Nutrition 79 80 (2020) 110948

Contents lists available at ScienceDirect

Nutrition
journal homepage: www.nutritionjrnl.com

Hypothesis

Vitamin C as prophylaxis and adjunctive medical treatment for

COVID-19?
Adam F. Feyaerts Ph.D. a,b,c,*, Walter Luyten Ph.D., M.D. d
a
VIB Center for Microbiology, KU Leuven, Leuven, Belgium
b
Laboratory of Molecular Cell Biology, KU Leuven, Leuven, Belgium
c
Department of Technology, UCLL, Leuven, Belgium
d
Department of Biology, KU Leuven, Leuven, Belgium

A R T I C L E I N F O A B S T R A C T

Article History: Severe acute respiratory syndrome coronavirus 2 causes the potentially fatal coronavirus disease 2019 (COVID-
Received 26 April 2020 19). Already during the outbreak of the severe acute respiratory syndrome coronavirus 1, the use of vitamin C
Received in revised form 14 June 2020 was suggested. Many patients with severe COVID-19 have elevated levels of the mediators interleukin-6 and
Accepted 4 July 2020
endothelin-1. These mediators may explain the age dependence of COVID-19 pneumonia, the preponderance
Keywords: of male and obese or hypertensive patients, as well as of persons of color and smokers. There is clear evidence
Vitamin C that vitamin C in high doses can reduce these mediators. Vitamin C is cheap and safe. Hence, using a relatively
COVID-19 low dose of vitamin C as prophylaxis, and in cases of severe COVID-19, an (intravenous) high-dose regimen
SARS-CoV-2 may be beneficial. Ongoing clinical trials are expected to provide more definitive evidence.
IL-6 © 2020 Elsevier Inc. All rights reserved.
drug discovery

Introduction (n = 3615) of critically ill patients with confirmed COVID-19 do not

survive [16].
A novel human coronavirus has recently been identified, the More than 100 animal studies have indicated that a daily dose
severe acute respiratory syndrome (SARS) coronavirus (CoV) 2, of a few grams of vitamin C may alleviate or prevent infections
which causes the potentially fatal coronavirus disease 2019 [17]. Already during the outbreak of SARS CoV 1 in 2003, the use
(COVID-19) [1]. SARS-CoV-2 is only the latest of three human coro- of vitamin C, an essential micronutrient for humans and free radi-
navirus strains (the other two are SARS-CoV-1 and Middle East cal scavenger, was suggested as a nonspecific treatment for severe
respiratory syndrome-CoV) that can cause severe illness, but the viral respiratory tract infections [4,18,19]. Indeed, vitamin C is
first to cause a pandemic [2]. Major efforts are under way world- known to support various cellular functions of both the innate and
wide in the search for pharmaceutical interventions, but no thera- adaptive immune systems, including modifying susceptibility to
pies with proven efficacy to treat COVID-19 are currently available, various viral infections, and by influencing inflammation [20,21].
although (hydroxy-)chloroquine with and without zinc supple- Moreover, in chick embryo tracheal organ cultures, vitamin C
mentation is used off-label as prophylaxis or treatment [3 11]. increased resistance to infection by a coronavirus [22]. Addition-
Approximately 5% of patients diagnosed with COVID-19 become ally, vitamin C treatment restores the stress response and improves
critically ill and require advanced respiratory support with (non) the survival of stressed humans [23]. However, a recent prelimi-
invasive mechanical ventilation and added oxygen as the standard nary open-label study of patients with sepsis and acute respiratory
of care [4,12,13]. A recent report suggests that hyperbaric oxygen distress syndrome showed that a 96-h infusion of high-dose vita-
therapy could be a promising alternative therapy, which is inter- min C compared with placebo did not significantly improve organ
esting in light of the suggestion that some SARS CoV 2 proteins dysfunction scores or change markers of inflammation [24]. In con-
may interfere with hemoglobin function [14,15]. According to the trast, early use of intravenous vitamin C in combination with corti-
latest Intensive Care National Audit and Research Center report costeroid agents and thiamine proved effective in preventing
from June 5, 2020 on COVID-19 in critical care, approximately 42% progressive organ dysfunction and reducing the mortality of
patients with severe sepsis and septic shock [25]. However, intra-
venous hydrocortisone alone had a similar effect on the survival of
patients with septic shock as the combination of high-dose vitamin
*Corresponding author. Tel.: 0479334963.
E-mail address: adamfeyaerts@gmail.be (A.F. Feyaerts).
C, hydrocortisone, and thiamine [26], which suggests little added

https://doi.org/10.1016/j.nut.2020.110948
0899-9007/© 2020 Elsevier Inc. All rights reserved.
2 A.F. Feyaerts and W. Luyten / Nutrition 79 80 (2020) 110948

value of vitamin C in sepsis. However, vitamin C may have benefi- 19 and severe comorbidities [12], such as hypertension, diabetes,
cial effects in adults and children with pneumonia [27], as well as and obesity. Patients with COVID-19 who receive angiotensin-con-
patients in intensive care units [28]. A Cochrane systematic review verting enzyme inhibitors and angiotensin II type 1 receptor block-
concludes that 1 to 2 g vitamin C per day is safe, inexpensive, and ers for their hypertension had a lower rate of severe disease and
has a consistent effect on the duration and severity of the common lower level of IL-6 in the peripheral blood [56]. Adipocytes also
cold [29,30]. Furthermore, the study concludes that mega-dose produce IL-6 and may explain why obese individuals have higher
prophylaxis is not rationally justified for community use, but may endogenous levels of C-reactive protein [53,57]. More nonwhite
be justified at times (e.g., in periods of heavy physical exercise). than white people become critically ill [45]. There is some evidence
Evidence is accumulating that many patients who are severely that ET-1 levels are significantly increased in black compared with
ill with COVID-19 have elevated cytokine levels, including the mul- white men [58]. Also, patients with COVID-19 who smoke seem to
tifunctional inflammatory key molecule interleukin (IL) 6, resem- be more susceptible, and ET-1 is known to potentiate smoke-
bling the cytokine storm described in SARS and the Middle East induced acute lung inflammation [59]. Finally, there is some pre-
respiratory syndrome [1,31 36]. This may indicate that high mor- liminary evidence that a need for mechanical ventilation was very
tality is due to virus-driven hyperinflammation. Preliminary data strongly associated with elevated IL-6 levels and that moderately
suggest that COVID-19 pneumonia is a late-stage complication elevated IL-6 levels are sufficient to identify patients with COVID-
caused by the hyperactivation of immune effector cells, and treat- 19 at a high risk of respiratory failure [1,60].
ment with (intravenous) high-dose vitamin C has been proposed Given the critical role of IL-6 in severe COVID-19 and the dem-
to suppress these effectors [37]. Treatment with vitamin C onstrated ability of vitamin C to prevent the increase of IL-6 in sev-
decreases IL-6 and blocks in vivo the release of IL-6 in the endothe- eral (pro)inflammatory conditions [61], vitamin C can logically be
lium induced by endothelin-1 (ET-1) in humans [23,38]. ET-1 is a assumed to benefit patients with COVID-19. Moreover, since vita-
potent vasoconstrictor peptide, but also recognized as a proinflam- min C inhibits the increase of a range of inflammatory cytokines
matory cytokine, including in the lungs, and its increased expres- [21,62,63], the vitamin may be therapeutically superior to blockers
sion has been associated with pneumonia, pulmonary of individual cytokine mediators. A randomized placebo-controlled
hypertension, interstitial lung fibrosis, and acute respiratory dis- study showed that vitamin C (500 mg twice daily) alleviates the
tress syndrome [39 41]. In patients with severe COVID-19 who inflammatory status by reducing, among others, IL-6 and C-reac-
survive, cytokine levels, including IL-6, gradually return later in the tive protein in hypertensive and/or diabetic obese patients [64].
course of the disease to levels comparable with those in mild cases This suggests that vitamin C may also be of use in severe forms of
[33]. Additionally, preliminary data from Chinese and U.S. studies COVID-19 [65]. Vitamin C may also inhibit the ability of neutrophils
treating COVID-19 pneumonia and mechanically ventilated to form neutrophil extracellular traps, which may contribute to
patients, respectively, with tocilizumab (a humanized recombinant organ damage and mortality in COVID-19 [66]. Finally, vitamin C
monoclonal antibody blocking the IL-6 receptor) support the path- may have beneficial effects on the thrombotic or thromboembolic
ogenic role of IL-6, although the treatment itself is controversial disease commonly found in patients with COVID-19 [67 69].
(ChiCTR2000029765, chinaXiv:202003.0002v1) [42 44]. Several More than 10 new COVID-19-related clinical trials have been
clinical studies to test the safety, tolerability, and efficacy of tocili- started or are announced since February 2020 to investigate the
zumab for COVID-19 pneumonia are under way (NCT04317092, therapeutic effect of vitamin C alone or in combination with one or
NCT04332913, NCT04320615). Also, a similar study is ongoing more other substances (e.g., vitamin D, zinc [gluconate], hydroxy-
with another human monoclonal antibody, sarilumab, that targets chloroquine [sulphate], and azithromycin) [70]. For example, a
the same IL-6 receptor (NCT04315298). clinical trial is ongoing in which vitamin C (6 to 12 g/d) is adminis-
Clearly, older patients have an increased risk to develop (severe tered intravenously for moderate and severe cases of COVID-19
forms of) COVID-19 pneumonia [45], which is thought to be a late pneumonia (NCT04264533). How the dose ranges were estab-
response of the immune system to the viral infection. This may lished in these different studies is not always clear. However, a
seem counterintuitive since many aspects of the immune response recent review suggests that (much) higher intravenous vitamin C
decrease in the elderly. However, both in mice and humans, serum doses may be necessary for the reduction of cytokine storms in
levels of IL-6 increase with age [46 48]. Overexpression of IL-6 in acute respiratory distress syndrome [63]. Even very high doses of
older mice is harmful and during systemic inflammation, IL-6 intravenous vitamin C have been shown to be safe. No serious
strongly increases. Moreover, this increase is prolonged with age adverse reactions occurred in patients receiving chemotherapy
in multiple tissues (e.g., the lungs, heart, and plasma) [49]. Elevated with concomitant intravenous doses of up to 1.5 g/kg vitamin C at
levels of IL-6 are associated with a higher frequency of multiple an infusion rate of up to 1 g/min, and no maximum-tolerated dose
organ failure [36,50]. Gene expression analyses revealed that older was reached [71,72]. High doses of vitamin C are generally
people mount a stronger immune response, including IL-6, to assumed to be administered intravenously because they are poorly
SARS-CoV-1, and there is no reason to assume this would be differ- tolerated orally. However, Cathcart argued that bowel tolerance
ent for SARS-CoV-2 [32,51]. for vitamin C increased with the severity of illness in many
IL-6 or ET-1 may not only explain the age-dependence of patients, so that oral doses of up to 200 g/d could be tolerated by
COVID-19 pneumonia, but also the preponderance of male and some patients [73]. This administration route may be preferable
obese or hypertensive patients, as well as persons of color and for patients treated at home or in facilities where intravenous
smokers. Almost three out of four patients critically ill with COVID- administration may be difficult. For intensive care patients, intra-
19 are male (70.8%; n = 6814) [16]. Men have on average higher venous administration may be preferred because virtually all have
plasma IL-6 levels than women [47,50,52,53]. In addition, under intravenous lines, and many cannot swallow or have gastrointesti-
basal conditions, estradiol induces a decrease and testosterone an nal problems that interfere with drug absorption [74].
increase in the number of cells secreting ET-1 when stimulated
with angiotensin-II [54]. Long-term hormone replacement therapy Conclusion
users and premenopausal woman have lower systemic levels of IL-
6 than their nonusing cotwins or postmenopausal woman, respec- COVID-19 pneumonia and its progression to respiratory failure
tively [55]. Higher mortality was observed in patients with COVID- appear to be driven by an immune hyperreaction in which IL-6
 A.F. Feyaerts and W. Luyten / Nutrition 79 80 (2020) 110948 3

and ET-1 play an important role. Vitamin C can reduce these (and Hyperbaric_oxygen_therapy_in_the_treatment_ofCOVID-19_Severe_Cases.pdf
other) inflammatory mediators in various inflammatory condi- Accessed April 17. 2020.
[16] Intensive Care National Audit & Research Centre. ICNARC report on COVID-19 in
tions, and is clinically beneficial in (non-COVID-19) hypertensive critical care. Available at: https://www.icnarc.org/Our-Audit/Audits/Cmp/Reports.
and/or diabetic obese adult patients. Considering the weight of the Accessed June 5, 2020.
evidence and because vitamin C is cheap and safe, an oral low dose [17] Hemila H. Vitamin C and infections. Nutrients 2017;9:339.
[18] Hemila H. Vitamin C and SARS coronavirus. J Antimicrob Chemother
(1 2 g/d) may be useful prophylactically, and in cases of severe 2003;52:1049–50.
COVID-19, a (very) high-dose regimen may be beneficial. Ongoing [19] Hemila H. Vitamin C intake and susceptibility to pneumonia. Pediatr Infect Dis
clinical trials are expected to provide more definitive evidence. J 1997;16:836–7.
[20] Ang A, Pullar JM, Currie MJ, Vissers MCM. Vitamin C and immune cell function
in inflammation and cancer. Biochem Soc Trans 2018;46:1147–59.
Acknowledgments [21] Carr AC, Maggini S. Vitamin C and immune function. Nutrients 2017;9:1211.
[22] Atherton JG, Kratzing CC, Fisher A. The effect of ascorbic acid on infection
chick-embryo ciliated tracheal organ cultures by coronavirus. Arch Virol
The authors thank Dr. Patrick Van Dijck for proofreading the 1978;56:195–9.
manuscript and Alan Feyaerts for his suggestions in the creation of [23] Marik PE. Vitamin C: An essential “stress hormone” during sepsis. J Thorac Dis-
this article. The authors thank a reviewer for pointing out the ease 2020;12:S84–8.
[24] Fowler AA 3rd, Truwit JD, Hite RD, Morris PE, DeWilde C, Priday A, et al. Effect
increased bowel tolerance for oral vitamin C in ill patients of vitamin C infusion on organ failure and biomarkers of inflammation and
described by Cathcart, and for providing additional useful litera- vascular injury in patients with sepsis and severe acute respiratory failure:
ture references. The CITRIS-ALI randomized clinical trial. JAMA 2019;322:1261–70.
[25] Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, vita-
min C, and thiamine for the treatment of severe sepsis and septic shock: A ret-
Declaration of interests rospective before-after study. Chest 2017;151:1229–38.
[26] Fujii T, Luethi N, Young PJ, Frei DR, Eastwood GM, French CJ, et al. Effect of vita-
min C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and
The authors declare that they have no known competing finan- free of vasopressor support among patients with septic shock: The VITAMINS
cial interests or personal relationships that could have appeared to randomized clinical trial. JAMA 2020;323:423–31.
influence the work reported in this paper. [27] Gombart AF, Pierre A, Maggini S. A review of micronutrients and the immune sys-
tem-Working in harmony to reduce the risk of infection. Nutrients 2020;12:236.
[28] Hemil€a H, Chalker E. Vitamin C can shorten the length of stay in the ICU: A
Credit Author Statement meta-analysis. Nutrients 2019;11:708.
[29] Hemila H, Chalker E. Vitamin C for preventing and treating the common cold.
The Cochrane Database Syst Rev 2013:CD000980.
A.F.F. conceived and coordinated the study; A.F.F. and W.L. con- [30] Douglas RM, Hemila H, Chalker E, Treacy B. Vitamin C for preventing and treat-
tributed to the writing, reviewing and editing of the manuscript. ing the common cold. Cochrane Database Syst Rev 2007:CD000980.
[31] Brandt C, Pedersen BK. The role of exercise-induced myokines in muscle
homeostasis and the defense against chronic diseases. J Biomed Biotechnol
References 2010;2010:520258.
[32] Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al.
[1] Wang Z, Yang B, Li Q, Wen L, Zhang R. Clinical features of 69 cases with corona- COVID-19: Consider cytokine storm syndromes and immunosuppression. Lan-
virus disease 2019 in Wuhan, China. Clin Infect Dis 2020;71:769–77. cet 2020;395:1033–4.
[2] Gabutti G, d'Anchera E, Sandri F, Savio M, Stefanati A. Coronavirus: Update [33] Liu J, Li S, Liu J, Liang B, Wang X, Wang H, et al. Longitudinal characteristics of
related to the current outbreak of COVID-19. Infect Dis Ther 2020;9:1–13. lymphocyte responses and cytokine profiles in the peripheral blood of SARS-
[3] Prajapat M, Sarma P, Shekhar N, Avti P, Sinha S, Kaur H, et al. Drug targets for CoV-2 infected patients. MedRxiv 2020;55:102763.
corona virus: A systematic review. Indian J Pharmacol 2020;52:56–65. [34] Zhang W, Zhao Y, Zhang F, Wang Q, Li T, Liu Z, et al. The use of anti-inflamma-
[4] Arabi YM, Fowler R, Hayden FG. Critical care management of adults with com- tory drugs in the treatment of people with severe coronavirus disease 2019
munity-acquired severe respiratory viral infection. Intensive Care Med (COVID-19): The perspectives of clinical immunologists from China. Clin
2020;46:315–28. Immunol 2020;214:108393.
[5] Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Res [35] Gao Y, Li T, Han M, Li X, Wu D, Xu Y, et al. Diagnostic utility of clinical labora-
2020;177:104762. tory data determinations for patients with the severe COVID-19. J Med Virol
[6] Colson P, Rolain JM, Raoult D. Chloroquine for the 2019 novel coronavirus 2020;92:791–6.
SARS-CoV-2. Int J Antimicrob Agents 2020;55:105923. [36] Liu B, Li M, Zhou Z, Guan X, Xiang Y. Can we use interleukin-6 (IL-6) blockade
[7] Xue J, Moyer A, Peng B, Wu J, Hannafon BN, Ding WQ. Chloroquine is a zinc for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome
ionophore. PloS One 2014;9:e109180. (CRS)? J Autoimmun 2020:102452.
[8] Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown appar- [37] Erol A. High-dose intravenous vitamin C treatment for COVID-19. Silivri-Istan-
ent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. bul, Turkey: Erol Project Development House for the Disorders of Energy Meg-
Biosci Trends 2020;14:72–3. abolism; 2020.
[9] te Velthuis AJW, van den Worm SHE, Sims AC, Baric RS, Snijder EJ, van Hemert [38] Bohm F, Settergren M, Pernow J. Vitamin C blocks vascular dysfunction and
MJ. Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in release of interleukin-6 induced by endothelin-1 in humans in vivo. Athero-
vitro and zinc ionophores block the replication of these viruses in cell culture. sclerosis 2007;190:408–15.
PLoS Pathog 2010;6:e1001176. [39] Freeman BD, Machado FS, Tanowitz HB, Desruisseaux MS. Endothelin-1 and its
[10] Scholz M, Derwand R. Does zinc supplementation enhance the clinical efficacy role in the pathogenesis of infectious diseases. Life Sci 2014;118:110–9.
of chloroquine/hydroxychloroquine to win today’s battle against COVID-19? [40] Teder P, Noble PW. A cytokine reborn? Endothelin-1 in pulmonary inflamma-
Med Hypotheses 2020;142:109815. tion and fibrosis. Am J Respir Cell Mol Biol 2000;23:7–10.
[11] U.S. Food and Drug Administration. Fact sheet for health care providers Emergency [41] Silver RM. Endothelin and scleroderma lung disease. Rheumatology (Oxford)
Use Authorization (EUA) of hydroxychloroquine sulfate supplied from the strategic 2008;47:v25–6.
national stockpile for treatment of COVID-19 in certain hospitalized patients. Avail- [42] Bersanelli M. Controversies about COVID-19 and anticancer treatment with
able at: https://www.fda.gov/media/136537/download. Accessed April 19, 2020. immune checkpoint inhibitors. Immunotherapy 2020;12:269–73.
[12] Wu Z, McGoogan JM. Characteristics of and important lessons from the coro- [43] Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe
navirus disease 2019 (COVID-19) outbreak in China: Summary of a report of COVID-19 patients with tocilizumab. Available at: http://www.chinaxiv.org/
72314 cases from the Chinese Center for Disease Control and Prevention. abs/202003.00026. Accessed April 17, 2020.
JAMA 2020;323:1239–42. [44] Somers EC, Eschenauer GA, Troost JP, Golob JL, Gandhi TN, Wang L, et al. Tocili-
[13] Brochard L. Mechanical ventilation: Invasive versus noninvasive. Eur Respir J zumab for treatment of mechanically ventilated patients with COVID-19.
2003;(Suppl 47). 31s 7. medRxiv 2020. 2005.2029.20117358.
[14] Liu W., Li H.COVID-19: Attacks the 1-beta chain of hemoglobin and captures [45] Intensive Care National Audit & Research Centre. ICNARC report on COVID-19
the porphyrin to inhibit human heme metabolism. 2020. Preprint: 10.26434/ in critical care. Available at: https://www.icnarc.org/Our-Audit/Audits/Cmp/
chemrxiv.11938173.v6 Reports. Accessed April 10, 2020.
[15] International Hyperbarics Association, Naval Specialty Medical Center Program [46] Raynor J, Karns R, Almanan M, Li KP, Divanovic S, Chougnet CA, et al. IL-6 and
Team. Demonstration report on inclusion of hyperbaric oxygen therapy in ICOS antagonize bim and promote regulatory T cell accrual with age. J Immu-
treatment of COVID-19 severe cases. Available at: https://www.ihausa.org/ nol 2015;195:944–52.
4 A.F. Feyaerts and W. Luyten / Nutrition 79 80 (2020) 110948

[47] Young DG, Skibinski G, Mason JI, James K. The influence of age and gender on [61] Canali R, Natarelli L, Leoni G, Azzini E, Comitato R, Sancak O, et al. Vitamin C
serum dehydroepiandrosterone sulphate (DHEA-S), IL-6, IL-6 soluble receptor supplementation modulates gene expression in peripheral blood mononuclear
(IL-6 sR) and transforming growth factor beta 1 (TGF-beta1) levels in normal cells specifically upon an inflammatory stimulus: A pilot study in healthy sub-
healthy blood donors. Clin Exp Immunol 1999;117:476–81. jects. Genes Nutr 2014;9:390.
[48] Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, Atkinson C, Malarkey WB, Glaser [62] Russell B, Moss C, George G, Santaolalla A, Cope A, Papa S, et al. Associations
R. Chronic stress and age-related increases in the proinflammatory cytokine between immune-suppressive and stimulating drugs and novel COVID-19-a
IL-6. Proc Natl Acad Sci U S A 2003;100:9090–5. systematic review of current evidence. Ecancermedicalscience 2020;14:1022.
[49] Starr ME, Evers BM, Saito H. Age-associated increase in cytokine production [63] Boretti A, Banik BK. Intravenous vitamin C for reduction of cytokines storm in
during systemic inflammation: Adipose tissue as a major source of IL-6. J Ger- acute respiratory distress syndrome. PharmaNutrition 2020;12:100190.
ontol A Biol Sci Med Sci 2009;64:723–30. [64] Ellulu MS, Rahmat A, Patimah I, Khaza’ai H, Abed Y. Effect of vitamin C on
[50] Sperry JL, Friese RS, Frankel HL, West MA, Cuschieri J, Moore EE, et al. Male inflammation and metabolic markers in hypertensive and/or diabetic
gender is associated with excessive IL-6 expression following severe injury. J obese adults: A randomized controlled trial. Drug Des Devel Ther
Trauma 2008;64:572–8. discussion 578 9. 2015;9:3405–12.
[51] Baas T, Roberts A, Teal TH, Vogel L, Chen J, Tumpey TM, et al. Genomic analysis [65] Herna ndez A, Papadakos PJ, Torres A, Gonzalez DA, Vives M, Ferrando C, et al.
reveals age-dependent innate immune responses to severe acute respiratory Two known therapies could be useful as adjuvant therapy in critical patients
syndrome coronavirus. J Virol 2008;82:9465–76. infected by COVID-19. Rev Esp Anestesiol Reanim 2020;67:245–52.
[52] Wei J, Xu H, Davies JL, Hemmings GP. Increase of plasma IL-6 concentration [66] Barnes BJ, Adrover JM, Baxter-Stoltzfus A, Borczuk A, Cools-Lartigue J, Craw-
with age in healthy subjects. Life Sci 1992;51:1953–6. ford JM, et al. Targeting potential drivers of COVID-19: Neutrophil extracellular
[53] Starr ME, Saito M, Evers BM, Saito H. Age-associated increase in cytokine produc- traps. J Exp Med 2020;217:e20200652.
tion during systemic inflammation-II: The role of IL-1beta in age-dependent IL-6 [67] Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, et al. COVID-19
upregulation in adipose tissue. J Gerontol A Biol Sci Med Sci 2015;70:1508–15. and thrombotic or thromboembolic disease: Implications for prevention, antith-
[54] Pearson LJ, Yandle TG, Nicholls MG, Evans JJ. Regulation of endothelin-1 rombotic therapy, and follow-up. J Am Coll Cardiol 2020;75:2950–73.
release from human endothelial cells by sex steroids and angiotensin-II. Pepti- [68] Sathler PC, Lourenço AL, Saito MS, Are ^as APG, Rodrigues CR, Cabral LM, et al.
des 2008;29:1057–61. The antihemostatic profile of vitamin C: Mechanisms that underlie the techni-
[55] Ahtiainen M, Po € lla
€nen E, Ronkainen PHA, Alen M, Puolakka J, Kaprio J, et al. cal application of a physiological molecule. Arch Biol Sci 2016;68:325–31.
Age and estrogen-based hormone therapy affect systemic and local IL-6 and € lschermann H. Vitamin
[69] Parahuleva MS, Jung J, Burgazli M, Erdogan A, Parviz B, Ho
IGF-1 pathways in women. Age (Dordr) 2012;34:1249–60. C suppresses lipopolysaccharide-induced procoagulant response of human
[56] Meng J, Xiao G, Zhang J, He X, Ou M, Bi J, et al. Renin-angiotensin system inhib- monocyte-derived macrophages. Eur Rev Med Pharmacol Sci 2016;20:2174–82.
itors improve the clinical outcomes of COVID-19 patients with hypertension. [70] U.S. National Library of Medicine. ClinicalTrials.gov. Available at: https://clini-
Emerg Microbes Infect 2020;9:757–60. caltrials.gov/ct2/results?term=vitamin+c+AND+COVID-19&Search=Search.
[57] Bastard JP, Jardel C, Delattre J, Hainque B, Bruckert E, Oberlin F. Evidence for a Accessed April 17, 2020.
link between adipose tissue interleukin-6 content and serum C-reactive pro- [71] Wang F, He MM, Wang ZX, Li S, Jin Y, Ren C, et al. Phase I study of high-dose
tein concentrations in obese subjects. Circulation 1999;99:2221–2. ascorbic acid with mFOLFOX6 or FOLFIRI in patients with metastatic colorectal
[58] Evans RR, Phillips BG, Singh G, Bauman JL, Gulati A. Racial and gender differen- cancer or gastric cancer. BMC Cancer 2019;19:460.
ces in endothelin-1. Am J Cardiol 1996;78:486–8. [72] PDQ Integrative, Alternative, and Complementary Therapies Editorial Board.
[59] Bhavsar TM, Liu X, Cerreta JM, Liu M, Cantor JO. Endothelin-1 potentiates PDQ high-dose vitamin C. Bethesda, MD: National Cancer Institute; 2020.
smoke-induced acute lung inflammation. Exp Lung Res 2008;34:707–16. [73] Cathcart RF, Vitamin C. titrating to bowel tolerance, anascorbemia, and acute
[60] Herold T, Jurinovic V, Arnreich C, Hellmuth JC, von Bergwelt-Baildon M, Klein induced scurvy. Med Hypotheses 1981;7:1359–76.
M, et al. Level of IL-6 predicts respiratory failure in hospitalized symptomatic [74] Power BM, Forbes AM, van Heerden PV, Ilett KF. Pharmacokinetics of drugs
COVID-19 patients. medRxiv 2020. 2004.2001.20047381. used in critically ill adults. Clin Pharmacokinet 1998;34:25–56.