High doses of vitamin C under study for treating COVID-19 may benefit some populations, but investigators exploring its potential in aging say key factors in effectiveness include levels of the natural transporter needed to get the vitamin inside cells.
Age, race, gender, as well as expression levels and genetic variations of those vitamin C transporters that make them less efficient, all may be factors in the effectiveness of vitamin C therapy against COVID-19 and other maladies, investigators at the Medical College of Georgia Center for Healthy Aging report in a commentary in the journal Aging and Disease.
The investigators recommend that those factors be considered in the design and execution of clinical trials, and when trial results are analyzed, for COVID-19 as well as other conditions, says Dr. Sadanand Fulzele, aging researcher and the article’s corresponding author.
The novel nature and lack of immunity against the coronavirus has prompted a worldwide pursuit of effective treatments for COVID-19, they write.
Both strategies are needed in response to infection with the novel coronavirus to ensure a strong immune response to stop the virus from replicating in the body, and to avoid the over-the-top, destructive immune response the virus itself can generate if it does.
There are at least 30 clinical trials underway in which vitamin C, alone or in combination with other treatments, is being evaluated against COVID-19, some with doses up to 10 times the recommended 65 to 90 milligrams daily of vitamin C.
Factors like whether or not vitamin C can get inside the cell, likely are an issue in the effectiveness the therapies ultimately show, says Dr. Carlos M. Isales, co-director of the MCG Center for Healthy Aging and chief of the MCG Division of Endocrinology, Diabetes and Metabolism.
In fact, without adequate transporters on a cell’s surface to get the water-soluble vitamin past the lipid layer of cell membranes, particularly large doses may enable the vitamin to cluster around the outside of cells where it actually starts producing oxidants, like damaging reactive oxygen species, rather than helping eliminate them, says Isales, a study coauthor.
They suspect low transporter expression is a factor in the mixed results from vitamin C’s use in a variety of other conditions.
Clinical trials in osteoarthritis, for example, an autoimmune disease where a misdirected immune system is attacking the joints, has gotten mixed results, Fulzele says.
However its usage in other viral-induced problems, like potentially deadly sepsis, has shown benefit in reducing organ failure and improving lung function in acute respiratory distress syndrome, which is also a major cause of sickness and death with COVID-19.
At the time their Aging and Disease paper was published, there were not yet published studies of the efficacies of high-dose, intravenous vitamin studies underway for COVID-19.
Fulzele, who works on vitamin C in aging, and others have shown that some conditions, like osteoarthritis and even normal aging, are associated with significant downregulation of at least one subtype of vitamin C transporter.
In fact, part of the paradox and concern with COVID-19 is that those most at risk mostly have both lower levels of vitamin C before they get sick and fewer transporters to enable the vitamin to be of benefit if they get more, Fulzele says.
Many of those most at risk from COVID-19, including individuals who are older, Black, male and with chronic medical conditions like osteoarthritis, hypertension and diabetes, tend to have lower levels of vitamin C, another reason vitamin C therapy would be considered a reasonable treatment, Isales says.
The investigators also note that patients may develop a vitamin C deficiency over the course of their COVID-19 illness since, during an active infection, vitamin C is consumed at a more rapid rate. Insufficient levels can augment the damage done by an overzealous immune response.
While not routinely done, transporter expression can be measured today using PCR technology, a method also used for novel coronavirus as well as influenza testing.
While increasing transporter expression is not yet doable in humans, one of Fulzele’s many research goals is to find a drug or other method to directly increase expression, which should improve the health of older individuals as well as those with other medical conditions that compromise those levels.
He notes that reduced transporter levels that occur naturally with age are a factor in the reduced immune function that also typically accompanies aging. That means that even when a 60-year-old and 20-year-old both have a healthy diet in which they consume similar, sufficient amounts of vitamin C, the vitamin is not as effective at boosting the older individual’s immune response. Reduced immune function in older individuals is known to put them at increased risk for problems like cancer and COVID-19.
Low vitamin C levels also have been correlated with higher mortality in older individuals from causes like cardiovascular disease. High oxidative stress, a major factor in conditions like cardiovascular disease as well as aging and now COVID-19, also is associated with significantly reduced expression of the vitamin C transporter.
Isales and Fulzele doubt that taking a lot of vitamin C is a good preventive strategy against COVID-19, except in those individuals with a known deficiency.
Vitamin C is an essential vitamin, which means people have to consume it in their food or supplements. Foods naturally high in vitamin C include oranges, potatoes, tomatoes, broccoli and Brussels sprouts. The vitamin’s diverse roles in the body also include formation of blood vessels, collagen and cartilage.
Correction of the redox imbalance as an antiviral therapeutic strategy
Understanding how coronaviruses cause damage to human cells and organs could offer clues for developing a more effective therapy. Viruses cause infections that are often associated with redox modification characteristic of oxidative stress.
Changes in redox homeostasis in infected cells are one of the key events in the pathogenesis of respiratory viral infections in all phases of the disease, contributing to severe inflammatory reaction and subsequent tissue damage .
Redox changes to an oxidised state also play a critical role in the activation of numerous cell pathways that are hijacked by viruses to assure their replication and to suppress the patient’s immune response.
Viruses use several strategies to manipulate host cell machinery to their advantage. Among these, the imbalance of intracellular redox state caused by viruses could play an important role in modulating the activity of several signalling pathways.
Oxidative imbalance caused by viral infections , ligand–receptor binding  or cytokine storm  could result in localised oxidation of reactive residues of redox-sensitive proteins.
Increased oxidative stress leads to a systemic inflammatory response due to increased production of cytokines, contributing to Acute Respiratory Distress Syndrome (ARDS), the key pathology in the high mortality of acute respiratory viral infections .
Despite the antiviral role of cytokines in respiratory infections, their overproduction during the cytokine storm is more damaging to lung tissue than the viruses themselves.
As a common immunological defence mechanism, immune cells respond to foreign infection by producing large quantities of reactive oxygen species (ROS) to destroy invading organisms .
Previous pathological and histological examinations showed that coronaviruses and influenza induced significant downregulation of the airway antioxidant system, leading to lethal lung injury and death from ARDS due to oxidative damage .
The autopsy pathology of the novel coronavirus is similar to other virus-induced ARDS. In a report of 29 patients with confirmed SARS-CoV-2 pneumonia, 27 (93%) showed increased high-sensitivity C-reactive protein (hs-CRP), a marker of oxidative stress injury .
Possible role of vitamin C in viral infection and related complications
Vitamin C has many properties that make it a valuable therapeutic agent for respiratory infections. It is a potent antioxidant with anti-inflammatory and immunosupportive properties. Vitamin C is a small, water-soluble molecule that readily acts as a one- or two-electron reducing agent for many free radicals and oxidants.
Specialised cells can take up reduced vitamin C (ascorbic acid) through Na+-dependent ascorbate cotransporters (SVCT1 and SVCT2). Most other cells take up vitamin C in its oxidised form, dehydroascorbic acid, via facilitative glucose transporters .
Almost all mammals, except for humans, primates and guinea pigs, can synthesise vitamin C in their livers, with increased production during stress.
Vitamin C is an essential vitamin that acts as a cofactor for several enzymes and facilitates the production of catecholamines, vasopressin, l‐carnitine, collagen neurotransmitters and cortisol , which are central to cellular function and homeostasis.
Additionally, vitamin C plays a significant role in viral infection, including attenuation of the pro-inflammatory response, enhancement of epithelial barrier function, increased alveolar fluid clearance, and prevention of sepsis-associated coagulation abnormalities .
This essential vitamin has a huge role in antiviral activity and immune enhancement.
It has been shown that vitamin C is an essential factor in the production of type I interferons during the antiviral immune response . Vitamin C has also been shown to upregulate natural killer cell and cytotoxic T-lymphocyte activity both in vitro and in vivo ,  and can be used as an inactivating agent for the fixed rabies virus .
Other studies have used this vitamin as an inactivating agent both for RNA and DNA viruses, lessening viral infectivity. In addition, vitamin C can detoxify viral products that produce pain and inflammation , . Evidence has shown the effectiveness of vitamin C in treating pneumonia and infection owing to its direct inhibitory effects on pathogens .
Also, vitamin C is present in the epithelial lining of the respiratory tract where it functions as a local mucosal protecting agent, helping to ameliorate symptoms of upper respiratory tract infection .
Sepsis is a life-threatening illness caused by a dysregulated host response to infection. Untreated, it can lead to severe organ damage throughout the body. It is difficult to manage, requiring a combination of different treatments and supportive care for critically ill patients.
Fisher et al. demonstrated in a mouse model that vitamin C plays a crucial role in multiple pathways associated with sepsis , .
Mice that were given vitamin C did not experience multiple organ dysfunction syndrome, whilst mice that were deficient in vitamin C were much more susceptible to sepsis-induced organ damage. A proposed mechanism is that ascorbate enhances the synthesis of the vasopressors norepinephrine and vasopressin by acting as a cofactor.
Therefore, administration of ascorbic acid (vitamin C) in patients with hypovitaminosis C during severe sepsis or septic shock supports the endogenous synthesis of vasoactive compounds, reducing the need for external vasopressors. These vasopressors help with the widespread vasodilation during sepsis, regulating blood pressure and fluid loss .
A high dose of vitamin C may be a proven therapeutic agent that not only ameliorates oxidative stress and inflammation during coronavirus infection, but also suppresses viral replication and improves antiviral immune defence and adrenal function.
Vitamin C in human clinical applications in viral infections, pneumonia and sepsis
In a study looking at the impact of vitamin C on oxidative stress and inflammation in community-acquired pneumonia (CAP), a common infectious disease, researchers measured values including reactive oxygen species (ROS), DNA damage, superoxide dismutase (SOD) activity, tumour necrosis factor-alpha (TNFα) and interleukin-6 (IL-6) in patients with CAP.
The results show that patients with severe CAP had significantly increased ROS, DNA damage, TNFα and IL-6, but significantly decreased SOD . Administration of vitamin C improved these redox imbalances by mitigating oxidative stress and pro-inflammatory markers, suggesting a possible therapeutic benefit for vitamin C in patients with severe CAP and other types of pneumonia.
This antioxidant and anti-inflammatory property has been shown in a multitude of studies, demonstrating efficacy in preventing lung injury and protection against damage to other organs such as the heart, kidneys and liver in animal models of oxidative stress , , .
Studies have shown that a high percentage of critically ill patients are deficient in vitamin C despite receiving standard nutrition.
In an observational study, Carr et al. found that 75% of critically ill patients had plasma levels of vitamin C that were abnormally low, resulting from increased metabolism due to an overactive inflammatory response . A common way to supplement vitamin C in the clinic is through intravenous (IV) vitamin C administration.
A phase I trial in patients with severe sepsis demonstrated that IV infusion of ascorbic acid was safe, well tolerated and had positive outcomes, including a significant reduction in multiple organ injury and reduced inflammatory biomarker levels .
High-dose IV vitamin C is commonly used by complementary and alternative medicine practitioners to treat a wide variety of conditions, including infections.
A survey sent to practitioners showed that over 20 000 patients received IV vitamin C over a period of 2 years, with a mean number of infusions per patient of 19–24. There were no definitive serious adverse events reported and a very small number of minor reported adverse effects .
Clinical trials have reported positive results for vitamin C therapy in respiratory infections. Nathens et al. infused ascorbic acid at 1 g every 8 h for 28 days in 594 critically ill surgical patients and found a significantly lower incidence of acute lung injury and multiple organ failure than in patients receiving mechanical ventilation .
Vitamin C also significantly improved the ‘total respiratory score’ in the most severely ill patients with respiratory infection . Fowler et al. reported a case study of a 20-year-old female who contracted respiratory enterovirus/rhinovirus infection that led to acute lung injury and ARDS.
At 12 h following the initiation of extracorporeal membrane oxygenation (ECMO), high-dose IV vitamin C was started with a dose of 200 mg/kg every 24 h divided equally into four doses and infused every 6 h. The patient recovered rapidly and ECMO and mechanical ventilation were discontinued by Day 7.
The patient recovered with no evidence of post-ARDS fibroproliferative sequelae . Dietary antioxidants rich in vitamin C significantly attenuate hyperoxia-induced acute inflammatory lung injury by enhancing macrophage function via reducing the accumulation of airway high-mobility group box 1 protein (HMGB1) .
In the critically ill patient population, there was a significant reduction in 28-day mortality in patients supplemented with antioxidant vitamin C and E .
Vitamin C has also been shown to be effective against other medical conditions. Marik et al. reported the use of IV vitamin C in 47 septic ICU patients, finding a significant reduction in mortality rate in the group treated with high-dose IV vitamin C .
Several other trials have also shown that administration of vitamin C to patients with sepsis is associated with better patient outcomes , . However, in the CITRIS-ALI randomised clinical trial, Fowler et al. did not observe significant differences in either organ failure scores or biomarker levels for 167 patients when comparing vitamin C infusion with placebo .
This lack of difference might be explained by the low vitamin C dose of 50 mg/kg body weight daily and short time frame of vitamin C infusion (only 96 h) in these patients with sepsis and ARDS.
Vitamin C has been widely utilised in the prevention and treatment of the common cold with varying degrees of effectiveness. Hemilä and Chalker determined that many of the studies showed that vitamin C reduces the duration and severity of colds , but the results were not consistent.
Conversely, a recent meta-analysis by Ran et al. of nine randomised placebo-controlled trials did not come to a consistent conclusion. They found that the combination of supplemental and therapeutic doses of vitamin C has effects on reducing symptoms and length of the disease, but only administration of a therapeutic dose of vitamin C (3.0–4.0 g/day) during the disease leads to better recovery .
Meta-analyses of randomised controlled studies have shown that vitamin C may protect against contrast-induced acute kidney injury and shorten the duration of hospital and ICU stay of cardiac surgery patients . Hemilä et al. identified 15 trials on the prevention of atrial fibrillation in high-risk patients and found that vitamin C decreased its incidence while shortening the length of hospital stay .
Other studies have shown that a high dose of IV vitamin C is effective against viral infections such as the common cold, rhinovirus, avian virus H1N1, Chikungunya virus, Zika virus and influenza , , .
Optimal dose and administration of vitamin C for treatment of pneumonia and acute respiratory distress syndrome (ARDS)
The dose and pharmacokinetics of vitamin C vary greatly, especially with high-dose vitamin C treatment . Pharmacokinetic trials concluded that 2–3 g/day of IV vitamin C was required only to normalise plasma levels, whilst a higher dose was required to achieve supraphysiological therapeutic levels .
For oral supplementation, doses >3 g appear to be safe and demonstrated efficacy in preventing and ameliorating respiratory and systemic infections .
The antioxidant capacity of vitamin C is dose-dependent, and direct radical scavenging capacity is maximal at a plasma vitamin C level of >175 mg/L (1000 μmol/L), more than ten times the normal physiological level.
Ascorbate prevents the interaction of superoxide and nitric oxide only at very high concentrations . Results from pharmacokinetic studies indicate that oral ascorbic acid doses of 1.25 g/day produce mean peak plasma vitamin C concentrations of 135 μmol/L, which is approximately two times higher than those produced by consuming 200–300 mg/day ascorbic acid from vitamin C-rich foods.
Pharmacokinetic modelling predicts that even doses as high as 3 g ascorbic acid taken every 4 h would produce peak plasma concentrations of only 220 μmol/L .
Different from oral administration, which is regulated via the sodium-dependent vitamin C transporter-1 (SVCT1), IV administration bypasses this pathway resulting in significantly higher plasma concentrations. Levine et al. documented the dramatic differences between the pharmacokinetics of oral and IV administration of vitamin C , .
They noted that IV vitamin C was much more bioavailable inside the body and there was a significant difference in the amount of ascorbic acid found in the urine between the two groups.
In other studies, IV administration was reported to produce plasma concentrations as high as 26 000 μmol/L  and vitamin C serum levels reached 70-fold compared with those that may be achieved through oral dosing alone . de Grooth et al. showed in their studies that plasma concentrations ≥1000 μmol/L can be achieved with the administration of 10 g IV vitamin C/day.
To restore plasma levels in critically ill patients, a minimum of 2–3 g IV vitamin C is necessary . For therapeutic purposes, the IV dose of vitamin C can be range between 10–16 g/day to achieve plasma levels of >1000 μmol/L and to obtain optimal benefit .
In one trial, 80% of the administered dose of vitamin C had been filtered by the kidneys in 6 h following IV administration, suggesting that the optimal frequency of vitamin C treatment should be four times daily .
Data from the abovementioned pharmacological studies of vitamin C indicate that IV administration is currently the only way to achieve the optimal therapeutic concentration for the treatment of patients with severe illnesses such as viral pneumonia, ARDS and sepsis. Treatment with a high dose of vitamin C should start with ≥10 g/day. Also, the daily dose of vitamin C as a preventive agent should be started at ≥2000 mg.
Safety and possible side effects of vitamin C
Vitamin C has been used for many decades with few significant adverse side effects reported. Only 10 mg/day of vitamin C is necessary to prevent scurvy, but the ‘tolerable upper intake level’, as recommended by US nutritional recommendations, is stated to be 2 g/day for adults .
High-dose IV vitamin C administration has been used clinically for several decades, and a phase I–II study of the effects of IV vitamin C in combination with cytotoxic chemotherapy in patients reported that a high dose of vitamin C (1.5 g/kg body weight per 24 h) is safe and without major side effects .
Stephenson et al. demonstrated in another phase I study a dose curve from 30 to 110 g/m2 of IV vitamin C and showed it to be safe and tolerable to patients even at the maximum dose .
Although there have been speculations about the potential harm of larger doses of vitamin C, research has shown that there is no concern for up to 2000 mg daily .
Pneumonia patients have been observed receiving as much as 100 g/day of vitamin C without developing diarrhoea or reported adverse side effects.
A possible mechanism has been attributed to the changes in vitamin C metabolism caused by a severe infection . Other possible side effects that have been reported with extremely high doses of IV vitamin C include dizziness, nausea, dry mouth, perspiration and weakness .
Prevention of these side effects includes proper hydration and fluids before and during treatment. Caution has been advised for the use of IV vitamin C in patients with end-stage renal failure predisposed to oxaluria. It has been reported that vitamin C intake is a possible cause of renal failure and kidney stones through the metabolic conversion of ascorbate to oxalate causing hyperoxaluria and crystalluria , .
However, this has not been supported by prospective trials where risks did not increase and kidney function even improved , .
Case reports have described oxalate nephropathy in burn patients after vitamin C administration (101 g and 224 g in.<24 h), but these levels are much higher than those used in most clinical applications .
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is typically screened for prior to high-dose IV vitamin C administration owing to two case reports of haemolytic anaemia in G6PD-deficient individuals following IV administration of 80 g of vitamin C .
However, the lower IV vitamin C doses typically used for prevention and therapy of <16 g/day would be unlikely to cause haemolytic anaemia in G6PD-deficient individuals owing to a lack of hydrogen peroxide generation at these doses. High concentrations of vitamin C can also affect blood glucose measurements for some point-of-care glucometers, leading to false results .
This can lead to hypoglycaemia if aggressive insulin therapy is applied. Therefore, glucose measurements after the administration of pharmacological doses of vitamin C should be performed at the central laboratory .
Ongoing clinical trials
Several ongoing clinical trials are investigating the effects of vitamin C, or ascorbic acid, in patients with COVID-19. According to the clinical trials database (www.clinicaltrials.gov), there are a total of 13 active studies which are recruiting patients that have listed vitamin C or ascorbic acid as one of the interventions.
Three of these studies are specifically studying the interaction of IV infusion vitamin C and its effects on COVID-19. One of these studies (ClinicalTrials.gov ID NCT04323514), conducted in Italy, is an uncontrolled longitudinal study in a cohort of 500 hospitalised patients with COVID-19 pneumonia.
The patients will be administered 10 g of vitamin C with 250 mL of saline intravenously on top of conventional therapy.
The study will measure endpoints such as mortality, CRP levels, lactate clearance levels, length of hospital stay and resolution of symptoms. A study in Virginia (USA) (ClinicalTrials.gov ID NCT04357782) is also studying the effects of administering IV vitamin C for coronavirus infection and decreased oxygenation.
They have a study cohort of 20 patients and are giving the infusion of ascorbic acid at 50 mg/kg l-ascorbic acid every 6 h for 4 days. Lastly, there is a randomised controlled trial being conducted in Quebec, Canada (ClinicalTrials.gov ID NCT04401150) comparing the effects of IV vitamin C (50 mg/kg every 6 h for 96 h) to normal saline for a reduction in morbidity and mortality in patients hospitalised with COVID-19.
This study is estimated to enrol 800 participants and is specifically measuring the effect of IV vitamin C on organ dysfunction.
There are currently two ongoing trials examining the effects of oral supplementation of vitamin C on COVID-19 symptoms. One ongoing trial being held in the Cleveland Clinic in the USA (ClinicalTrials.gov ID NCT04342728) is specifically examining the impact of oral ascorbic acid and zinc gluconate on the management of COVID-19.
Patients will be randomised into groups receiving either 8000 mg of ascorbic acid, 50 mg of zinc gluconate, or the combination of both supplements in this controlled trial.
The primary outcome measure is to see whether there is any symptom reduction after 28 days. The other trial is being hosted at King Saud University in Saudi Arabia (ClinicalTrials.gov NCT04323228) studying the effects of oral supplement enriched in antioxidants, including 1500 μg of vitamin A (as β-carotene), 250 mg of vitamin C, 90 mg of vitamin E, 15 μg of selenium and 7.5 mg of zinc.
Forty COVID-19-positive patients will be randomised into either receiving this supplementation or a placebo and their health status, clinical assessment and biochemical data will be measured from baseline to up to 3 months.
Other ongoing clinical trials are studying the effects of ascorbic acid as a prophylactic taken alongside conventional medication. In a 600-participant double-blinded randomised trial (ClinicalTrials.gov ID NCT04335084), ascorbic acid is being given alongside hydroxychloroquine, vitamin D and zinc to test whether the drug hydroxychloroquine has more effect than normal nutritional supplements.
This study is mirrored in a trial sponsored by ProgenaBiome (ClinicalTrials.gov ID NCT04334512) who are testing the same treatment. While a study in Turkey (ClinicalTrials.gov ID NCT04326725) is testing the effects of vitamin C and zinc alongside hydroxychloroquine to see whether the supplement can boost the effects of an experimental drug.
Other trials are using ascorbic acid as a control in double-blinded studies. In a randomised, multicentre, blinded trial (ClinicalTrials.gov ID NCT04328961), ascorbic acid (500 mg daily) is being given as the placebo arm to test against the hydroxychloroquine experimental arm.
Viral infections such as SARS-CoV-2 (COVID-19), influenza, respiratory syncytial virus and many others are usually associated with increased oxidative stress leading to oxidative cellular and tissue damage resulting in multiorgan failure.
Vitamin C has demonstrated favourable therapeutic properties and a good safety profile throughout a wide range of clinical applications.
Administration of high-dose vitamin C as a therapeutic agent can favourably impact patients with viral pneumonia and ARDS in severe SARS-CoV-2 infection by decreasing inflammation and pathogen infectiveness and virulence, optimising immune defence, reducing tissue and organ injury, and improving the overall outcome of the disease.
Application of a high dose of vitamin C can dramatically reduce the need for treatment with high doses of corticosteroids, antibacterials and antiviral drugs. Vitamin C also can be effective for primary prevention of viral infections by boosting the innate immune response. In infected patients, vitamin C therapy may shorten the disease course and prevent complications of the disease , .
In addition to vitamin C, other nutraceutical antioxidants widely available as over-the-counter drugs or food supplements can be used to improve the redox balance and reduce tissue damage in patients with viral pneumonia and ARDS. These possible agents include, but are not limited to, tocopherol, lipoic acid, N-acetylcysteine, glutathione, l-carnitine, coenzyme-Q10, zinc and selenium compounds.
Given the fact that vitamin C is inexpensive and has a history of efficacy and safety in similar clinical circumstances, further investigation should be done on its prophylactic ability in low doses and therapeutic ability in high doses. Instead of traditional double-blind controlled clinical trials, we recommend conducting comprehensive retrospective studies comparing disease progression and post-infection complications among patients who were or were not self-administering vitamin C during the course of their disease.
This may provide timely data on the possible preventive and therapeutic values of vitamin C for medical and public interest in the current COVID-19 pandemic.
- 1. Ksiazek T.G., Erdman D., Goldsmith C.S. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med. 2003;348:1953–1966. [PubMed] [Google Scholar]
- 2. Kuiken T., Fouchier R.A., Schutten M. Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome. Lancet. 2003;362:263–270. [PMC free article] [PubMed] [Google Scholar]
- 3. de Groot R.J., Baker S.C., Baric R.S. Commentary: middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the Coronavirus Study Group. J Virol. 2013;87:7790–7792. [PMC free article] [PubMed] [Google Scholar]
- 4. World Health Organization (WHO) WHO; Geneva, Switzerland: 2020. Coronavirus disease (COVID-19) weekly epidemiological update and weekly operational update.https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports [accessed 13 October 2020] [Google Scholar]
- 5. Subbarao K., Murphy B.R., Fauci A.S. Development of effective vaccines against pandemic influenza. Immunity. 2006;24:5–9. [PubMed] [Google Scholar]
- 6. Yang X., Yu Y., Xu J., Shu H., Xia J., Liu H. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8:475–481. [PMC free article] [PubMed] [Google Scholar]
- 7. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506. [PMC free article] [PubMed] [Google Scholar]
- 8. Wang D., Hu B., Hu C., Zhu F., Liu X., Zhang J. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323:1061–1069. [PMC free article] [PubMed] [Google Scholar]
- 9. Chen N., Zhou M., Dong X., Qu J., Gong F., Han Y. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395:507–513. [PMC free article] [PubMed] [Google Scholar]
- 10. Li G., De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV) Nat Rev Drug Discov. 2020;19:149–150. [PubMed] [Google Scholar]
- 11. Stockman L.J., Bellamy R., Garner P. SARS: systematic review of treatment effects. PLoS Med. 2006;3:e343. [PMC free article] [PubMed] [Google Scholar]
- 12. Arabi Y.M., Mandourah Y., Al-Hameed F. Corticosteroid therapy for critically ill patients with Middle East respiratory syndrome. Am J Respir Crit Care Med. 2018;197:757–767. [PubMed] [Google Scholar]
- 13. Cao B., Gao H., Zhou B. Adjuvant corticosteroid treatment in adults with influenza A (H7N9) viral pneumonia. Crit Care Med. 2016;44:e318–28. [PubMed] [Google Scholar]
- 14. Zhang Y., Sun W., Svendsen E.R. Do corticosteroids reduce the mortality of influenza A (H1N1) infection? A meta-analysis. Crit Care. 2015;19:46. [PMC free article] [PubMed] [Google Scholar]
- 15. Lamontagne F., Briel M., Guyatt G.H., Cook D.J., Bhatnagar N., Meade M. Corticosteroid therapy for acute lung injury, acute respiratory distress syndrome, and severe pneumonia: a meta-analysis of randomized controlled trials. J Crit Care. 2010;25:420–435. [PubMed] [Google Scholar]
- 16. Boudreault A.A., Xie H., Leisenring W., Englund J., Corey L., Boeckh M. Impact of corticosteroid treatment and antiviral therapy on clinical outcomes in hematopoietic cell transplant patients infected with influenza virus. Biol Blood Marrow Transplant. 2011;17:979–986. [PMC free article] [PubMed] [Google Scholar]
- 17. Dua K., Malyla V., Singhvi G. Increasing complexity and interactions of oxidative stress in chronic respiratory diseases: an emerging need for novel drug delivery systems. Chem Biol Interact. 2019;299:168–178. [PubMed] [Google Scholar]
- 18. Fraternale A., Paoletti M.F., Casabianca A. Anti-viral and immunomodulatory properties of new pro-glutathione (GSH) molecules. Curr Med Chem. 2006;13:1749–1755. [PubMed] [Google Scholar]
- 19. Nakashima I., Kato M., Akhand A.A. Redox-linked signal transduction pathways for protein tyrosine kinase activation. Antioxid Redox Signal. 2002;4:517–531. [PubMed] [Google Scholar]
- 20. Nakamura H., Nakamura K., Yodoi J. Redox regulation of cellular activation. Ann Rev Immunol. 1997;15:351–369. [PubMed] [Google Scholar]
- 21. Fowler A.A., 3rd, Kim C., Lepler L., Malhotra R., Debesa O., Natarajan R. Intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory distress syndrome. World J Crit Care Med. 2017;6:85–90. [PMC free article] [PubMed] [Google Scholar]
- 22. Al Ghouleh I., Khoo N.K., Knaus U.G. Oxidases and peroxidases in cardiovascular and lung disease: new concepts in reactive oxygen species signaling. Free Radic Biol Med. 2011;51:1271–1288. [PMC free article] [PubMed] [Google Scholar]
- 23. Huang K.J., Su I.J., Theron M. An interferon‐γ‐related cytokine storm in SARS patients. J Med Virol. 2005;75:185–194. [PMC free article] [PubMed] [Google Scholar]
- 24. Chen L., Liu H., Liu W., Liu J., Liu K., Shang J. Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia [in Chinese] Zhonghua Jie He He Hu Xi Za Zhi. 2020;43:E005. [PubMed] [Google Scholar]
- 25. Vera J.C., Rivas C.I., Velásquez F.V., Zhang R.H., Concha I.I., Golde D.W. Resolution of the facilitated transport of dehydroascorbic acid from its intracellular accumulation as ascorbic acid. J Biol Chem. 1995;270:23706–23712. [PubMed] [Google Scholar]
- 26. Carr A.C., Maggini S. Vitamin C and immune function. Nutrients. 2017;9:1211. [PMC free article] [PubMed] [Google Scholar]
- 27. Bharara A., Grossman C., Grinnan D. Intravenous vitamin C administered as adjunctive therapy for recurrent acute respiratory distress syndrome. Case Rep Crit Care. 2016;2016 [PMC free article] [PubMed] [Google Scholar]
- 28. Kim Y., Kim H., Bae S. Vitamin C is an essential factor on the anti-viral immune responses through the production of interferon-α/β at the initial stage of influenza A virus (H3N2) infection. Immune Netw. 2013;13:70–74. [PMC free article] [PubMed] [Google Scholar]
- 29. Jariwalla R.J., Harakeh S. Antiviral and immunomodulatory activities of ascorbic acid. Subcell Biochem. 1996;25:213–231. [PubMed] [Google Scholar]
- 30. Madhusudana S.N., Shamsundar R., Seetharaman S. In vitro inactivation of the rabies virus by ascorbic acid. Int J Infect Dis. 2004;8:21–25. [PubMed] [Google Scholar]
- 31. Zarubaev V., Slita A., Lavrentyeva I., Smirnov V. Protective activity of ascorbic acid at influenza infection. Infektsiia Immunitet. 2017;7:319–326. [Google Scholar]
- 32. Wilson J.X. Evaluation of vitamin C for adjuvant sepsis therapy. Antioxid Redox Signal. 2013;19:2129–2140. [PMC free article] [PubMed] [Google Scholar]
- 33. Maggini S., Maldonado P., Cardim P., Fernandez Newball C., Sota Latino E. Vitamins C, D and zinc: synergistic roles in immune function and infections. Vitam Miner. 2017;6:3. doi: 10.4172/2376-1318.1000167. [CrossRef] [Google Scholar]
- 34. Fisher B.J., Seropian I.M., Kraskauskas D., Thakkar J.N., Voelkel N.F., Natarajan R. Ascorbic acid attenuates lipopolysaccharide-induced acute lung injury. Crit Care Med. 2011;39:1454–1460. [PubMed] [Google Scholar]
- 35. Fisher B.J., Kraskauskas D., Martin E.J. Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid. Am J Physiol Lung Cell Mol Physiol. 2012;303:L20–32. [PubMed] [Google Scholar]
- 36. Carr A.C., Shaw G.M., Natarajan R. Ascorbate-dependent vasopressor synthesis: a rationale for vitamin C administration in severe sepsis and septic shock? Crit Care. 2015;19:418. [PMC free article] [PubMed] [Google Scholar]
- 37. Chen Y., Luo G., Yuan J., Wang Y., Yang X., Wang X. Vitamin C mitigates oxidative stress and tumor necrosis factor-α in severe community-acquired pneumonia and LPS-induced macrophages. Mediators Inflamm. 2014;2014 [PMC free article] [PubMed] [Google Scholar]
- 38. Hosakote Y.M., Jantzi P.D., Esham D.L. Viral-mediated inhibition of antioxidant enzymes contributes to the pathogenesis of severe respiratory syncytial virus bronchiolitis. Am J Respir Crit Care Med. 2011;183:1550–1560. [PMC free article] [PubMed] [Google Scholar]
- 39. Andrades M., Ritter C., de Oliveira M.R., Streck E.L., Moreira J.C.F., Dal-Pizzol F. Antioxidant treatment reverses organ failure in rat model of sepsis: role of antioxidant enzymes imbalance, neutrophil infiltration, and oxidative stress. J Surg Res. 2011;167:e307–13. [PubMed] [Google Scholar]
- 40. Carr A.C., Rosengrave P.C., Bayer S., Chambers S., Mehrtens J., Shaw G.M. Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Crit Care. 2017;21:300. [PMC free article] [PubMed] [Google Scholar]
- 41. Syed A.A., Knowlson S., Sculthorpe R. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014;12:32. [PMC free article] [PubMed] [Google Scholar]
- 42. Padayatty S.J., Sun A.Y., Chen Q., Espey M.G., Drisko J., Levine M. Vitamin C: Intravenous use by complementary and alternative medicine practitioners and adverse effects. PLoS One. 2010;5 [PMC free article] [PubMed] [Google Scholar]
- 43. Nathens A.B., Neff M.J., Jurkovich G.J. Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg. 2002;236:814. [PMC free article] [PubMed] [Google Scholar]
- 44. Hemilä H. Vitamin C and community-acquired pneumonia. Am J Respir Crit Care Med. 2011;184:621–622. [PubMed] [Google Scholar]
- 45. Patel V., Dial K., Wu J., Gauthier A.G., Wu W., Lin M. Dietary antioxidants significantly attenuate hyperoxia-induced acute inflammatory lung injury by enhancing macrophage function via reducing the accumulation of airway HMGB1. Int J Mol Sci. 2020;21:977. [PMC free article] [PubMed] [Google Scholar]
- 46. Crimi E., Liguori A., Condorelli M. The beneficial effects of antioxidant supplementation in enteral feeding in critically ill patients: a prospective, randomized, double-blind, placebo-controlled trial. Anesth Analg. 2004;99:857–863. [PubMed] [Google Scholar]
- 47. Marik P.E., Khangoora V., Rivera R., Hooper M.H., Catravas J. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before–after study. Chest. 2017;151:1229–1238. [PubMed] [Google Scholar]
- 48. Zabet M.H., Mohammadi M., Ramezani M., Khalili H. Effect of high-dose ascorbic acid on vasopressor’s requirement in septic shock. J Res Pharm Pract. 2016;5:94. [PMC free article] [PubMed] [Google Scholar]
- 49. Fowler A.A., 3rd, Truwit J.D., Hite R.D., Morris P.E., DeWilde C., Priday A. Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS-ALI randomized clinical trial. JAMA. 2019;322:1261–1270. [PMC free article] [PubMed] [Google Scholar]
- 50. Hemilä H., Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev. 2013;(1) [PubMed] [Google Scholar]
- 51. Ran L., Zhao W., Wang J., Wang H., Zhao Y., Tseng Y. Extra dose of vitamin C based on a daily supplementation shortens the common cold: a meta-analysis of 9 randomized controlled trials. Biomed Res Int. 2018;2018 [PMC free article] [PubMed] [Google Scholar]
- 52. Sadat U., Usman A., Gillard J.H., Boyle J.R. Does ascorbic acid protect against contrast-induced acute kidney injury in patients undergoing coronary angiography: a systematic review with meta-analysis of randomized, controlled trials. J Am Coll Cardiol. 2013;62:2167–2175. [PubMed] [Google Scholar]
- 53. Hemilä H., Suonsyrjä T. Vitamin C for preventing atrial fibrillation in high risk patients: a systematic review and meta-analysis. BMC Cardiovasc Disord. 2017;17:49. [PMC free article] [PubMed] [Google Scholar]
- 54. Marcial-Vega V., Idxian G.G.-T., Levy T.E. Intravenous ascorbic acid and hydrogen peroxide in the management of patients with chikungunya. Bol Asoc Med P R. 2015;107:20–24. [PubMed] [Google Scholar]
- 55. Duconge J., Rodríguez-López J.L., Pedro A., Adrover-López B. High dose intravenous vitamin C treatment for zika fever. JOM. 2016;31:19–22. [Google Scholar]
- 56. Hemilä H. Vitamin C and infections. Nutrients. 2017;9:339. [PMC free article] [PubMed] [Google Scholar]
- 57. Lykkesfeldt J., Tveden-Nyborg P. The pharmacokinetics of vitamin C. Nutrients. 2019;11:2412. [Google Scholar]
- 58. Jackson T.S., Xu A., Vita J.A., Keaney Jr J.F. Ascorbate prevents the interaction of superoxide and nitric oxide only at very high physiological concentrations. Circ Res. 1998;83:916–922. [PubMed] [Google Scholar]
- 59. Padayatty S.J., Sun H., Wang Y. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004;140:533–537. [PubMed] [Google Scholar]
- 60. Levine M., Conry-Cantilena C., Wang Y. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci U S A. 1996;93:3704–3709. [PMC free article] [PubMed] [Google Scholar]
- 61. Levine M., Rumsey S.C., Daruwala R., Park J.B., Wang Y. Criteria and recommendations for vitamin C intake. JAMA. 1999;281:1415–1423. [PubMed] [Google Scholar]
- 62. Padayatty S.J., Riordan H.D., Hewitt S.M., Katz A., Hoffer L.J., Levine M. Intravenously administered vitamin C as cancer therapy: three cases. CMAJ. 2006;174:937–942. [PMC free article] [PubMed] [Google Scholar]
- 63. Chen Q., Espey M.G., Sun A.Y. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc Natl Acad Sci U S A. 2007;104:8749–8754. [PMC free article] [PubMed] [Google Scholar]
- 64. de Grooth H.-J., Manubulu-Choo W.-P., Zandvliet A.S. Vitamin C pharmacokinetics in critically ill patients: a randomized trial of four IV regimens. Chest. 2018;153:1368–1377. [PubMed] [Google Scholar]
- 65. de Grooth H.-J., Manubulu-Choo W.-P., Zandvliet A.S. Vitamin C pharmacokinetics in critically ill patients: a randomized trial of four IV regimens. Chest. 2018;153:1368–1377. [PubMed] [Google Scholar]
- 66. de Grooth H.-J., Manubulu-Choo W.-P., Zandvliet A.S. Vitamin C pharmacokinetics in critically ill patients: a randomized trial of four IV regimens. Chest. 2018;153:1368–1377. [PubMed] [Google Scholar]
- 67. Hoffer L.J., Robitaille L., Zakarian R., Melnychuj D., Kavan P., Agulnik J. High-dose intravenous vitamin C combined with cytotoxic chemotherapy in patients with advanced cancer: a phase I–II clinical trial. PLoS One. 2015;10 [PMC free article] [PubMed] [Google Scholar]
- 68. Stephenson C.M., Levin R.D., Spector T., Lis C.G. Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer Chemother Pharmacol. 2013;72:139–146. [PMC free article] [PubMed] [Google Scholar]
- 69. Cathcart R.F. Vitamin C, titrating to bowel tolerance, anascorbemia, and acute induced scurvy. Med Hypotheses. 1981;7:1359–1376. [PubMed] [Google Scholar]
- 70. Welsh J., Wagner B., Van’t Erve T. Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial. Cancer Chemother Pharmacol. 2013;71:765–775. [PMC free article] [PubMed] [Google Scholar]
- 71. Auer B., Auer D., Rodgers A. Relative hyperoxaluria, crystalluria and haematuria after megadose ingestion of vitamin C. Eur J Clin Investig. 1998;28:695–700. [PubMed] [Google Scholar]
- 72. Simon J.A., Hudes E.S. Relation of serum ascorbic acid to serum vitamin B12, serum ferritin, and kidney stones in US adults. Arch Intern Med. 1999;159:619–624. [PubMed] [Google Scholar]
- 73. Gerster H. No contribution of ascorbic acid to renal calcium oxalate stones. Ann Nutr Metab. 1997;41:269–282. [PubMed] [Google Scholar]
- 74. Curhan G.C., Willett W.C., Rimm E.B., Stampfer M.J. A prospective study of the intake of vitamins C and B6, and the risk of kidney stones in men. J Urol. 1996;155:1847–1851. [PubMed] [Google Scholar]
- 75. Buehner M., Pamplin J., Studer L. Oxalate nephropathy after continuous infusion of high-dose vitamin C as an adjunct to burn resuscitation. J Burn Care Res. 2016;37:e374–9. [PMC free article] [PubMed] [Google Scholar]
- 76. Quinn J., Gerber B., Fouche R., Kenyon K., Blom Z., Muthukanagaraj P. Effect of high-dose vitamin C infusion in a glucose-6-phosphate dehydrogenase-deficient patient. Case Rep Med. 2017;2017 [PMC free article] [PubMed] [Google Scholar]
- 77. Cho J., Ahn S., Yim J. Influence of vitamin C and maltose on the accuracy of three models of glucose meters. Ann Lab Med. 2016;36:271–274. [PMC free article] [PubMed] [Google Scholar]
- 78. Flannery A.H., Bastin M.L.T., Magee C.A., Bensadoun E.S. Vitamin C in sepsis: when it seems too sweet, it might (literally) be. Chest. 2017;152:450–451. [PubMed] [Google Scholar]
- 79. Hemilä H., Chalker E. Vitamin C can shorten the length of stay in the ICU: a meta-analysis. Nutrients. 2019;11:708. [PMC free article] [PubMed] [Google Scholar]
More information: Gregory Patterson,Carlos M. Isales,Sadanand Fulzele. Low level of Vitamin C and dysregulation of Vitamin C transporter might be involved in the severity of COVID-19 Infection[J]. Aging and disease, www.aginganddisease.org/EN/10.14336/AD.2020.0918