Low level of Vitamin C and dysregulation of Vitamin C transporter might be involved in the severity of COVID-19 Infection

doi:10.14336/AD.2020.0918

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Abstract

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.

Keywords Vitamin C Coronavirus Aging Immune response

Corresponding Authors: Fulzele Sadanand

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Meiqian Xu and Xiaodong Su contributed equally to this work.

Just Accepted Date: 28 September 2020 Issue Date: 11 January 2021

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	Patterson Taylor
	Isales Carlos M
	Fulzele Sadanand

Cite this article:

Patterson Taylor,Isales Carlos M,Fulzele Sadanand. 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, 2021, 12(1): 14-26.

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http://www.aginganddisease.org/EN/10.14336/AD.2020.0918 OR

Table 1 Selected studies showing dysregulation of vitamin C transporter (SVCT1 and SVCT2) in different pathological condition or stress.

Table 2 Risk factors for developing severe covid-19 infections and relationship to serum vitamin C levels.

Author	Viral infection	Age	Dose	Outcome
Zabet et al. 2016 Type: RCT	Sepsis	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	N/A	-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	-Mortality rate -Treatment: 8.5% (4 of 47) - Control: 40.4% (19 of 47) (P < .001) -72 hr ΔSOFA -Treatment: 4.8 ± 2.4 -Control: 0.9 ± 2.7 (P<.001)
Fujii et al. 2020 Type: RCT	Patients in ICUs suffering from Sepsis	Mean age 61.7 years old	-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	N/A	-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.

S.No.	Identification Number	Country	Participant	Intervention	Register with
1	ChiCTR2000029768	Wuhan, Hubei, China	60 Participants	Diammonium Glycyrrhizinate Enteric-coated Capsules (oral, 150mg, Tid), Oral Vit C tablets (.5 g) every day	Chictr.org
2	ChiCTR2000030135	Xi'an, Shaanxi, China	39 Participants	High dose Vit C	WHO.int
3	NCT04264533	Wuhan, Hubei, China	140 participants	IV 12g Vit C every 12 hours	Clinicaltrail.gov
4	NCT04323514	Palermo, Italy	500 participants	IV 10g Vit C plus conventional therapy	Clinicaltrial.gov
5	NCT03680274	Sherbrooke, Quebec, Canada	800 participants	IV 50 mg/kg Vit C every 6 hours for 96 hours	Clinicaltrial.gov
6	NCT04326725	Istanbul, Turkey	80 participants	Hydroxychloroquine 200mg plus vitamin C and zinc every day	Clinicaltrial.gov
7	IRCT20190917044805N2	Tehran, Iran	60 participants	IV 12g Vit C in .5% dextrose (total volume 200ml)	IRCT.ir
8	IRCT20200324046850N5	Abadan, Khuzestan Province, Iran	40 participants	Hydroxychloroquine 200 mg plus oral 500 mg Vit C every 12 hours for 5 days	IRCT.ir
9	NCT04347889	N/A	1212 participants	Hydroxychloroquine 800 mg followed by once weekly oral hydroxychloroquine 400 mg for 3 months vs. Oral Vitamin C 1,000 mg daily	Clinicaltrial.gov
10	ChiCTR2000032400	Huangpu, Shanghai, China	120 participants	IV 100mg/kg Vit C every day	WHO.int
11	NCT04344184	Richmond, Virginia, United States	200 participants	IV 100 mg/kg Vit C every 8 hours	Clinicaltrial.gov
12	NCT04357782	Richmond, Virginia, United States	20 participants	IV 50mg/kg Vit C every 6 hours for 4 days	Clinicaltrial.gov
13	NCT04370288	Mashhad, Razavi Khorasan, Iran	20 participants	Treatment with mixture of methylene blue, Vit C, N-acetyl cysteine	Clinicaltrial.gov
14	ChiCTR2000032717	Xi'an, Shaanxi, China	60 participants	High dose vitamin C plus Chinese medicine for treatment of COVID-19	CHICTR.org.in
15	ChiCTR2000032716	Shanghai, Shanghai, China	12 participants	High dose IV vitamin C treatment upon diagnosis of severe COVID-19	CHICTR.org.in
16	NCT04363216	Philadelphia, Pennsylvania, United States	66 participants	Escalating dose of oral Vit C (0.3g/kg, 0.6g/kg, 0.9g/kg) every 6 hours	Clinicaltrial.gov
17	ACTRN12620000557932	Australia, United States, Germany	200 participants	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	WHO.ir
18	IRCT20200411047025N1	Tehran, Iran	110 participants	IV 1.5g Vit C 4 times a day plus hydroxychloroquine 400 mg	IRCT.ir
19	IRCT20140305016852N4	Sabzevar, Razavi Khorasan, Iran	30 participants	Treatments of 500mg Vit C daily for a week	IRCT.ir
20	IRCT20200418047121N1	Kermanshah, Kermanshah, Iran	40 participants	250mg Azithromycin once daily, 100 mg of doxycycline twice daily, 1.5g Vit C every 6 hours, and 500mg metformin	IRCT.ir
21	TCTR20200404004	Bangkok, Thailand	400 participants	Trial arms: 1) Chloroquine 10 mg base/kg once a day 2) Vitamin C 1000 mg once a day	Clinicaltrials.in.th
22	NCT04334512	Ventura, California, United States	600 participants	Quintuple therapy consisting of hydroxychloroquine, azithromycin, zinc, vit C and D for 10 days	Clinicaltrials.gov
23	NCT04335084	Ventura, California, United States	600 participants	hydroxychloroquine, Vitamin C, Vitamin D, and Zinc can prevent symptoms of COVID-19	Clinicaltrials.gov
24	NCT04342728	Weston, Florida, United States and Cleveland, Ohio, United States	520 participants	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	Clinicaltrials.gov
25	NCT04328961	Various cities throughout the united states	2000 participants	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	Clinicaltrials.gov
26	ChiCTR2000033050	Shanghai, China	110 participants	High dose IV Vitamin C to patients with COVID-19	CHICTR.org.in
27	NCT04395768	Hawthorn, Victoria, Australia	200 participants	IV vitamin C, Hydroxycholorquine, azithromycin, Zinc citrate, Vitamin D3, Vitamin B12 for treating COVID-19	Clinicaltrials.gov
28	NCT04334967	Portland, Oregon, United States	13 participants	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	Clinicaltrials.gov
29	NCT04354428	Various cities throughout the United States	630 participants	Trial arms: 1) Vit C plus folic acid 2) Hydroxychloroquine plus Folic Acid 3) Hydroxychloroquine and Azithromycin	Clinicaltrials.gov
30	NCT04401150	Sherbrooke, Quebec, Canada	800 participants	IV 50 mg/kg Vit C every 6 hours	Clinicaltrial.gov

Table 4 Ongoing clinical trials register for using Vitamin C alone or in combination with other drug for treatment of COVID-19 infections.

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