamin C concentrations in non-smoking men (35). Vitamin C homeostasis is finely regulated by at least four mechanisms: intestinal absorption, transport to tissue, renal reuptake, and ‘urine excretion, mainly regulated by a family of proteins named Sodium-Dependent Vitamin C Transporters (SVCT) (36) Considering the individual variability in healthy subjects, studies suggest that a daily intake of vitamin C from 100 10 4400 mg ensures 100% of the bioavailability and blood saturation with a steady state of plasma concentration that reaches a maximum level of approximately 70-80 pmol/L (37, 38). Generally, if the intake of vitamin C exceeds 500 mg/day, a further increase in plasma concentration is inhibited and the bioavailability can decrease close to 30% when more than 1,000 :mg of vitamin C is administered ina single bout (39). This occurs byecauise when 500-1,000 mg of vitamin C is administered orally, the intestinal transporter (SVCT) rapidly achieves its maximal (etober 2000 | Vue 17 | Arce 574029Cont ota saturation, while the urine excretion of the vitamin is progressively inereased (38, 39). The measure of plasma concentration may be considered, even though the circulant values cannot be used as a reliable marker of the body stores (about 5 g) (40). A plasma concentration value of vitamin C lower than 23 mol/L reflects a depletion ofthe vitamin C pool (state of hypovitaminosis), while clinical symptoms of scurvy ‘occur when plasma values are lower than 11 jtmol/L (41), Recommended Dietary Allowances To maintain adequate body stores, recommended dietary allowance (RDA) for vitamin C has been proposed over the years The RDAs vary among countries eg, current recommendations in the United States and Canada is 90 mg/day for adult men and 75 mg/day for adult women (42), while in Italy the suggested Intakes are 105 mg/day and 85 mg/day for adult men and women, respectively (43). This variation in RDAs can be explained by the different criteria used by various authorities to define the estimated average requirement (FAR) for vitamin C, including prevention of scurvy, immune cell support, maintenance of an adequate plasma vitamin C level, and optimizing health (44). Furthermore, RDAs vary among subjects as several factors can modify vitamin C requirements, including gender, age, smoking, pregnancy, and lactation (4), Several authors and guidelines indicated that males ned more vitamin C than females (45~S1) probably due to the higher body eight and fat-free mass of men compared to women (52). In children and adolescents the RDAs for vitamin C are generally derived from adult needs and adjusted in relation to their lower body mass (46, 47, 53) as reported by Carr and Lykkesfeldt (44). In Italy, for example, SINU recommends an intake of 45 mg for children from 4 to 6 years of age (15). Epidemiological studies indicate that a lower vitamin C. status can be found in the elderly, suggesting that they require a higher intake compared to adults (54-56). However, currently only France has developed specific guidelines for subjects from 73 years of age, indicating a daily intake of 120 mg (57) Vitamin C requirements are higher in women during pregnancy (44): the hemodilution due to thi ‘of blood Volume and the active absorption of vitamin C by the fetus dduring its development lead to a reduction of the vitamin status (G8). Even lactation increases the vitamin C requirement of women, to satisfy the vitamin needs of the infant normal growth. Most countries recommend an extra daily intake of 10-20 mg for pregnant women and an extra daly intake of 20-60 mg/day lor women during lactation (44). ‘Smokers usually have lower plasma values than non-smokers, probably du to increased oxidative stress and higher turnover of vitamin C. In addition to this, a reduced vitamin C status in smokers is also due to the dietary intake of vitamin C, which is "usually lower compared to non-smokers (59). Therefore, in order to compensate these conditions, authorities have recommended an additional intake of 20 to $0 mg/day of vitamin C for these subjects, setting the RDAs for smokers at 120-155 mg/day (44) Some other factors have been recognized as reducing vitamin C status (60), even though they were not considered in general guidelines and the daily additional values of vitamin C Fronts in inmundbay | wen torso ‘Yamin Can Perspectives on COMD-19 potentially required are not currently available, These factors include: 1) passive exposure to tobacco smoking and environmental pollutants, which can enhance oxidative stress 2) geographic influence, socioeconomic and cultural status, which may have an impact on production, selection and consumption of foods typically rich in vitamin CG; 3) food preparation and cooking methods, which can reduce the content of vitamin C in foods since this vitamin is water- soluble and heat-labile. The potential variability of the metabolism of vitamin C among various ethnic groups is practically unknown and this topic should certainly be further explored, Only one study reported that lower vitamin C concentrations were significantly associated with a higher leukocyte count in African Americans ‘but not in Caucasians, suggesting hypothetical metabolic or pharmacokinetic differences among races (61). VITAMIN C AND IMMUNE SYSTEM REGULATION Besides an extensive range of biochemical pathways in which vitamin C is involved, it also participates inthe response of the innate and adaptive immune system (1). The intracellular conteat of vitamin C:in immune eells depends on the plasma availabilty. In healthy adults the content of vitamin C in leukocytes can be saturated with an intake of at least 100 mg of vitamin C per day, through foods, obtaining a concentration of about 35, 3, and 1.5 mmol/L, respectively, in lymphocytes, monocytes and neutrophils (3%, 62-65). Leukocytes’ absorption of vitamin from the blood is very efficient, through SVCT proteins (6), resulting in an intracellular content which i 50 to 100 times greater than the plasma concentration (67,68). As an fective antioxidant, vitamin C contributes to protecting neutrophils from oxidative stess during the eay stages of an immune response, when neutrophils activate phagocytosis and produce reactive oxygen species (ROS) to destroy antigens (69, 70). Once the phagocytic capacity is exhausted and neutrophils start to die, vitamin C seems to regulate the process in favor of apoptosis, through the activation of a caspase-dependent «cascade, inhibiting the transition to necrosis, and resulting in a ‘more efficent resolution of inflammation (1). Vitamin C is also involved in the migration of phagocytes {neutrophils and macrophages) toward the infection sites in response to chemoattractants (72, 73). This is particulary important since an impaired neutrophilic chemotaxis has been observed in patients with severe infection (74-76). Furthermore in subjects with low blood concentrations of vitamin C (<50 mol/L), a daily intake of 250 mg of vitamin C can result in a 20% increase of neutrophils’ migration capacity (6). Conversely, in individuals with a physiological blood concentration of vitamin C, neutrophils’ mobility cannot be enhanced, as demonstrated by Bozonet et al. (4), in which neutrophils isolated from healthy volunteers and incubated with a vitamin C solution (200 pmol/L) to artificially inerease their content of ascorbate did not show a major chemotactic ability (etober 2000 | Vue 17 | Arce 574029Cont ota Similarly to neutrophils, vitamin C protects lymphocytes from oxidative damage (77) and has a pivotal role in the development and function of these cells, even though the exact, ‘mechanisms have not yet been clarified (3). In T lymphocytes, vitamin C stimulates differentiation and proliferation from precursors to mature ‘T cells, in a dose-dependent way (78). Studies on the influence of vitamin C on subtypes of T cells are ‘mainly related to the Th1/Th2 balance. Reports underline that vitamin C can induce a shift of immune responses from Th2 (0 Thi (3), while only one study suggests that vitamin C can induce the ThI7 polarization of naive CD4+ cells in murine model, affecting epigenetic mechanism (79). At present, no studies, exploring the effects of vitamin G on cytotoxic T cells are available (3). In B lymphocytes, vitamin C seems to affect the production of antibodies, despite conflicting evidence (80-87). Physiological levels of Vitamin C are also necessary for normal natural killer (NK) cell development and function (3). In vitamin deficient mice, NK cytotoxic activity (NKCA) was lower than. that in mice with normal levels of vitamin C (88), whi supraphysiological levels of ascorbate do not further increase NKCA (8). Vitamin C also regulates inflammatory response. In animal studies, vitamin C deficiency has been linked with higher circulating histamine levels, which can be rebalanced once vitamin C blood level has been normalized (90-92). Furthermore, vitamin C can reduce the production of pro- inflammatory leukocyte-derived cytokines (e44» TNF and IL- 6). through the modulation of nuclear transcription factor kappa. B (NFKB) (2, 93, 94) in at least two ways: 1) through its reduced, form (ascorbate), by scavenging cellular ROS and inhibiting ROS-related signaling for the transcription of NFKB (95-98); 2) through its oxidized form (dehydroascorbate), produced as a consequence of quenching ROS, by directly inhibiting the activity of several kinases involved in the TNFd-mediated activation of NTKB (p38 mitogen-activated protein kinase, IB kinase and B) (99-101), However, the effect of vitamin C on the balance of cytokine responses (pro- and anti-inflammatory) is very complex and seems to be dependent on cell type and/or inflammatory condition (1). Moreover, authors (102, 103) have recently suggested that vitamin © may interact with molecular pathways related to inflammatory stress and immune dysfunction during sepsis, involving particular mediators: Epidermal Growth Factor Receptor (EGER), Mitogen-Activated Protein Kinase-1 (MAPK1), ne ¢ JUN), C-C chemokine Receptor type 5 (CCRS), Mitogen Activated Protein Kinase 3 (MAPK3),, Angiotensin II Receptor type 2 (AGTR2), and Signal Transducer and Activator of Transcription-3 (STATS). ‘The effects of vitamin C on immune function may also be expressed through epigenetic regulations, although this topic is, still poorly understood (104, 105). The epigenetic remodeling associated with immune cell activation and differentiation includes DNA and histone modification (106). Vitamin C. plays an important role by increasing the activity of epigenetic enzymes, including ten-eleven translocation (TET) proteins and. Jumoni-C domain-containing histone demethylases (JHDMs) Fronts in inmundbay | wen torso ‘Yamin Can Perspectives on COMD-19 (107). In fact, since TET and JHDMS belong to the Fe"/e- Ketoglutarate-dependent dioxygenases superfamily (105), vitamin C, as ascorbate, being able to donate eletzons, ats as 4 cofactor for these enzymes, reducing Fe" to its catalytically active form (Fe) (63). TET proteins are involved in the demethylation of cytosine residues in DNA, while JHDMs regulate the methylation of lysine and arginine residues in histones, resulting in modifications of gene transcription (63, 108, 108) that are involved inthe response of both the innate and the adaptive immune system (106, 110). The utility of these recently-discovered gene-regulatory functions of vitamin C for the assessment of dietary recommendations has not yet been clucidated and further research is needed to indicate the ‘minimum dose at which vitamin C may have an effective impact on functional or clinical outcomes through epigenetic changes (44), ORAL SUPPLEMENTATION OF VITAMIN C FOR THE PREVENTION AND TREATMENT OF THE COMMON COLD AND UPPER RESPIRATORY TRACT INFECTIONS The common cold is one of the most widespread viral upper respitatory tract infections (URTI), characterized by coughing, tiredness, fever, sore throat, and muscle pain, which persist for 4 period ranging from a few days to not more than 3 weeks (111, 112). The term “common cold” refers to an unspecific syndrome caused by several viruses, although the rhinovirus is the most frequent pathogen involved, being found in 30% to 50% of sufferers (113). Despite symptomatology usually being very mild, the common cold is a major cause of absentesism from work and school (114). The popular myth that a very high intake of vitamin C may lead to a lower susceptibility to respiratory tract infections originates from Linus Pauling’s theories published in the seventies. According to Pauling, daily vitamin C intake of 1,000 mg can reduce the incidence of colds by about 45% and the optimal daily intake of vitamin C to live healthily and prevent disease should be at least 2.3 g (115, 116). The response of the US market to this pioneering point of view was immediate and the sales of vitamin C dietary supplements almost doubled over a couple of years (117) However, other clinical studies with similar aims failed to demonstrate its efficacy (118-121) and, in general contemporary authors completely refuted Pauling’s ideas, mainly based on non-randomized controlled trials or incorrect application of animal background to humans (122, 123), Although a high daily dose of vitamin C does not seem to prevent viral infections in the general population, some categories of subjects with potentially higher risk of viral infection may require particular consideration. These subjects include individuals undergoing a daly heavy physical workload such as soldiers and athletes, who may develop an immune stress condition, (etober 2000 | Vue 17 | Arce 574029Cont ota General Population If we exclude some results that reported only small or inconsistent effects attributable to vitamin C (124), after decades of investigations, the scientific community established that a high intake of vitamin C is useless in preventing the common co (11), and therefore, a regular daly supplementation is not jusiied in the general population (12). Recent meta- alysis has reached similar conclusions regarding the incidence of infection, underlining, however, the possibility of reducing the dluration of a cold, Géme etal. (125), demonstrated that 8,472 Subjects from eight randomized clinical tials (RCTS), showed very strong evidence that vitamin C intake above 80 mg/day does not prevent the common cold in healthy adults and children. Vorilhon et al, (126), analyzed eight RCTs and confirmed that vitamin C supplementation dosage from 05 gto 2 gay) is not effective, compared to placebo, in reducing the incidence of upper respiratory trac infections (URTI) in 3,135 children (Grom 3 months to 18 years of ag), although the administration can reduce the duration of URTI by 14%, as previously highlighted by Rondaneliet al. (127) Positive results on the duration of colds was also suggested by the meta-analysis of Ran et al, (128) in which the combination of a small, long-term daily dose of vitamin € (ao more than 1 giday) to sustain immunity and a larger dose of vitamin C during the onset of the common cold (usually 3-4 g/day) was associated with the ability to relieve chest pain, fever, and chills, reducing the staying indoors duration, as well as the mean duration of disease People Under Heavy Physical Stress Some authors have reported a high incidence of respiratory infections in military training centers, probably also due to an overcrowding of individuals often coming from different geographical areas (129-131). More data are available on Athletes, for whom daily high-intensity training and competitions have been associated with transient immune perturbations, inflammation conditions, and increased susceptibility to infections (132-134). Furthermore, compared to the general population, athletes have a higher exposure to pathogens, due to frequent travel and sports events (135, 136), which may potentially inctease the risk of developing viral infections Data in literature referring to the effect of vitamin supplementation on the prevention of the common cold in these subjects are interesting, despite being limited at present. AAs was well deseribed by Hemilé and Chalker, (12) vitamin C supplementation may decrease the incidence of colds by about 50% in people under extreme physical stress. More recently, Kim et al. (137) carried out a large randomized, double-blind, placebo-controlled tril in 1,444 Korean soldiers, 695 of whom received vitamin C (6 g/day) for 30 days. They showed that the vitamin C group had a 0.80-fold lower risk of geting the common cold compared to the placebo group (n = 749). ‘The theoretical basis for the use of vitamin C in physically stressed subjects resides in the significant increase of ROS production due to intense exercise (138), with remarkable Fronts in inmundbay | wen torso ‘Yamin Can Perspectives on COMD-19 tissue damage/nflammatory response that may have harmful consequences on preventing URTI (138), possibly requiring a higher antioxidant intake compared to the general population (140). Despite this, it has recently been established that the administration of a high dose of antioxidants can negatively interfere with exercise-induced redox signaling and muscle adaplations (Id1-147) and the use of high doses of vitamin C toabolish ROS, especially over a long period, should be avoided (148, 149, Even though the elects of isolated vitamin C on oxidative stress, inflammatory markers, muscle damage and immune response following exercise remain to be clarified in depth (146), a recent scientific society position stand (150), a recent review (140), and a meta-analysis (146) agre on recommending vitamin C supplementation (0.25-1.0 g/day) as an option to prevent URTI symptoms in athletes under heavy exertion and/or during periods of increased risk of infection (eg. travel abroad) (140); athletes with low inital blood concentrations of vitamin C are the major candidates for supplementation (146, 148, 151, 152). ORAL SUPPLEMENTATION OF VITAMIN C FOR THE PREVENTION AND TREATMENT OF PNEUMONIA Pneumonia is lower respiratory tract infection characterized by 4 cough, difficulty in breathing, chest pain, fever, and lung. inflammation (153). Pneumonia is the first cause of death by infection in the United States and the fifth most common cause of death overall (154, 155). Streptococcus pneumoniae and Haemophilus influenzae are recognized as the most common agents responsible for pneumonia (156) but other pathogens are also able to induce pneumonia, including viruses and fungi (153, 154), Results obtained in rats and mice suggested that orally supplemented vitamin C may be useful in reducing susceptibility to viral pneumonia and potentially in reducing the development of ARDS (157, 158), which is recognized as the most severe form of acute respiratory infection (158), However, human findings on vitamin C supplementation and pneumonia remain scarce, with few dated observations mainly based on particular subjects and conditions (eg., military people, developing countries) and not generalizable (5, 160). On this topic, the most recent meta-analysis including 2,774 participants from seven clinical studies, underlined that current evidence is insuficient to sustain the eficacy of vitamin C supplementation in proventing or treating pneumonia, due to the small number of trials and very low quality of the existing results (161). However, the meta-analysis of Padhani et al. (161) considered studies from different populations, including three studies on children, without subgroup analysis. Since the pharmacokinetics of vitamin C varies betwen subgroups and is not yet known in children, an analysis of data should have been done independently and, therefore, conclusions ofthis study may be questionable. (etober 2000 | Vue 17 | Arce 574029ORAL SUPPLEMENTATION OF VITAMIN C FOR THE PREVENTION OF COVID-19 COVID-19 is a new, worldwide recognized form of viral pneumonia, caused by SARS-CoV? infection (162, 163). The symptomatology often begins within 2 weeks fom contagion and mainly includes fever, fatigue, cough, and shortness of breath (164). Current knowledge suggests that while the majority of infected subjects (80%-90%) exhibit mild symptoms or can be asymptomatic, about 5% may develop pneumonia, ARDS and multi-organ dysfunction leading to death (165). It is unquestionable that an optimal autritional status effectively reduces inflammation and oxidative stress, improving the immune system regulation (166). However, no data are currently available on the regular use of high doses of oral vitamin C to reduce the risk of infection by SARS-CoV2 ina healthy general population (167-169) and further studies are needed to explore the role of vitamin C in prevention of COVID- 19 (169). For heavily stressed subjects (athletes in particular), specific data are not currently reported regarding the incidence, prevalence, or natural history of disease related to COVID-19 (134), despite these subjects’ potentially high risk of exposure to this virus (136, 170), Furthermore, scientific opinions have not been expressed regarding the use of oral vitamin C to prevent SARS-CoV? infection in extreme exercisers. However, a vitamin C supplementation may be elfective for improving the health status of patients considered at high risk of viral infections (171). ORAL SUPPLEMENTATION OF VITAMIN C FOR PATIENTS WITH METABOLIC DISORDERS, CARDIOVASCULAR DISEASE, AND FRAIL ELDERLY SUBJECTS: POTENTIAL RELATIONSHIP: WITH COVID-19 There are notably some factors that increase the risk of developing SARS-CoV2 infection and affect the severity of COVID-19 (172). People with pre-existing non-communicable diseases (NCDs) appear to be more susceptible to developing COVID.19 (173, 174). NCDs include obesity, diabetes mellitus, chronic ung diseases, cardiovascular diseases (CVD) and various other conditions which are characterized by systemic inflammation which impairs immune response and may exacerbate the cytokine storm related to COVID-19 (173, 178, Obese Subjects Some studies have shown that obesity is associated to a more severe form of COVID-19 (175, 176), even in younger patents (age <50) (177), anda BMI > 40 kg/m? was identified 35 one of| the strongest risks of hospitalization due to SARS-CoV2 infection (178) These findings are worrying considering that obesity is global phenomenon and in countries such a the US about 36% of population is obese (175). Ths association could be iain C ac Perspect on COWD-19 linked to inlammatory mechanisms, sine authors suggest that, compared to individuals with a normal weight, obese subjects havea higher plasma concentration of C-reactive Protein (CRP), an inflammatory biomarker used to predict cardiovascular disease (180). Based on this, a vitamin C supplementation in these subjects may be useful in reducing. inflammation, considering data that showed how a treatment of orl vitamin € (1,000 mg/day) for two months can significantly reduce plasma CRP in healthy, overweight, non-smokers with baseline CRP 2 1.0 mgil. (181). This finding is very interesting, taking into account that participants had an adequate dietary intake of| vitamin C, with a baseline mean plasma level of 57.8 mol/L, and it suggests that the RDAs for vitamin Cin obese individuals may bbe underestimated, as was recently underlined by Rychter etal (182, 183). Research is needed to understand whether by reducing the CRP with vitamin C it could be possible to influence the incidence and/or the progression of inlammation mediated disases associated with obesity, including infections and potentially covib-19 (17). Diabetic Subjects A recent meta-analysis including 33 studies (16003 patients) confirmed that diabetics have a two-fold higher increase in ‘mortality, as well as severity of COVID-19, compared to non- diabetic COVID-19 patients (184). Type 2 diabetes mellitus (T2DM) is the most common form of diabetes (185), characterized by chronic hyperglycemia, inflammation and ‘oxidative stress (186). The inflammatory condition observable in diabetes may possibly be a mechanism that increases the susceptibility to COVID-19. Low plasma concentrations of vitamin C in people with T2DM was observed (187, 188), despite adequate vitamin C intake (189, 190). Two ‘mechanisms could particularly explain lower vitamin C levels im these patients: 1) increased urinary excretion, especially in those with microalbuminuria (191); 2) higher depletion of vitamin C caused by an increase of oxidative stress (190, 192). [An interesting study on the use of oral vitamin C in diabetic subjects was reported by Mason et al. (193). It showed an approximately two-fold enhanced SVCT2 expression in skeletal ‘muscle afer vitamin C supplementation (1,000 mg for 4 months) in poople with T2DM, with an increase of musele concentration of vitamin C and a decrease of muscle oxidative stress, However, given the small number of subjects investigated in this study (seven participants, six males and one female), larger studies are needed to confirm similar results. Findings from an RCT showed that vitamin C supplementation (1,000 mg/day for 8 weeks) significantly reduced CRP, IL-6, fasting blood glucose (FBG), and triglycerides (TG) in 64 obese, hypertensive and/or diabetic patients, with high levels of CRP > 6 mg/L. (194). In addition, ‘meta-analytic data indicated that vitamin C supplementation for ‘more than 30 days with a dosage ranging from 200 to 1,000 mg significantly reduces FBG in patients with T2DM (195). Based on the above, vitamin C supplementation may represent a promising option to modulate inflammation and blood glucose in patients with hyperglycemia and elevated CRP, it could potentially be able to improve the health of these individuals and reduce the susceptibility to infections, Investigations are (etober 2000 | Vue 17 | Arce 574029Cont ota strongly encouraged to establish a possible correlation between an extra intake of vitamin C and a possible decrease of incidence, severity and mortality for COVID-19. Subjects With CVDs GYDs (as well as hypertension) are the most common comorbidities among COVID-19 patients (174, 196, 197). Individuals with a CVD are five-fold more at risk of developing the critical stage of the disease, as indicated in a meta-analysis involving over 3000 patients with COVID-19 (198). tn this ease, the main reason for a higher risk of SARS: Cov? infection is related to the high angiotensin converting enzyme 2 (ACE2) expression observed in these patients (199 201, since this enzyme is used by the virus to invade calls, promoting vial colonization (202). tis known that low plasma Concentrations of vitamin C are predictive of heightened CVD risk (203-205), but the current iterature provides tle support for a widespread use of vitamin C supplements to reduce CVD risk or mortality (206), and available data are also controversial Many cohort studies and RCTs have shown no relationship betven vitamin C intake and CVD risk However, in most RCTs the participants were not prescreened for a depleted status and this seriously limits the posit of concluding on the results as the potential impact ofthe vitamin C supplementation on the outcomes considered may vary from highly significant to negligible in ration to ther vitamin C status at study start (207), ‘A ow other studies have suggested moderate bencits, and some references have registred a light increas in ik (206). A significant barrier to the comprehension of the relationship between vitamin C and CVDs i the lack of mechanistic studies in humans (206). At present, there are no recommendations for an additonal daily doe of vitamin C in CVDs to potentially prevent diseases, including pulmonary infections and COVID-19. Frail Elderly Subjects It is particularly important to consider elderly communi when trying to prevent COVID-19. The elderly are more vulnerable compared to the general population due to an increased risk of malnourishment and infections and a high prevalence of NCDs (208). Age itself is a risk factor for developing COVID-19 (209), due toa functional decline of the immune system (210, 211). Furthermore, malnourishment in these subjects is very frequent for several reasons (€4» poor socioeconomic conditions, mental status, social status) (212) and nutritional deficiencies (including vitamin C) have been reported (213). Malnourishment ean worsen an impaired immune system in the elderly, making them more susceptible to infections (214). In elderly hospitalized subjects (mean age 81 years) sufering from acute bronchitis or pneumonia, a mean plasma vitamin C level at baseline of 23 mol/L. was reported and a concentration of 11 pmol/L was found in one third ofthe patients (215). This s particularly important since a low vitamin C concentration (<17 mol/L) in older people (aged 75-82 years) is considered strong predictor of all-cause mortality (216), Notably, in Hunt's study (215) administration of vitamin C (02 glday) reduced the respiratory symptom score in the more severe patients However, at present, it is not known whether a regular Fronts in inmundbay | wen torso ‘Yamin Can Perspectives on COMD-19 supplementation with vitamin C can protect these subjects from chronic inflammation NCDs-related and/or can prevent the onset of viral infections including COVID-19. ORAL SUPPLEMENTATION AND SIDE EFFECTS Vitamin C has an excellent safety profile, primarily due to its hhigh water solubility and rapid clearance of excess levels by the kidneys (44,217). Although itis not possible to establish a UL for vitamin C, values of 1,000~2,000 mg/day have been suggested as prudent limits by some countries, based on a potential risk of ‘osmotic diarrhea and related gastrointestinal distress in some individuals at higher doses (44, 3). Since vitamin C is partially converted to oxalate and excreted in the urine, high doses of vitamin C could be associated with calcium oxalate stone formation (218, 219). Ferraro et al. (220) studied 156,735 women and 40,536 men, who reported episodes of kidney stones during an average follow-up of 11.3-11.7 years. ‘The authors significantly correlated the total vitamin C intake with a higher risk of incident kidney stones in men, but not in ‘women. However, itis important to outline that this study had limitations to be considered. The presence of confounding factors (eg, comorbidities, dehydration, dietary intakes of coxalate-forming foods) were not taken into account during the follow-up, and the authors assessed vitamin C intake only through a questionnaire (without measuring blood levels) and with very long time intervals (every 4 years) INTRAVENOUS ADMINISTRATION OF VITAMIN C: A POTENTIAL ROLE IN THE TREATMENT OF COVID-19? While an extra dietary intake of vitamin Cto counter pneumonia does not seem promising, several interesting data have emerged from the use of vitamin C through IA, providing an encouraging, bout questioned, hypothesis on its potential pharmacological use for the treatment of pneumonia caused by SARS-CoV? infection, In fact, as opposed to oral supplementation, in which the ‘maximum peak plasma concentration that was achieved with @ high-dose (3 g every 4h) was 220 jumoV/L. (221), the 1A of vitamin C, bypassing the limitations induced by intestinal transporters (SVCTI), may lead to @ higher plasma level (eg up to 3,000 pmol/L at day 4 with 200 mg/kg/day, administered in 50 mglkg/dose every 6 h). Although the potential antsepsis therapeutic mechanism exerted by vitamin C has not yet been understood (103), besides the effects described in the previous paragraphs, the use of vitamin C in an infectious emergency may be justified for some reasons: 1) significant clinical evidence from pneumonia, critical illnesses and ‘other acute infections suggests that plasma levels of vitamin C can rapidly drop off (eg, <30 umol/L) during the inflammatory response (2, 93, 9M ) probably due to an increased (etober 2000 | Vue 17 | Arce 574029Cont ota consumption of vitamin C by leukocytes. Considering that intracellular ascorbate concentrations in mononuclear cells and in granulocytes are respectively 80 and 25 times greater than in plasma, an increased replacement and turnover of these cells during these ‘medical conditions can contribute toa decrease of vitamin C in the blood (229};2) a negative regulation of SVCT2 transporters induced by inflammatory cytokines, in particular IL-1 and TNF (220); 3) the antioxidant defense system of the pulmonary epithelium involves enzymes and vitamin C (231) and according to Banerjee and Kaul a sustained high dose of vitamin C available in respiratory secretion could exhibit an efective anti-viral activity (232). This last Point, however, is sill a hypothesis at present, since the level of vitamin Cin the bronchoalveolar fluid is normally too low toachieve antiviral activity and furthermore very litle is known about the potential increase of vitamin C concentration in bronchial tissue and fluid secretion following a high-dose 1A (36) Therefore, considering the aspects mentioned above, the Infusion of vitamin C has recently been suggested to treat COVID-19 in ICU hospitalized patients (13-18). Below, we summarize the most substantial evidence obtained in critical illness studies based on IA of vitamin C regarding the most relevant outcomes (inflammation, ventilation time, and ‘mortality) which may relate to SARS-CoV2-induced ARDS. Effects of IA of Vitamin C on Inflammation Markers In COVID-19 patients the inflammatory response is very dramatic and has been defined as a “cytokine storm’, associated. with Increased plasma concentration of IL-1B, IL-2, IL-6, IL-10, IFNy, and TNF-ct (233, 234), able to induce an acute lung injury (ALI) Which results in ARDS and requires urgent ICU interventions (162). Physiopathology of ARDS involves alteration of pulmonary permeability, rapid lung leukocyte infiltration with a large increase ‘Yamin Can Perspectives on COMD-19 of tissue oxidative stress, lading to respiratory failure and death, which in most cassis due to massive alveolar damage (24,235). A ‘promising background on the use of vitamin Cin an experimental ‘model of ALI was found (236-241), with postive evidence on rebalancing cytokine production and specific physiopathological mechanisms involving neutrophils (.e, neutrophil extracellular traps) (4) which may contribute to organ damage and mortality in COVID-19 (233) (Figure 1). Two studies by Fowier et al are currently available on IA of vitamin Cin ICU hospitalized patients and inflammatory response, with mixed results (227, 242). I the first preliminary study (227), vitamin C showed a significant reduction in proinflammatory biomarkers (CRP and procalcitonin) over the first 96 h, without adverse effects registered during the infusion, but the number of ARDS.alfected patient treated with vitamin C was too smal (50 mgykg/24 h, n= 5 200 mg/ky/24 h,n = 8) tallow safe conclusions. In the second larger study (242), 167 patents with sepsis and ARDS were randomized to receive vitamin C (50 mg/kg every 6 h for 96 h) ‘or placebo; no changes in CRP and thrombomodulin were detected, although the study was ertcized for the choice ofthe inflammatory markers assessed (243) Effects of IA of Vitamin C on Intensive Care Ventilation Time ‘The above-mentioned study (242) also reported a lower duration time of mechanical ventilation support in the supplemented ‘group, with a higher number of ventilator-free days in the vitamin C group than in the placebo group (mean values: 10.6 vs. 13,1 days, respectively). Ventilator-tree days were defined as the number of extubated days, considering the time between ICU hospitalization and day 28. Another previous randomized controlled trial (RCT), including burn patients with severe respiratory dysfunction receiving a very high dose of vitamin C ymax tas FIGURE 1 | Schoratc mectansm in which an A of tain C coud mete spec unions of neutophis (AOS and TNF. Li moda, rhbting ‘batways rvohod inthe Nowreph Exraclur Trp eration (NETode) ard recucng the unceotatl ntarmary kina reducten tha hola space. Pott efects on reducng ck producto rave abo been specatd in hraecytas and mactopages. ROS, reacbe anoen species: NES. ruc ‘rnscrptn factor kappa &-L anbien sims; dashes aro, exes eect pron. Fronts in inmundbay | wen torso (etober 2000 | Vue 17 | Arce 574029Cont ota (66 mg/kg/h for 24 h), showed a significant decrease ofthe time of ventilation (mean values: 12.1 vs, 21.3 days, respectively) in those who received vitamin C infusion compared to the control group (85). The pulmonary benefit reported by these authors is probably due to the antioxidant, anti-inflammatory and ‘microvascular action of the vitamin C (244) Different positions on the topic derive from systematic evaluation of the literature, suffering because of the gross limitations of the available primary data, For example, the meta-analysis of Langlois et al. (245), failed to find any improvement on ventilation time, This work, however, included studies with vitamin C administrated through diferent routes (enteral or parenteral), most of which (9 out of a total of 11 studies) used antioxidant mixtures instead of vitamin C alone; Zhang and Jativa (244) analyzed the efficacy of IA of vitamin C on vasopressor sparing effects and the lower need for mechanical ventilation in critical illness, underlining several weaknesses ofthe available studies considered (four RCTs and one retrospective review), such as the paucity of the sample size, the heterogeneity of subjects enrolled, hospitalization selting, dosages and follow-up; recently, the meta-analysis from Hemila and Chalker (246), including eight trials and 685 patients, with promising results on ventilation time, pointed ‘out that the great variation in the reported ellets of vitamin C ‘may be linked to the non-homogencous severity of the illness Which mostly impacts the ventilation time required. From this point of view, vitamin C shortened ventilation time on average by 2596 when the analysis was restricted to patients requiring ‘mechanical support for more than 10 h, Effects of IA of Vitamin C on Mortality Of the critical outcomes considered the potential effect of vitamin > on morality rates appears tobe the most controversial one, with RCTs studies that underline promising results which are not supported by recent meta-analysis. A significant reduction of 28-day mortality during ICU hospitalization was observed in a small group of patients with sepsis treated with LA of vitamin TABLE 1 | Surmay of eco ning on ha uso of visrin © ere, ie Genera popuaton ‘Yamin Can Perspectives on COMD-19 (25 mgikg every 6 h, for 72 h) compared to the control group (14.28% Vs, 61.28%, respectively) (247). More recently, findings {rom the CITRIS-ALI study (242) showed a reduced mortality at day 28 in the vitamin C group (29.8%) compared to the placebo, group (463%). Conversely, according to the meta-analysis of Zhang and Jativa, although vitamin C IA seems to be linked to positive vasopressor elects, temporally reducing the need for ‘mechanical ventilation, no positive effect in favor of overall mortality emerged (244), leading the authors to conclude that it does seem improbable that vitamin C, considered asa single agent, could be so dramatically decisive on the physiopathology of a critical illness as to influence the incidence of mortality (244). Similar conclusions were drawn by Wei et al. (248), who, by including recently published retrospective studies in their meta- analysis, suggest the lack of benefit on 28-day mortality, both in ICU and in-hospital patients with sepsis, Itis important to consider that the effect of vitamin C infusion seems to exert different results on mortality in relation tothe type of critical patients involved, especially when administration is in association with other drugs. From this point of view, two retrospective studies showed that vitamin C (15 g every 6 h), Jn combination with hydrocortisone (50 mg every 6 h), and thiamine (200 mg every 12 h) may dramatically reduce mortality ‘by 5696 in ICU patients with severe pneumonia (249) and by 79% Jn severe sepsis (250), compared with patients who did not receive vitamin C and thiamine, Unlike these data, a recently published RCT (VITAMINS) showed no benefit from the combination of IA of vitamin C, hydrocortisone and thiamine in comparison to hydrocortisone alone among patients with septic shock (251). However, as underlined by Carr (252), since the VITAMINS tral did not include a monotherapy vitamin C subgroup, this trial does not provide any information as 10 whether LA of vitamin C offers some benefit to septic patients in the absence of corticosteroid administration, and further tials are needed in this direction, ‘Another critical issue that should be highlighted is the timing of treatment administration. On this topic, important results That ae no commendations thal vlarinC supplementation mpects re ince and ation of be common colle pau, crear suplerentaton st carer used in the aera pope, [Data on pretmana sr ss cna chica, because he prarmaclineis cf amin Cin this ager linkin a present ‘Acupplemersion of 0.2 gay of arin C may be rexorab mh subets wth ow sma amin C coreataten, ‘jects with nonconmenicabl dstases(NCOS| and al ey sues ao roogrized as bong at ih sk va rectens. amin Csuppemeniaton (12-1 fay) can duce nfaraen and, ahough Greener silk, may docraso the suscepti to rectors anor ho covery ofthe aso lamin © suppeenartston (02 e/a) may reduce th espatoy syploms hd parts. amin supp ay sss fo, sports compat ton may dozrata th htenco of oh poople under exers psa sos. arin © suppeertston does not seam io imeroe yscal pafomance n wel nourehed ates, and rogue nose warn © suppeenaten ry eso nf the excreendaced edox pang adaptation and shade ok subpcts Nise spo cosice aver C semen 25-1 gf oper UAT Symons dan Ke eros eet Inercaly i patents, wtarinG doicency scone, and Af figh dosas asbeon usd o normals plasma tain Cel “To date no recorrenisers ar vat as data inirnairy merks, mochorcal Yeisen ta and mera rats Nave boon reported n thee patos. Furbo corvlod lea ara ancaraged epecaly fr COV. Fronts in inmundbay | wen torso (etober 2000 | Vue 17 | Arce 574029Cont ota come feom a retrospective cohort study of 208 patients in septic shock (253), which suggested thatthe ICU mortality ratio [based on the APACHE (Acute Physiology and Chronic Health Evaluation)-predicted ICU mortality of patients who received vitamin C with thiamine and hydrocortisone, increased linearly with the delay in treatment from inital sepsis presentation. Indeed, the APACHE-adjusted ICU morality was significantly reduced only in patients who received vitamin C, thiamine, and steroids within 6 h from sepsis presentation (253). CONCLUSION Apart from some specific individuals and conditions (Table 1), the evidence described is insulicient to support the eficacy of a regular supplementation with vitamin C for the prevention or treatment of the common cold or pneumonia in the general population, Interesting data on the possible use of vitamin C to prevent infections regard special conditions (eg, soldiers and athletes) and subjects with metabolic disorders, CVDs or frailty, in which the potential control of inflammation by a vitamin C supplementation could represent an effective aid in reducing the risk of infection, even for COVID-19, However, this last statement needs to be properly supported by future RCTs. Even though the IA of vitamin C could be an adjuvant therapy to quickly restore plasma levels of vitamin C during severe sepsis and ARDS in ICU hospitalized patients (254), its elects on inflammation response, ventilation time and mortality rats sil REFERENCES (Caer AC, MagginiS. 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