Update: Vitamin C in COVID-19 by Journal of Orthomolecular Medicine

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volume 36 , number 1 published 1 march 2021

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Update: Vitamin C in COVID-19 Paul S. Anderson Citation: Anderson PS (2021) Update: Vitamin C in COVID-19. J Orthomol Med. 36(1)

The use of vitamin C (ascorbic acid) in the prevention and treatment of COVID-19 (aka SARS-CoV-2) has received much attention in the popular media and in scientific journals for the past year. This review will look at two critical updates from the science:

sources and supplementation. Couple that with the fact that when humans are ill or under stress, vitamin C levels drop to sometimes to undetectable levels, it might seem logical that supplementation has the potential to improve immune response.

1. W hat do we know, and what has been published about intravenous vitamin C (IVC) in patients with COVID-19?

Following the ISOM webinar, I was asked by some interested government officials in a few US States to provide a protocol for hospital use which would mirror that used in China with early reports of success. I wrote that protocol (Anderson, 2020a), and at about the same time a group of authors led by Ba X Hoang began publication of a paper entitled “Possible application of high-dose vitamin C in the prevention and therapy of coronavirus infection” which was published in October of 2020 (Hoang et al., 2020). At that point, early in 2020, we were all basing our recommendations on two main factors – one being our own experience with the use of IVC in infections and sepsis, and the other being the early case reports from China where IVC was being used for hospitalized COVID-19 patients.

2. What about this new study that was just published on oral vitamin C and zinc that said it did not help COVID-19 patients? vitamin C and COVID-19 : W hat do we know ?

Almost a year ago I was asked by the International Society for Orthomolecular Medicine (ISOM) to develop and present a webinar on vitamin C and viral illness, focused specifically on its potential for improving outcomes in COVID-19. I was invited to present on this topic because I have been involved in cancer research, as the principal investigator in the IV therapy portion of a trial that was partially funded by the US National Institutes of Health. I also have extensive experience with the administration of IVC. In the webinar, I describe ascorbate pharmacokinetics and in depth concepts around the use of vitamin C in humans, including our biological requirements for it during times of illness. I also highlighted the early use of IVC as an adjunctive treatment for COVID-19, as it was being applied in clinical settings in China. Why would IVC or oral vitamin C help ?

There are many potential immune system dependent processes supported by the vitamin C in our bodies. In addition to that, humans are one of only a few mammals who do not make their own vitamin C. We must obtain it from dietary

What was the early Chinese experience with hospitalized COVID-19 patients and IVC?

As mentioned above, in March 2020, Dr. Richard Cheng and I both reported individual cases and one unpublished case series from China that showed incredible results. (Anderson, 2020; Cheng, 2020) These included ICU patients in respiratory failure recovering with the administration of IVC, and a group of hospitalized COVID-19 patients who received IVC resulting in shorter hospital stays and lower mortality when compared to patients who did not receive IVC. In July of 2020 Dr. Cheng and colleauges provided an update, and added to the case reports and scientific rationale in an excellent publication (Cheng et al., 2020).

Update: Vitamin C in COVID-19 Regarding the IVC and COVID-19 studies , what have we found out ?

As is usual in science it is important to verify observations through controlled trials to find out if the initial observations can be reproduced. Starting early in 2020 many groups began just such controlled trials on IVC and oral vitamin C. While there are several trials pending (most reported on by Hoang, et al.) there are two IVC trials in human COVID-19 patients which have been published. In this communication I outline the major findings from these trials. Kumari et. al (2020) enrolled 75 patients in the placebo arm (standard care only) and 75 in the IVC arm (IVC plus standard care), all of whom were hospitalized with COVID19. The dose of IVC was modest by many standards (a 70 kilogram patient received 3,500 milligrams of sodium ascorbate every 24 hours). For those in the IVC arm the number of days to become symptom free were less (average 2.5 less days) and they also had shorter hospital stays (by almost three days). Both outcomes were statistically significant. The study did not reach statistical significance (so no conclusion can be made) in overall mortality or the need for mechanical ventilation. Zhang et. al (2021) enrolled 29 patients in the placebo arm and 27 in the IVC arm. (Of note they wanted a larger study population, but they were not having as many new COVID-19 hospitalizations, so they capped the number at 56). All patients received standard care in the hospital. The IVC group received 24,000 milligrams of sodium ascorbate every 24 hours, and and the placebo group received sterile water in their IV. The IVC dose in this trial is significantly higher than the dose used by Kumari et al., and consistent with the dose I published in the hospital use guidelines (Anderson, 2020). The researchers measured many biochemical and physical parameters. A lot of the data collected did not reach statistical significance (primarily due to the small number of patients), so while they are reported in the paper no conclusions can be drawn from them. The need for mechanical ventilation was not different between the two groups. Overall mortality was not different between the groups, but the probability of death was lower in the IVC group in general, and much lower in those with severe COVID-19 who received IVC. A critical lung function measurement “P/F” (PaO2/FiO2) was increased in the IVC group by over 1.5 times that of the placebo group. Additionally, statistical significance was found in a critical inflammatory marker “Interleukin-6” which was eight times lower in the IVC group. This is highly-significant as some of the new biological drugs being

studied, and proposed to improve the course of COVID-19 hospitalization through reduction of the “cytokine storm”, are monoclonal antibodies against Il-6. These drugs block Il-6, while IVC lowers it (Salama et al., 2021). There were no negative interactions between IVC and the standard hospital therapies, and no patients had to drop out due to reactions to IVC in either of the studies. These may seem like small findings but are critically important for hospitals that are not currently employing IVC as an adjunctive therapy. What about that oral vitamin C and zinc study ?

The recent publication entitled “Effect of high-dose zinc and ascorbic acid supplementation vs usual care on symptom length and reduction among ambulatory patients with SARS-CoV-2 infection: The COVID A to Z randomized clinical trial.” in the Journal of the American Medical Association (Thomas et al., 2021) is currently making the rounds in the media as a negative study for both vitamin C and zinc, and their combined use in COVID-19 patients. Above I mentioned that I was only going to report on data from studies that reached “statistical significance” which is the idea that the result is not due to pure chance but rather some factor (such as the one being studied). One measurement of statistical significance is the “p” value of the data, and typically the lower the number the better (for example on the IVC studies p values of 0.01 to 0.00001 reached statistical significance and those of 0.04, 0.17, 0.40 and higher did not). Although this study set out originally to use a cut off p-value under 0.001 compared with placebo as a “superior therapy”, none of its findings reached that level or even 0.01. What does this mean? Based on their criteria, the primary and secondary endpoints had p values of 0.28 to 0.97 (statistically insignificant). In their critique of this data, the authors did not address this but did mention “Furthermore, the doses of zinc and ascorbic acid, while well tolerated, could be lower than amounts needed to shorten the duration of symptoms…” A valid point, but with no data reaching statistical significance that statement is purely speculation. Another concern highlighted in the paper suggesting that there was “not enough treatment time” is also accurate. If we use the rules I started with and only report statistically significant data there is nothing at all to report from this study. Publishing a study with no significant data may be acceptable to some, but reporting “vitamin C and zinc fail with COVID” as is currently happening in the media, is dishonest and calls in to question their biases.

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Update: Vitamin C in COVID-19 This study did not reach statistical significance and should not be used to make clinical decisions or influence the need for conducting further research in this area. Many of the publications referenced below support the idea that oral vitamin C and many other nutrients are not only generally helpful for immune system maintenance and support, but also in the context of viral illness such as COVID-19 (Hoang et al., 2020; Cheng et al., 2020; Feyaerts & Luyten, 2020; Anderson, 2020b). Where do we go from here ?

IVC is a viable intervention that can certainly be used as an adjunctive therapy in hospitals, as is currently happening in a few US hospitals and in hospitals in several other countries. IVC has an exceptional safety profile, as well as benefit to symptoms, length of hospital stay, certain lung functions and potential mortality. No negative effects on any other hospital therapies has been demonstrated, and no study patients have dropped out due to adverse events resulting from IVC administration. Additionally, IVC is known to lower Il-6 which is the target of much more expensive therapies being fast tracked in COVID-19 hospital care (Salama et al., 2021) Information from my own collection of data on hospitalized COVID-19 patients, demonstrates that facilities with hospital staff who implemented IVC were able to get patients off of mechanical ventilation and discharge them, while those who did not utilize IVC had higher mortality rates in the ICU. This may be considered anecdotal or observational, but it does match what is being published in the peer-reviewed data. Any hospitals not currently using IVC should strongly consider it. Valuable data is presented here, and a straightforward hospital use guideline has been published in the Journal of Orthomolecular Medicine (Anderson, 2020a). Ascorbic acid (vitamin C) is an FDA approved medication for intravenous use, sold under the trade name ‘Ascor’ (McGuff Pharmaceuticals Inc.) and is available to any hospital pharmacy. Vitamin C for intravenous use is also available from most compounding pharmacies. There is no reason to exclude IVC as an adjunctive therapy in hospitalized patients.

Resources

ISOM webinar presented by Paul S. Anderson, NMD, on March 19, 2020: Vitamin C for the Treatment of Coronavirus (COVID-19) Micronutrients for Viral Infections – Reference Bibliography https://isom.ca/micronutrients-viral-infections/ References Anderson PS (2020a) Intravenous ascorbic acid for supportive treatment in hospitalized COVID-19 patients. J Orthomol Med. 35(1). https://isom. ca/article/intravenous-ascorbic-acid-for-supportive-treatment-in-hospitalized-covid-19-patients/ Anderson PS (2020b) Nutrients and COVID – A review of recent research. https://www.consultdranderson.com/nutrients-and-covid-19/ Cheng RZ (2020) Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)? Med Drug Discov. 5:100028. https://doi.org/10.1016/j.medidd.2020.100028 Cheng RZ, Kogan M, Davis D (2020) Ascorbate as prophylaxis and therapy for COVID-19-Update from Shanghai and U.S. medical institutions. Glob Adv Health Med 9:2164956120934768. https:// doi.org/10.1177/2164956120934768 Feyaerts AF, Luyten W (2020).Vitamin C as prophylaxis and adjunctive medical treatment for COVID-19? Nutrition. 79-80:110948. https://doi. org/10.1016/j.nut.2020.110948 Hoang BX, Shaw G, Fang W, Han B (2020) Possible application of high-dose Vitamin C in the prevention and therapy of Coronavirus infection. J Glob Antimicrob Resist. 23:256-262. https://doi.org/10.1016/j.jgar.2020.09.025 Kumari P, Dembra S, Dembra P, Bhawna F, Gul A, Ali B, Sohail H, Kumar B, Memon MK, Rizwan A (2020) The role of Vitamin C as adjuvant therapy in COVID-19. Cureus. 12(11):e11779. https://doi.org/10.7759/cureus.11779 Salama C, Han J, Yau L, et al. (2021) Tocilizumab in patients hospitalized with Covid-19 pneumonia. N Engl J Med. 384(1):20-30. https://doi. org/10.1056/NEJMoa2030340 Thomas S, Patel D, Bittel B, Wolski K, Wang Q, Kumar A, Il’Giovine ZJ, Mehra R, McWilliams C, Nissen SE, Desai MY (2021) Effect of high-dose zinc and ascorbic acid supplementation vs usual care on symptom length and reduction among ambulatory patients with SARS-CoV-2 infection: The COVID A to Z randomized clinical trial. JAMA Netw Open. 4(2):e210369. https://doi.org/10.1001/jamanetworkopen.2021.0369 Zhang J, Rao X, Li Y, et al (2021) Pilot trial of high-dose vitamin C in critically ill COVID-19 patients. Ann. Intensive Care 11:5. https://doi. org/10.1186/s13613-020-00792-3

As for oral supplements, while none have been proven curative there is a substantial amount of data on vitamins D, C, and zinc, as well as many other nutrients involved in immune function (Anderson, 2020b). There are numerous reasons to consider the use of supplemental nutrients for most people, especially in consideration of their favourable risk to benefit ratio. 3 | Journal of Orthomolecular Medicine, Volume 36, Number 1, 2021