Low level of Vitamin C and dysregulation of Vitamin C transporter might be involved in the severity of COVID-19 Infection
Gregory Patterson1, Carlos M. Isales2,3, Sadanand Fulzele1,2,3,*
1Department of Medicine, Augusta University, Augusta, GA 30912, USA. 2Center for Healthy Aging, Augusta University, Augusta, GA 30912, USA 3Department of Cell biology and anatomy, Augusta University, Augusta, GA 30912, USA
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been spreading around the world at an exponential pace, leading to millions of individuals developing the associated disease called COVID-19. Due to the novel nature and the lack of immunity within humans, there has been a collective global effort to find effective treatments against the virus. This has led the scientific community to repurpose Food and Drug Administration (FDA) approved drugs with known safety profiles. Of the many possible drugs, vitamin C has been on the shortlist of possible interventions due to its beneficial role as an immune booster and inherent antioxidant properties. Within this manuscript, a detailed discussion regarding the intracellular function and inherent properties of vitamin C is conducted. It also provides a comprehensive review of published research pertaining to the differences in expression of the vitamin C transporter under several pathophysiologic conditions. Finally, we review recently published research investigating the efficacy of vitamin C administration in treating viral infection and life-threatening conditions. Overall, this manuscript aims to present existing information regarding the extent to which vitamin C can be an effective treatment for COVID-19 and possible explanations as to why it may work in some individuals but not in others.
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,
-Increase SVCT 2 expression in adrenals -Decrease SVCT 1 expression in kidney
Michels et al. 2003
-Decrease in hepatic SVCT 1 expression -No change in hepatic SVCT 2 expression in aged rats
Bayram et al. 2013
Fast aging phenotypic mice
-Increase in hepatic SVCT 1 expression -No change in hepatic SVCT 2 expression
Sangani et al. 2013
Decrease SVCT2 in bone and bone marrow
Sangani et al. 2015
Apoptosis and Autophagy
SVCT2 regulates Apoptosis and Autophagy
Table 1 Selected studies showing dysregulation of vitamin C transporter (SVCT1 and SVCT2) in different pathological condition or stress.
Relative Serum Vit C Concentration
Relative Chance of Severe Covid-19
+ + [37, 38]
+ + + [7, 40]
+ + + [37, 38]
+ + [7, 40]
+ + + [37, 38]
+ + [7, 41]
+ + [37, 38]
+ + + [7, 41]
+ + 
+ + + 
+ + [42, 47]
+ + + 
+ + [36, 45]
+ + + [7, 44]
+ + + [37, 38]
+++ [14, 42]
++ [14, 42]
++ [7, 44]
+ [14, 42]
+++ [7, 44]
“+” = arbitrary unit
Table 2 Risk factors for developing severe covid-19 infections and relationship to serum vitamin C levels.
Zabet et al. 2016 Type: RCT
18-65 years old
-Vitamin C (25mg/kg) every 6 hours
-28 day mortality was significantly lower (14.28% vs. 64.28%, respectively; P = 0.009)
Fowler et al. 2019 -Type: double blinded, RCT
Patients with Sepsis or ARDS for less than 24 hours
Mean age of 54.8 years old
-IV infusion of vitamin C (50 mg/kg in dextrose 5% in water, n?=?84) every 6 hours
-No significant difference in mean modified SOFA score, C-reactive protein or thrombomodulin levels -HOWEVER, strong indication of lower all-cause mortality in vit C group
Sawyer et al. 1986 Type: RCT
Patients with ARDS
-IV injection of vitamin C (1000 mg) every 6 hours
-Dramatic reduction in mortality in vit. C group compared with control (37% vs. 71% (p<.01))
Fowler et al. 2014 Type: Double Blinded, RCT
Patients in MICU with severe Sepsis
30-70 years old in low dose group 49-92 years old in high dose group 54-68 years old in placebo group
-Low dose group: IV Vitamin C (50 mg/kg/24 h, n?=?8) -High dose group: IV Vitamin C (200 mg/kg/24 h, n?=?8) -Placebo group: IV (5% dextrose/water, n?=?8)
-SOFA score -Hi: 10.4±?4.4 -Lo: 10.1?±?2.0 -Placebo: 13.3?±?2.9 -Vit. C groups decreased levels of C-reactive protein and procalcitonin -No significant difference between thrombomodulin levels between groups
Marik et al. 2017 Type: Retrospective clinical study
Patients diagnosed with severe Sepsis of septic shock
Study group mean age was 58.3 years old Control group mean age was 62.2 years old
-Patients treated with triple therapy of hydrocortisone, HDIVC, Thiamine
-Intervention group: IV vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), thiamine (200 mg every 12 hours) -Control group: IV hydrocortisone (50 mg every 6 hours)
-No difference in time alive and free of vasopressor administration up to 7 days between intervention group and control group (122.1 hours vs. 124.6 hours; respectively) -ninety-day mortality -28.6% (intervention group) vs. 24.5% (control group)
Hemilä et al. 2013 Type: meta-analysis
Patients suffering from the common cold
-First arm: 29 trials with vitamin C supplementation (>.2 g/day) -Second arm: 31 trials with regular vitamin C intake (>.2 g/day) -Third arm: 7 trials with therapeutic use of IV or oral vitamin C (>.2 g/day)
-First arm -Risk Ratio of .97 -Second arm -Regular vit C reduced cold duration by 8% in adult population studied -Regular vit C reduced cold duration by 12% in children population studied -Third arm: no consistent effect of therapeutic use of vit C
Fowler et al. 2017 Type: case report
Single patient presenting with enterovirus/rhinovirus induced ARDS
20 years old
-high does Intravenous vitamin C injections (200 mg/kg per day)
-12 hours following initiation of treatment, symptoms dramatically improved -mechanical ventilation was discontinued 7 days post treatment -No long term ARDS sequelae noted
Table 3 Selected studies pertaining to the efficacy behind Vitamin C supplementation for patients with diseases and/or viral infections.
Wuhan, Hubei, China
Diammonium Glycyrrhizinate Enteric-coated Capsules (oral, 150mg, Tid), Oral Vit C tablets (.5 g) every day
Xi'an, Shaanxi, China
High dose Vit C
Wuhan, Hubei, China
IV 12g Vit C every 12 hours
IV 10g Vit C plus conventional therapy
Sherbrooke, Quebec, Canada
IV 50 mg/kg Vit C every 6 hours for 96 hours
Hydroxychloroquine 200mg plus vitamin C and zinc every day
IV 12g Vit C in .5% dextrose (total volume 200ml)
Abadan, Khuzestan Province, Iran
Hydroxychloroquine 200 mg plus oral 500 mg Vit C every 12 hours for 5 days
Hydroxychloroquine 800 mg followed by once weekly oral hydroxychloroquine 400 mg for 3 months vs. Oral Vitamin C 1,000 mg daily
Huangpu, Shanghai, China
IV 100mg/kg Vit C every day
Richmond, Virginia, United States
IV 100 mg/kg Vit C every 8 hours
Richmond, Virginia, United States
IV 50mg/kg Vit C every 6 hours for 4 days
Mashhad, Razavi Khorasan, Iran
Treatment with mixture of methylene blue, Vit C, N-acetyl cysteine
Xi'an, Shaanxi, China
High dose vitamin C plus Chinese medicine for treatment of COVID-19
Shanghai, Shanghai, China
High dose IV vitamin C treatment upon diagnosis of severe COVID-19
Philadelphia, Pennsylvania, United States
Escalating dose of oral Vit C (0.3g/kg, 0.6g/kg, 0.9g/kg) every 6 hours
Australia, United States, Germany
Trial arms: 1)Hydroxychloroquine plus zinc plus Vit D3/B12 plus azithromycin plus IV Vitamin C 2) Hydroxychloroquine plus zinc plus Vit D3/B12 plus azithromycin
IV 1.5g Vit C 4 times a day plus hydroxychloroquine 400 mg
Sabzevar, Razavi Khorasan, Iran
Treatments of 500mg Vit C daily for a week
Kermanshah, Kermanshah, Iran
250mg Azithromycin once daily, 100 mg of doxycycline twice daily, 1.5g Vit C every 6 hours, and 500mg metformin
Trial arms: 1) Chloroquine 10 mg base/kg once a day 2) Vitamin C 1000 mg once a day
Ventura, California, United States
Quintuple therapy consisting of hydroxychloroquine, azithromycin, zinc, vit C and D for 10 days
Ventura, California, United States
hydroxychloroquine, Vitamin C, Vitamin D, and Zinc can prevent symptoms of COVID-19
Weston, Florida, United States and Cleveland, Ohio, United States
Trial arms: 1)Vit C 8000mg in 2-3 doses 2)Zinc Gluconate 50mg daily 3)Vit C 8000mg plus Zinc gluconate 50mg daily 4)Standard of care
Various cities throughout the united states
Trial arms: 1) Oral 500mg Vit C daily for 3 days then 250mg for 11 days 2) 400mg Hydroxychloroquine for 3 days then 200mg for 11 days
High dose IV Vitamin C to patients with COVID-19
Hawthorn, Victoria, Australia
IV vitamin C, Hydroxycholorquine, azithromycin, Zinc citrate, Vitamin D3, Vitamin B12 for treating COVID-19
Portland, Oregon, United States
Trial arms: 1) 800mg hydroxychloroquine on day 1, 400mg on days 2-5 2) 2000mg of Vit C on day 1, 1000mg on days 2-5
Various cities throughout the United States
Trial arms: 1) Vit C plus folic acid 2) Hydroxychloroquine plus Folic Acid 3) Hydroxychloroquine and Azithromycin
Sherbrooke, Quebec, Canada
IV 50 mg/kg Vit C every 6 hours
Table 4 Ongoing clinical trials register for using Vitamin C alone or in combination with other drug for treatment of COVID-19 infections.
Dong E, Du H, Gardner L (2020). An interactive web-based dashboard to track COVID-19 in real time. The Lancet, 20:533-534.
Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB (2020). Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. Jama, 323:1824-1836.
Zhang L, Liu Y (2020). Potential interventions for novel coronavirus in China: A systematic review. J of Med Vir, 92:479-490.
Shanmugaraj B, Siriwattananon K, Wangkanont K, Phoolcharoen W (2020). Perspectives on monoclonal antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19). Asian Pac J Allergy Immunol, 38:10-18.
Qin X, Liu J, Du Y, Li Y, Zheng L, Chen G, et al. (2019). Different doses of vitamin C supplementation enhances the Th1 immune response to early Plasmodium yoelii 17XL infection in BALB/c mice. International Immunopharmacology, 70:387-395.
Bozonet SM, Carr AC, Pullar JM, Vissers M (2015). Enhanced human neutrophil vitamin C status, chemotaxis and oxidant generation following dietary supplementation with vitamin C-rich SunGold kiwifruit. Nutrients, 7:2574-2588.
Li X, Xu S, Yu M, Wang K, Tao Y, Zhou Y, et al. (2020). Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J of All and Clin Immun.
CL L (2007). Van Schaftingen E. Vitamin C. FEBS J, 274:1-22.
Padayatty SJ, Levine M (2016). Vitamin C: the known and the unknown and Goldilocks. Oral Dis, 22:463-493.
Kashiouris MG, L’Heureux M, Cable CA, Fisher BJ, Leichtle SW (2020). The emerging role of vitamin C as a treatment for sepsis. Nutrients, 12:292.
Hemilä H (2017). Vitamin C and infections. Nutrients, 9:339.
Kodama Y, Kishimoto Y, Muramatsu Y, Tatebe J, Yamamoto Y, Hirota N, et al. (2017). Antioxidant nutrients in plasma of Japanese patients with chronic obstructive pulmonary disease, asthma‐COPD overlap syndrome and bronchial asthma. The Clin Resp J, 11:915-924.
Wilson R, Willis J, Gearry R, Skidmore P, Fleming E, Frampton C, et al. (2017). Inadequate vitamin C status in prediabetes and type 2 diabetes mellitus: Associations with glycaemic control, obesity, and smoking. Nutrients, 9:997.
Fletcher AE, Breeze E, Shetty PS (2003). Antioxidant vitamins and mortality in older persons: findings from the nutrition add-on study to the Medical Research Council Trial of Assessment and Management of Older People in the Community. The Amer J Clinical Nut, 78:999-1010.
Washko P, Rotrosen D, Levine M (1989). Ascorbic acid transport and accumulation in human neutrophils. J of Bio Chem, 264:18996-19002.
Winterbourn CC, Vissers MC (1983). Changes in ascorbate levels on stimulation of human neutrophils. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 763:175-179.
Fulzele S, Chothe P, Sangani R, Chutkan N, Hamrick M, Bhattacharyya M, et al. (2013). Sodium-dependent vitamin C transporter SVCT2: expression and function in bone marrow stromal cells and in osteogenesis. Stem Cell Research, 10:36-47.
Tsukaguchi H, Tokui T, Mackenzie B, Berger UV, Chen X-Z, Wang Y, et al. (1999). A family of mammalian Na+-dependent L-ascorbic acid transporters. Nature, 399:70-75.
Rajan DP, Huang W, Dutta B, Devoe LD, Leibach FH, Ganapathy V, et al. (1999). Human placental sodium-dependent vitamin C transporter (SVCT2): molecular cloning and transport function. Biochem and Biophys Research Commun, 262:762-768.
Sangani R, Pandya CD, Bhattacharyya MH, Periyasamy-Thandavan S, Chutkan N, Markand S, et al. (2014). Knockdown of SVCT2 impairs in-vitro cell attachment, migration and wound healing in bone marrow stromal cells. Stem Cell Research, 12:354-363.
Seno T, Inoue N, Matsui K, Ejiri J, Hirata K-i, Kawashima S, et al. (2004). Functional expression of sodium-dependent vitamin C transporter 2 in human endothelial cells. J of Vasc Research, 41:345-351.
Blackburn AR, Hamrick MW, Chutkan N, Sangani R, Waller JL, Corpe R, et al. (2014). Comparative analysis of sodium coupled vitamin C transporter 2 in human osteoarthritis grade 1 and grade 3 tissues. BMC Musculoskeletal Dis, 15:9.
Larsson N, Rankin GD, Bicer EM, Roos-Engstrand E, Pourazar J, Blomberg A, et al. (2015). Identification of vitamin C transporters in the human airways: a cross-sectional in vivo study. BMJ open, 5:e006979.
Macias RI, Hierro C, de Juan SC, Jimenez F, Gonzalez-San Martin F, Marin JJ (2011). Hepatic expression of sodium-dependent vitamin C transporters: ontogeny, subtissular distribution and effect of chronic liver diseases. Br J Nutr, 106:1814-1825.
Miao F, Su MY, Jiang S, Luo LF, Shi Y, Lei TC (2019). Intramelanocytic Acidification Plays a Role in the Antimelanogenic and Antioxidative Properties of Vitamin C and Its Derivatives. Oxid Med Cell Longev, 2019:2084805.
Wu X, Iguchi T, Hirano J, Fujita I, Ueda H, Itoh N, et al. (2007). Upregulation of sodium-dependent vitamin C transporter 2 expression in adrenals increases norepinephrine production and aggravates hyperlipidemia in mice with streptozotocin-induced diabetes. Biochem Pharm, 74:1020-1028.
Kang JS, Kim HN, Kim JE, Mun GH, Kim YS, Cho D, et al. (2007). Regulation of UVB-induced IL-8 and MCP-1 production in skin keratinocytes by increasing vitamin C uptake via the redistribution of SVCT-1 from the cytosol to the membrane. J of Invest Derm, 127:698-706.
Subramanian VS, Srinivasan P, Said HM (2016). Uptake of ascorbic acid by pancreatic acinar cells is negatively impacted by chronic alcohol exposure. Amer J of Phys-Cell Phys, 311:C129-C135.
Ludke AR, Sharma AK, Akolkar G, Bajpai G, Singal PK (2012). Downregulation of vitamin C transporter SVCT-2 in doxorubicin-induced cardiomyocyte injury. Amer J of Phys-Cell Phys, 303:C645-C653.
Michels AJ, Joisher N, Hagen TM (2003). Age-related decline of sodium-dependent ascorbic acid transport in isolated rat hepatocytes. Archives of Biochem and Biophys, 410:112-120.
Cahill LE, El-Sohemy A (2009). Vitamin C transporter gene polymorphisms, dietary vitamin C and serum ascorbic acid. Lifestyle Genomics, 2:292-301.
Michels AJ, Hagen TM, Frei B.2010. A new twist on an old vitamin: human polymorphisms in the gene encoding the sodium-dependent vitamin C transporter 1. Oxford Univ Press.
Michels AJ, Hagen TM, Frei B (2013). Human genetic variation influences vitamin C homeostasis by altering vitamin C transport and antioxidant enzyme function. Annual review of Nutr, 33:45-70.
Timpson NJ, Forouhi NG, Brion M-J, Harbord RM, Cook DG, Johnson P, et al. (2010). Genetic variation at the SLC23A1 locus is associated with circulating concentrations of L-ascorbic acid (vitamin C): evidence from 5 independent studies with> 15,000 participants. The Amer J of Clinical Nutr, 92:375-382.
Corpe CP, Tu H, Eck P, Wang J, Faulhaber-Walter R, Schnermann J, et al. (2010). Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice. The J of Clinical Investigation, 120:1069-1083.
Birlouez-Aragon I, Delcourt C, Tessier F, Papoz L, Group PS (2001). Associations of age, smoking habits and diabetes with plasma vitamin C of elderly of the POLA study. International J for Vit and Nutr Research, 71:53-59.
Hampl JS, Taylor CA, Johnston CS (2004). Vitamin C deficiency and depletion in the United States: the third national health and nutrition examination survey, 1988 to 1994. Amer J of Pub Health, 94:870-875.
Schleicher RL, Carroll MD, Ford ES, Lacher DA (2009). Serum vitamin C and the prevalence of vitamin C deficiency in the United States: 2003-2004 National Health and Nutrition Examination Survey (NHANES). The Amer Journal of Clinical Nutr, 90:1252-1263.
Pearson JF, Pullar JM, Wilson R, Spittlehouse JK, Vissers M, Skidmore PM, et al. (2017). Vitamin C status correlates with markers of metabolic and cognitive health in 50-year-olds: findings of the CHALICE cohort study. Nutrients, 9:831.
Bwire GM (2020). Coronavirus: Why Men are More Vulnerable to Covid-19 Than Women? Sn Comprehensive Clinical Medicine:1.
Yancy CW (2020). COVID-19 and African Americans. Jama.
Harrison FE (2012). A critical review of vitamin C for the prevention of age-related cognitive decline and Alzheimer's disease. J of Alzheimer's Dis, 29:711-726.
Will JC, Byers T (1996). Does diabetes mellitus increase the requirement for vitamin C? Nutrition Reviews, 54:193-202.
Leung JM, Yang CX, Tam A, Shaipanich T, Hackett T-L, Singhera GK, et al. (2020). ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19. European Resp J, 55.
Pirabbasi E, Shahar S, Manaf ZA, Rajab NF, Manap RA (2016). Efficacy of ascorbic acid (vitamin C) and/N-acetylcysteine (NAC) supplementation on nutritional and antioxidant status of male chronic obstructive pulmonary disease (COPD) patients. J of Nutr Sci and Vit, 62:54-61.
MacNee W (2000). Oxidants/antioxidants and COPD. Chest, 117:303S-317S.
Ghosh S, Ekpo E, Shah I, Girling A, Jenkins C, Sinclair A (1994). A double-blind, placebo-controlled parallel trial of vitamin C treatment in elderly patients with hypertension. Gerontology, 40:268-272.
Juraschek SP, Guallar E, Appel LJ, Miller III ER (2012). Effects of vitamin C supplementation on blood pressure: a meta-analysis of randomized controlled trials. The American J of Clinical Nutr, 95:1079-1088.
Gutierrez A, Duran-Valdez E, Robinson I, de Serna D, Schade D (2013). Does short-term vitamin C reduce cardiovascular risk in type 2 diabetes? Endocrine Practice, 19:785-791.
Ashor A, Werner A, Lara J, Willis N, Mathers J, Siervo M (2017). Effects of vitamin C supplementation on glycaemic control: a systematic review and meta-analysis of randomised controlled trials. European J of Cinical Nutr, 71:1371-1380.
El-Aal AA, El-Ghffar EAA, Ghali AA, Zughbur MR, Sirdah MM (2018). The effect of vitamin C and/or E supplementations on type 2 diabetic adult males under metformin treatment: A single-blinded randomized controlled clinical trial. Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 12:483-489.
Li H, Liu L, Zhang D, Xu J, Dai H, Tang N, et al. (2020). SARS-CoV-2 and viral sepsis: observations and hypotheses. The Lancet.
Kim W-Y, Hong S-B (2016). Sepsis and acute respiratory distress syndrome: recent update. Tuberculosis and Resp Diseases, 79:53-57.
Borrelli E, Roux-Lombard P, Grau GE, Girardin E, Ricou B, Dayer J-M, et al. (1996). Plasma concentrations of cytokines, their soluble receptors, and antioxidant vitamins can predict the development of multiple organ failure in patients at risk. Critical Care Med, 24:392-397.
Sawyer M, Mike J, Chavin K, Marino P (1989). Antioxidant Therapy and Survival in ARDS. Crit Care Med, 17:S153.
Syed AA, Knowlson S, Sculthorpe R, Farthing D, DeWilde C, Farthing CA, et al. (2014). Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J of Trans Med, 12:32.
Fowler III AA, Kim C, Lepler L, Malhotra R, Debesa O, Natarajan R, et al. (2017). Intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory distress syndrome. World J of Critical Care Med, 6:85.
Truwit JD, Hite RD, Morris PE, DeWilde C, Priday A, Fisher B, et al. (2019). 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, 322:1261-1270.
Fujii T, Luethi N, Young PJ, Frei DR, Eastwood GM, French CJ, et al. (2020). Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: the vitamins randomized clinical trial. Jama, 323:423-431.
Mikirova NA, Hunninghake R (2014). Effect of high dose vitamin C on Epstein-Barr viral infection. Medical Sci Monitor: International Med J of Exper and Clin Res, 20:725.
Schencking M, Vollbracht C, Weiss G, Lebert J, Biller A, Goyvaerts B, et al. (2012). Intravenous vitamin C in the treatment of shingles: results of a multicenter prospective cohort study. Medical Sci Monitor: International Med J of Exper and Clin Res, 18:CR215.
Johnston CS, Barkyoumb GM, Schumacher SS (2014). Vitamin C supplementation slightly improves physical activity levels and reduces cold incidence in men with marginal vitamin C status: A randomized controlled trial. Nutrients, 6:2572-2583.
Hemilä H, Chalker E (2013). Vitamin C for preventing and treating the common cold. Cochrane Database of Systematic Reviews.
Chalmers TC (1975). Effects of ascorbic acid on the common cold: an evaluation of the evidence. The Amer J of Med, 58:532-536.
Padayatty SJ, Sun H, Wang Y, Riordan HD, Hewitt SM, Katz A, et al. (2004). Vitamin C pharmacokinetics: implications for oral and intravenous use. Annals of Int Med, 140:533-537.
Colunga Biancatelli RML, Berrill M, Marik PE.2020. The antiviral properties of vitamin C. Taylor & Francis.
Hagel AF, Albrecht H, Dauth W, Hagel W, Vitali F, Ganzleben I, et al. (2018). Plasma concentrations of ascorbic acid in a cross section of the German population. J of Inter Med Res, 46:168-174.
Chen J-Y, Chang C-Y, Feng P-H, Chu C-C, So EC, Hu M-L (2009). Plasma vitamin C is lower in postherpetic neuralgia patients and administration of vitamin C reduces spontaneous pain but not brush-evoked pain. The Clin J of Pain, 25:562-569.
Wintergerst ES, Maggini S, Hornig DH (2006). Immune-enhancing role of vitamin C and zinc and effect on clinical conditions. Ann of Nutr and Metab, 50:85-94.
Geber WF, Lefkowitz SS, Hung CY (1975). Effect of ascorbic acid, sodium salicylate, and caffeine on the serum interferon level in response to viral infection. Pharmacology, 13:228-233.
Nir Barzilai, James C Appleby, Steven N Austad, Ana Maria Cuervo, Matt Kaeberlein, Christian Gonzalez-Billault, Stephanie Lederman, Ilia Stambler, Felipe Sierra. Geroscience in the Age of COVID-19[J]. Aging and disease, 2020, 11(4): 725-729.