Vitamin C. Why It’s Not FAKE NEWS: Here are All the Scientific Proofs

    Vitamin C. Why It’s Not FAKE NEWS: Here are All the Scientific Proofs

     

    The entire world, during the times of coronavirus, has been swept by a wave of indignation. And it’s not because the government shut everything down at least 45 days too late after absurdly crying racism, fascism, and nazism, but because someone dared to recommend vitamin C. It doesn’t matter that it was Nobel Prize winner Luc Montagnier who said it (here). It doesn’t even matter that vitamin C is also supported by Giulio Tarro, voted the world’s best virologist in 2018 and a Nobel Prize nominee. It doesn’t even matter that there are as many as 625 scientific citations on the correlation between vitamin C and viruses.

    Despite these incontrovertible facts (supported by Nobel laureates, not just by Belen) in favor of ascorbic acid, we have witnessed some of the darkest pages of Italian journalism, with 90% of the outlets branding as FAKE NEWS the possibility that this vitamin could be useful against the coronavirus.

    Even the most ‘prestigious’ newspapers, such as Repubblica, Corriere della Sera, and news agencies like Adn Kronos, among dozens of others, lent themselves to this absurd uproar.

    I could say many things, but here I would like to report the translation of an independent review of studies on the relationship between vitamin C and viruses.

    It’s titled ‘The Antiviral Properties of Vitamin C’, published in February 2020 in the ‘Journal Expert Review of Anti-infective Therapy’. This report begins with a shocking statement against vitamin C:

    “Many misconceptions about vitamin C have been perpetuated by two-time Nobel Prize winner Linus Pauling.”

    However, in the face of a large mass of favorable data on vitamin C, the researchers themselves are eventually forced to admit that:

    “The suggestion that vitamin C may be useful in a range of viral infections is based on two concepts, namely:

    1. patients with acute infectious diseases have low levels of circulating vitamin C (probably due to metabolic consumption) [9, 30] and
    2. vitamin C has beneficial immunomodulatory properties in patients with viral infections, primarily by increasing the production of interferons α/β and regulating the production of pro-inflammatory cytokines.”

    For all the skeptics, I report the complete research, with all supporting studies.

    1. Introduction

    There is growing interest in the administration of vitamin C beyond the treatment of hypovitaminosis C in malnourished patients.

    This has been driven by a 2016 “before-after” study that suggested a substantial survival benefit from a protocol that included hydrocortisone, ascorbic acid (vitamin C), and thiamine (HAT therapy) in the treatment of patients with severe sepsis and septic shock [1].

    Currently, ClinicalTrials.gov lists 29 ongoing or completed studies investigating the administration of vitamin C in sepsis.

    Historically, there have been misguided and erroneous suggestions about the effectiveness of vitamin C in promoting longevity, preventing and treating the common cold [2], and a collection of poorly evidenced health claims encouraged by a billionaire in the over-the-counter vitamin supplement industry.

    Many misconceptions about vitamin C have been perpetuated by two-time Nobel Prize winner Linus Pauling [3, 4].

    The resurgence of interest in vitamin C therapy for acute inflammatory disorders, founded on solid biological rationale, follows decades of research.

    The current focus of interest centers on bacterial sepsis and septic shock in critical patients. Over 300 basic scientific and clinical studies provide strong mechanistic data to support the use of vitamin C in this context [5, 6].

    However, there is emerging literature suggesting that vitamin C may play an additional role in the treatment of a variety of viral infections. The purpose of this article is to review the biological rationale and evidence for the administration of vitamin C in viral infections.

    1. Biological Rationale of Vitamin C in Viral Infections

    Numerous observers, including Linus Pauling, have suggested that high doses of vitamin C are directly virucidal [3].

    This hypothesis was based on in vitro studies, where very high doses of vitamin C, in the presence of free copper and/or iron, have virucidal activity, presumably through the generation of hydrogen peroxide and other radical species [7, 8].

    Moreover, a low pH may have contributed to the antiviral effects in vitro of vitamin C; however, it is highly unlikely that vitamin C is directly virucidal in vivo.

    It is now well known that while vitamin C is a potent antioxidant, at high pharmacological concentrations it can paradoxically exert pro-oxidant effects (generation of reactive oxygen species) through the reduction of transition metal [9].

    Avici et al. demonstrated that very high doses of sodium ascorbate (90 mM) kill Candida albicans in vitro through the iron-catalyzed Fenton reaction [10].

    However, this effect was completely inhibited by the iron chelator 2,2′-bipyridyl.

    Nonetheless, an experimental model has shown that vitamin C reduced the viral load of cells infected with Epstein-Barr Virus (EBV) [11].

    This suggests that other mechanisms must be at play.

    Cinatl and colleagues have shown that pretreating human foreskin fibroblasts and endothelial cells with vitamin C before infection with cytomegalovirus (CMV) significantly reduced the expression of viral antigens and cellular viral load [12].

    This result was not replicated when vitamin C was added after the virus infection.

    The authors concluded that this effect was likely due to the immunomodulatory properties of vitamin C, rather than a direct antiviral effect.

    Vitamin C is concentrated in leukocytes, lymphocytes, and macrophages, reaching high concentrations in these cells [13, 14].

    Vitamin C enhances chemotaxis, improves the phagocytic capacity of neutrophils and oxidative killing, and supports the proliferation and function of lymphocytes [13, 15, 16].

    L-gulono-γ-lactone oxidase (Gulo) is the rate-limiting step in the biosynthesis of vitamin C in animals.

    However, anthropoid primates and guinea pigs have lost the ability to synthesize vitamin C due to mutations in the gene for this enzyme.

    Gulo knockout mice (-/-) provide a model for studying the role of vitamin C deficiency in viral infections; a model of “humanized mouse” infection.

    Kim et al. demonstrated that nasal inoculation of the H3N2 influenza virus was highly lethal in Gulo (-/-) mice compared to wild-type mice [17].

    In this study, viral titers in the lungs of vitamin C-deficient Gulo (-/-) mice were increased, while the production of the antiviral cytokine interferon (IFN) -α/β was reduced.

    Moreover, the infiltration of inflammatory cells into the lungs and the production of pro-inflammatory cytokines, tumor necrosis factor (TNF), and interleukin-1 (IL-1) -α/β were increased in the lungs.

    These effects were corrected in Gulo (-/-) mice replenished with vitamin C prior to viral exposure. Compromised phosphorylation of signal transducers and activators of transcription (STAT) may underlie the deceased production of IFN in Gulo (-/-) mice [17].

    Similarly, Li et al. demonstrated that Gulo (-/-) mice, compared to wild-type mice, had a compromised immune response with increased pathological lung damage when exposed to the H1N1 influenza virus [18].

    Cai et al. demonstrated that stress-restrained mice (mice physically restrained in a holding tube) with H1N1-induced pneumonia showed a dose-dependent reduction in mortality with vitamin C, and histopathological lung sections showed reduced lesions in treated mice [19].

    In this study, administration of vitamin C significantly recovered the reduced potential of the mitochondrial membrane and deceased the gene expression of pro-inflammatory cytokines.

    In addition to demonstrating activity against influenza and herpes virus, vitamin C has been reported to have activity against a number of other viruses including poliovirus, Venezuelan equine encephalitis virus, human T-lymphotropic virus type 1 (HTLV-1), human immunodeficiency virus (HIV), parvovirus, and rabies virus among others [20–27].

    Many infections lead to the activation of phagocytes, with the release of reactive oxygen species (ROS).

    Reactive Oxygen Species (ROS) play a role in deactivating viruses.

    However, many of the ROS are harmful to host cells and can be involved in the pathogenesis of virus-induced host injury.

    Respiratory Syncytial Virus (RSV) is one of the most important causes of upper and lower respiratory tract infections in infants and young children.

    RSV infection of airway epithelial cells induces the production of ROS with the inhibition of pulmonary antioxidant enzymes; this oxidant-antioxidant cellular imbalance plays an important role in the pulmonary toxicity of RSV [28].

    In an experimental model, the administration of antioxidants significantly reduced pulmonary inflammation and lung injury [29].

    Vitamin C is a powerful antioxidant that directly eliminates oxygen free radicals and restores other cellular antioxidants, including tetrahydrobiopterin and α-tocopherol [5, 14].

    Therefore, vitamin C can improve virus-induced oxidative damage.

    1. Clinical Evidence of Efficacy in Viral Infections

    The suggestion that vitamin C may be useful in a variety of viral infections is based on two concepts, namely:

    1. i) patients with acute infectious diseases have low levels of circulating vitamin C (probably due to metabolic consumption) [9, 30], and
    2. ii) vitamin C has beneficial immunomodulatory properties in patients with viral infections, primarily by increasing the production of interferons α/β and regulating the production of pro-inflammatory cytokines (as discussed above).

    (Note: Interferons are protein molecules that, based on different antigenic characteristics, have been divided into three main classes: α, β, and γ.

    The expression of genes containing the necessary information for the synthesis of messenger RNAs for interferons α and β is activated, in most animal cells, by various inducers (not exclusively viruses) and is generally considered a response of organisms to such agents.

    It has also been demonstrated that the antiviral activity of endogenous interferons α and β is apparent at concentrations lower than 10−14 M. This activity is interpreted as a defensive system of the organism during viral infections that, thanks to the earliness of its activation, represents the first response to infection even preceding the production of antibodies.)

    Despite the biological plausibility that vitamin C could be useful in viral infections, there are evidence-based clinical data supporting this thesis.

    Largely driven by the controversy sparked by Linus Pauling’s promotion of vitamin C for treating the “common cold”, most of the randomized controlled trials (RCTs) conducted so far have focused on the role of vitamin C in preventing and treating this syndrome.

    In a meta-analysis of 29 RCTs [2], furthermore, no consistent effect of vitamin C on the duration or severity of the common cold was observed.

    (Actually, a study published shortly after this review demonstrated that vitamin C is effective against the common cold. It is about “Vitamin C supplementation reduces the likelihood of developing a common cold in army recruits of the Republic of Korea: a randomized controlled trial.” published in “BMJ Military Health” [2.A])

    Methodological issues with many of the studies included in this meta-analysis (most published before 1980), the variable dosage of vitamin C in the treatment group, and the inability to control vitamin C intake in control groups complicate the interpretation of these studies.

    Vitamin C appears to have clinical benefits in patients with infections caused by various herpes viruses.

    Herpes zoster infection (HZV) results from the reactivation of latent Varicella-Zoster Virus (VZV) generally due to age-related loss of cell-mediated immunity.

    Chen et al. demonstrated that plasma concentrations of vitamin C are reduced in patients with postherpetic neuralgia compared to healthy volunteers (4.6 ± 3.1 vs 13.5 ± 6.0 mg/L; p <0.001) [31].

    These authors then conducted a double-blind RCT in which 41 patients were randomly assigned to receive intravenous vitamin C (50 mg/kg on days 1, 3, and 5) or placebo [31].

    Those patients who received vitamin C had a significant reduction in pain scale scores by day 7. In a non-blind RCT, the effect of vitamin C on acute herpetic pain and postherpetic neuralgia was evaluated [32].

    In this study, 87 patients were randomized to receive 5 g of vitamin C intravenously on the first, third, and fifth day or placebo.

    Although there was no difference between the groups in the severity and duration of pain during the acute phase, the treatment group showed a lower incidence of postherpetic neuralgia (31.1% vs. 57.1%, p <0.05) and a lower pain score at 8 weeks (0.64 ± 0.9 vs. 1.98 ± 0.7, p = 0.004) [32].

    Vitamin C is concentrated in the aqueous humor of the anterior chamber of the eye.

    A retrospective cohort study indicated that oral vitamin C reduced the risk of recurrence of herpes simplex keratitis, particularly in combination with oral antiviral therapy [33].

    1. The Urgent Need for Further Research

    The influenza A virus is responsible for regular epidemics and pandemics that cause thousands of fatalities each year.

    While experimental models demonstrate a beneficial effect of vitamin C in influenza infections (as reviewed above), this therapy has not been reported in patients.

    Anecdotally, we have treated about a dozen patients with life-threatening respiratory failure due to influenza A infection with our modified HAT protocol (without corticosteroids); these patients demonstrated rapid improvement after starting this therapy.

    It should be noted that the role of corticosteroids in patients with viral infections is complex; corticosteroids can modulate the inflammatory response, but on the other hand, they may stimulate infection.

    Currently, corticosteroids are not recommended in patients with severe influenza A infections [34, 35].

    Well-designed clinical studies are urgently needed to study the use of vitamin C as adjunct therapy in severe infections due to influenza, RSV, herpes, and other common viral diseases.

    Disclosure of Interests

    The authors have no affiliations or financial involvement with any organization or entity with a financial interest or conflict with the subject matter or materials discussed in the manuscript.

    Reviewer Disclosure

    The peer reviewers on this manuscript have no financial or other relationships to disclose.

     

     

    References

    Documents of special note have been highlighted as of interest (•) or notable interest (••) to readers.

    • Marik PE, Khangoora V, Rivera R, et al. Hydrocortisone, vitamin C and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study. Chest. 2017;151:1229–1238.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]
    • • This landmark study received much “notoriety” and led to the reniewed interest in the use of vitamin C as adjunctive treatment in sepsis and other inflammaory disorders.
    • • This is an outstanding experimental model demonstraing the virulence of influenzae virus in Gulo knockout mice and the immunomodulaing protective effect of vitamin C.
    • A comprehensive review on the scientifc basis for the use of vitamin C in the treatment of infective disorder.
    • Chen JY, Chang CY, Feng PH, et al. Plasma vitamin C is lower in postherpetic neuralgia patients and administration of vitamin C reduces spontaneous pain but not brush-evoked pain. Clin J Pain. 2009;25:562–569.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]
    • This is one of the few studies that has evlaluated the role of vitmamin C in a well conducted randomized controlled trial.
    • Kim MS, Kim DJ, Na CH, et al. A study of intravenous administration of vitamin C in the treatment of acute herpetic pain and postherpetic neuralgia. Ann Dermatol. 2016;28:677–683.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]
    • Kim GN, Yoo WS, Park MH, et al. Clinical features of herpes simplex keratitis in a Korean tertiary referral center: efficacy of oral antiviral and ascorbic acid on Recurrence. Korean J Opthal. 2018;32:353–360.[Crossref], [PubMed], [Google Scholar]
    • Lansbury LE. Corticosteroids as adjunctive therapy in the treatment of influenza: an updated cochrane systematic review and meta-analysis. Crit Care Med. 2019;1. ePub. DOI:10.1097/CCM.0000000000004093.[Crossref], [PubMed], [Google Scholar]
    • Rodrigo C. Effect of corticosteroid therapy on influenza-related mortality: a systematic review and meta-analysis. J Infect Dis. 2015;212:183–194.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]

     

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