Vitamin C for COVID-19: real-time analysis of all 64 studies

Vitamin C for COVID-19: real-time meta analysis of 42 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvements are seen for mortality, ICU admission, progression, and recovery. 14 studies from 14 independent teams in 7 different countries show statistically significant improvements in isolation (7 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 18% [8‑27%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, and similar for peer-reviewed studies. Clinical outcomes suggest benefit while viral and case outcomes do not, consistent with an intervention that aids recovery but is not antiviral. Early treatment is more effective than late treatment.

• The treatment regimen varies widely across studies and may be high-dose IV vitamin C.

• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 2% of vitamin C studies show zero events in the treatment arm.

Multiple treatments are typically used in combination, and other treatments are significantly more effective.

• No treatment, vaccine, or intervention is 100% available and effective for all variants. All practical, effective, and safe means should be used. Denying the efficacy of treatments increases mortality, morbidity, collateral damage, and endemic risk.

• All data to reproduce this paper and sources are in the appendix.

Covid Analysis et al., 5/16/2022, preprint, 1 author.

Unravelling Vitamin B12 as a potential inhibitor against SARS-CoV-2: A computational approach

Pandya et al., Informatics in Medicine Unlocked, doi:10.1016/j.imu.2022.100951

In Silico study showing significant interaction with SARS-CoV-2 targets for multiple vitamins.

Pandya et al., 4/20/2022, peer-reviewed, 9 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

High-dose intravenous vitamin C decreases rates of mechanical ventilation and cardiac arrest in severe COVID-19

Hess et al., Internal and Emergency Medicine, doi:10.1007/s11739-022-02954-6

Retrospective 100 severe condition hospitalized patients in the USA, 25 treated with high dose IV vitamin C, showing lower mechanical ventilation and cardiac arrest, and increased length of survival with treatment. 3g IV vitamin C every 6h for 7 days.

risk of death, 20.0% lower, HR 0.80, p = 0.54, treatment 10 of 25 (40.0%), control 37 of 75 (49.3%), NNT 11, time to event analysis, inverse propensity weighting.

risk of mechanical ventilation, 39.5% lower, RR 0.60, p = 0.0499, treatment 18 of 25 (72.0%), control 54 of 75 (72.0%), OR converted to RR, inverse propensity weighting.

risk of mechanical ventilation, 50.0% lower, HR 0.50, p = 0.03, treatment 18 of 25 (72.0%), control 54 of 75 (72.0%), time to event analysis, inverse propensity weighting.

risk of ICU admission, 27.2% lower, RR 0.73, p = 0.10, treatment 22 of 25 (88.0%), control 63 of 75 (84.0%), OR converted to RR, inverse propensity weighting.

risk of ICU admission, 30.0% lower, HR 0.70, p = 0.19, treatment 22 of 25 (88.0%), control 63 of 75 (84.0%), time to event analysis, inverse propensity weighting.

Hess et al., 3/29/2022, retrospective, USA, North America, peer-reviewed, 9 authors, study period March 2020 - July 2020.

Pharmacologic Ascorbic Acid as Early Therapy for Hospitalized Patients with COVID-19: A Randomized Clinical Trial

Coppock et al., Life, doi:10.3390/life12030453

RCT with 66 very late stage (8 days from symptom onset) hospitalized patients, 44 treated with vitamin C and 22 control patients, showing no significant differences with treatment.

risk of progression, 5.0% lower, HR 0.95, p = 0.64, treatment 4 of 44 (9.1%), control 2 of 22 (9.1%), adjusted, within 36 hours.

risk of no improvement, 49.7% better, RR 0.50, p = 0.16, treatment 6 of 44 (13.6%), control 6 of 22 (27.3%), NNT 7.3, adjusted, OR converted to RR, within 36 hours.

risk of no hospital discharge, 22.5% lower, RR 0.78, p = 0.07, treatment 31 of 44 (70.5%), control 20 of 22 (90.9%), NNT 4.9, within 36 hours.

Coppock et al., 3/19/2022, Randomized Controlled Trial, USA, North America, peer-reviewed, 14 authors, average treatment delay 8.1 days.

Risk factors of death in mechanically ventilated COVID-19 patients: a retrospective multi-center study

Salehi et al., Research Square, doi:10.21203/rs.3.rs-1362678/v1 (Preprint)

Retrospective 125 mechanically ventilated ICU patients in Iran, showing no significant difference with vitamin C treatment in unadjusted results.

risk of death, 10.1% lower, RR 0.90, p = 0.56, treatment 22 of 40 (55.0%), control 52 of 85 (61.2%), NNT 16.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Salehi et al., 3/11/2022, retrospective, Iran, Middle East, preprint, mean age 62.0, 11 authors, study period April 2021 - September 2021.

Immune-boosting effect of natural remedies and supplements on progress of, and recovery from COVID-19 infection

Shehab et al., Tropical Journal of Pharmaceutical Research, doi:10.4314/tjpr.v21i2.13

Retrospective survey-based analysis of 349 COVID-19 patients, showing no significant difference with vitamin C prophylaxis in unadjusted analysis. REC/UG/2020/03.

risk of severe case, 4.3% lower, RR 0.96, p = 1.00, treatment 14 of 139 (10.1%), control 12 of 114 (10.5%), NNT 220, unadjusted, severe vs. mild cases.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Shehab et al., 2/28/2022, retrospective, multiple countries, multiple regions, peer-reviewed, survey, 7 authors, study period September 2020 - March 2021.

The impact of vitamin and mineral supplements usage prior to COVID-19 infection on disease severity and hospitalization

Nimer et al., Bosnian Journal of Basic Medical Sciences, doi:10.17305/bjbms.2021.7009

Retrospective survey based analysis of 2,148 COVID-19 recovered patients in Jordan, showing lower risk of severity and hospitalization with vitamin C prophylaxis, without statistical significance.

risk of hospitalization, 24.7% lower, RR 0.75, p = 0.08, treatment 52 of 651 (8.0%), control 167 of 1,497 (11.2%), NNT 32, adjusted, OR converted to RR, multivariable.

risk of severe case, 17.0% lower, RR 0.83, p = 0.18, treatment 66 of 651 (10.1%), control 194 of 1,497 (13.0%), NNT 35, adjusted, OR converted to RR, multivariable.

Nimer et al., 2/28/2022, retrospective, Jordan, Middle East, peer-reviewed, survey, 4 authors, study period March 2021 - July 2021.

“MATH+” Multi-Modal Hospital Treatment Protocol for COVID-19 Infection: Clinical and Scientific Rationale

Kory et al., Journal of Clinical Medicine Research, doi:10.14740/jocmr4658 (Review)

Review of the data supporting the MATH+ hospital treatment protocol for COVID-19.

Kory et al., 2/24/2022, peer-reviewed, 6 authors.

Effect of Vitamin C on Clinical Outcomes of Critically Ill Patients With COVID-19: An Observational Study and Subsequent Meta-Analysis

Gavrielatou et al., Frontiers in Medicine, doi:10.3389/fmed.2022.814587

Retrospective 113 consecutive mechanically ventilated COVID+ ICU patients in Greece, 10 receiving high dose IV vitamin C, showing lower mortality with treatment, without statistical significance (p=0.11).

The associated meta analysis includes only 11 studies, while there are currently 42 studies, 27 with mortality results. Authors only include critical patients, however not all studies with critical patients are included, for example [Hamidi-Alamdari, Majidi, Yüksel, Özgünay]. The meta analysis also uses unadjusted results, while PSM, Cox proportional hazards, or KM results are reported by [Al Sulaiman, Gao, Zhang, Zheng]. For [Zhang] authors use 28 day mortality, while the study reports longer term in-hospital mortality.

1. Al Sulaiman et al., Research Square, doi:10.21203/rs.3.rs-354711/v1, Ascorbic Acid as an Adjunctive Therapy in Critically Ill Patients with COVID-19: A Multicenter Propensity Score Matched Study, https://www.researchsquare.com/article/rs-354711/v1.

2. Gao et al., Aging, doi:10.18632/aging.202557, The efficiency and safety of high-dose vitamin C in patients with COVID-19: a retrospective cohort study, https://www.aging-us.com/article/202557/text.

3. Hamidi-Alamdari et al., Clinical and Translational Investigation, doi:10.24875/RIC.21000028, Methylene blue for treatment of hospitalized COVID-19 patients: a randomized, controlled, open-label clinical trial, phase 2, https://www.clinicalandtranslation..stigation.com/frame_esp.php?id=375.

4. Majidi et al., Frontiers in Immunology, doi:10.3389/fimmu.2021.717816, ``, https://www.frontiersin.org/articles/10.3389/fimmu.2021.717816/full.

5. Özgünay et al., The European Research Journal, doi:10.18621/eurj.938778, The use of vitamin C in the intensive care unit during the COVID-19 pandemic, https://dergipark.org.tr/en/download/article-file/1774154.

6. Yüksel et al., Intensive Care Medicine Experimental, 9:S1, 001458, doi:10.1186/s40635-021-00413-8, Effects of high dose vitamin c on patient outcomes in ARDS patients admitted to intensive care with COVID-19; multi-center retrospective study, https://icm-experimental.springero..pdf/10.1186/s40635-021-00413-8.pdf.

7. Zhang et al., Annals of Intensive Care, doi:10.1186/s13613-020-00792-3, Pilot Trial of High-dose vitamin C in critically ill COVID-19 patients (preprint 8/10/2020), https://annalsofintensivecare.spri..rticles/10.1186/s13613-020-00792-3.

8. Zheng et al., Open Medicine, doi:10.1515/med-2021-0361, No significant benefit of moderate-dose vitamin C on severe COVID-19 cases, https://www.degruyter.com/document/doi/10.1515/med-2021-0361/html.

risk of death, 58.0% lower, RR 0.42, p = 0.11, treatment 2 of 10 (20.0%), control 49 of 103 (47.6%), NNT 3.6.

Gavrielatou et al., 2/11/2022, retrospective, Greece, Europe, peer-reviewed, 10 authors, study period 21 October, 2020 - 8 March, 2021, average treatment delay 5.5 days.

The difference in the dietary inflammatory index, functional food, and antioxidants intake between COVID -19 patients and healthy persons

Mohajeri et al., Mediterranean Journal of Nutrition and Metabolism, doi:10.3233/MNM-211521

Retrospective dietary survey analysis of 500 COVID-19 patients and 500 healthy matched controls in Iran, showing dietary inflammatory index associated with increased risk of COVID-19. IR.ARUMS.REC.1400.008.

Mohajeri et al., 1/29/2022, retrospective, Iran, Middle East, preprint, 4 authors.

The difference in the dietary inflammatory index, functional food, and antioxidants intake between COVID -19 patients and healthy persons

Mohajeri et al., Mediterranean Journal of Nutrition and Metabolism, doi:10.3233/MNM-211521

Retrospective dietary survey analysis of 500 COVID-19 patients and 500 healthy matched controls in Iran, showing that COVID-19 patients had lower daily consumption of vitamin C, vitamin D, vitamin E, zinc, and selenium. IR.ARUMS.REC.1400.008.

Mohajeri et al., 1/29/2022, retrospective, Iran, Middle East, peer-reviewed, 4 authors.

Inhibitory effects of specific combination of natural compounds against SARS-CoV-2 and its Alpha, Beta, Gamma, Delta, Kappa, and Mu variants

Goc et al., European Journal of Microbiology and Immunology, doi:10.1556/1886.2021.00022 (In Vitro)

In Vitro study testing combinations of plant extracts and micronutrients with several variants of SARS-CoV-2. A combination of vitamin C, N-acetylcysteine, curcumin, quercetin, resveratrol, theaflavin, naringenin, baicalin, and broccoli extract showed the highest inhibition of RBD binding, and also decreased RdRp, furin, and cathepsin L activity.

Goc et al., 1/21/2022, peer-reviewed, 5 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Traditional Chinese medicine together with high-dose vitamin C improves the therapeutic effect of western medicine against COVID-19

Yang et al., Am. J. Transl. Res., 14:1

Prospective study of 60 patients in China with three arms: SOC, SOC+TCM, and SOC+TCM+high dose vitamin C, showing successively faster recovery with the addition of TCM and the addition of high dose vitamin C. TCM included low dose vitamin C. ChiCTR2000032717. IV vitamin C 10g/60kg twice a day, and oral vitamin C 3g three times a day.

recovery time, 15.4% lower, relative time 0.85, p = 0.15, treatment mean 13.45 (±3.11) n=10, control mean 15.89 (±4.06) n=10, severe patients, group C vs. group B.

recovery time, 14.6% lower, relative time 0.85, p = 0.02, treatment mean 7.0 (±0.94) n=10, control mean 8.2 (±1.14) n=10, non-severe patients, group C vs. group B.

time to viral-, 14.2% lower, relative time 0.86, p = 0.25, treatment mean 9.7 (±1.49) n=10, control mean 11.3 (±4.03) n=10, severe patients, group C vs. group B.

time to viral-, 19.0% lower, relative time 0.81, p = 0.02, treatment mean 5.1 (±0.95) n=10, control mean 6.3 (±1.06) n=10, non-severe patients, group C vs. group B.

Yang et al., 1/15/2022, Randomized Controlled Trial, China, Asia, peer-reviewed, 11 authors, study period 1 February, 2020 - 29 February, 2020.

Characteristics of the COVID-19 patients treated at Gulu Regional Referral Hospital, Northern Uganda: A cross-sectional study

Baguma et al., Research Square, doi:10.21203/rs.3.rs-1193578/v1 (Preprint)

Retrospective COVID+ hospitalized patients in Uganda, 385 patients receiving vitamin C treatment, showing higher mortality with treatment, without statistical significance.

risk of death, 48.5% higher, RR 1.48, p = 0.54, treatment 385, control 96, adjusted, OR converted to RR, multivariable, control prevalance approximated with overall prevalence.

Baguma et al., 12/28/2021, retrospective, Uganda, Africa, preprint, 16 authors, study period March 2020 - October 2021.

``

Majidi et al., Frontiers in Immunology, doi:10.3389/fimmu.2021.717816

RCT 100 ICU patients in Iran, 31 treated with vitamin C, showing lower mortality with treatment. IRCT20151226025699N5.

risk of death, 13.6% lower, RR 0.86, p = 0.03, treatment 26 of 31 (83.9%), control 67 of 69 (97.1%), NNT 7.6, day 28.

Majidi et al., 12/15/2021, Double Blind Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 16 authors, study period May 2020 - July 2020.

Vitamin C inhibits Angiotensin-Converting Enzyme-2 in Isolated Rat Aortic Ring

Amssayef et al., Cardiovascular & Hematological Disorders-Drug Targets, doi:10.2174/1871529X21666211214153308 (Ex Vivo)

Ex Vivo study showing vitamin C inhibiting vascular ACE2.

Amssayef et al., 12/14/2021, peer-reviewed, 3 authors.

Ex Vivo studies are an important part of preclinical research, however results may be very different in vivo.

Therapies to Prevent Progression of COVID-19, Including Hydroxychloroquine, Azithromycin, Zinc, and Vitamin D3 With or Without Intravenous Vitamin C: An International, Multicenter, Randomized Trial

Ried et al., Cureus, doi:10.7759/cureus.19902

RCT 237 patients in Turkey, 162 treated with IV vitamin C in addition to HCQ/AZ/zinc/vitamin D used for all patients, showing significantly faster recovery with the addition of IV vitamin C.

97% of patients were vitamin D deficient, and lower vitamin D levels were associated with ICU admission and longer hospital stay.

Only 1 of 237 hospitalized patients died (average age 63, range 22-99) - a 70-year-old patient with heart and lung disease and severely deficient vitamin D levels (6 nmol/L). IV vitamin C (sodium ascorbate) was given as 50 mg/kg every six hours on day 1, followed by 100 mg/kg every six hours (four times daily, 400 mg/kg/day) for seven days. ACTRN12620000557932.

risk of no recovery, 30.6% lower, RR 0.69, p = 0.008, treatment 69 of 162 (42.6%), control 46 of 75 (61.3%), NNT 5.3, day 15 mid-recovery.

Ried et al., 11/25/2021, Randomized Controlled Trial, Turkey, Europe, peer-reviewed, 3 authors, average treatment delay 4.0 days.

The effect of supplementation with vitamins A, B, C, D, and E on disease severity and inflammatory responses in patients with COVID-19: a randomized clinical trial

Beigmohammadi et al., Trials, doi:10.1186/s13063-021-05795-4

Small RCT 60 ICU patients in Iran, 30 treated with vitamins A, B, C, D, and E, showing significant improvement in SOFA score and several inflammatory markers at day 7 with treatment.

5,000 IU vitamin A daily, 600,000 IU vitamin D once, 300 IU of vitamin E twice a day, 500 mg vitamin C four times a day, and one ampule daily of B vitamins [thiamine nitrate 3.1 mg, sodium riboflavin phosphate 4.9 mg (corresponding to vitamin B2 3.6 mg), nicotinamide 40 mg, pyridoxine hydrochloride 4.9 mg (corresponding to vitamin B6 4.0 mg), sodium pantothenate 16.5 mg (corresponding to pantothenic acid 15 mg), sodium ascorbate 113 mg (corresponding to vitamin C 100 mg), biotin 60 μg, folic acid 400 μg, and cyanocobalamin 5 μg]. IRCT20200319046819N [irct.ir].

1. irct.ir, https://www.irct.ir/trial/46838.

risk of death, 88.9% lower, RR 0.11, p = 0.11, treatment 0 of 30 (0.0%), control 4 of 30 (13.3%), NNT 7.5, relative risk is not 0 because of continuity correction due to zero events.

risk of hospitalization >7 days, 41.0% lower, RR 0.59, p = 0.25, treatment 4 of 30 (13.3%), control 16 of 30 (53.3%), NNT 2.5, adjusted, OR converted to RR.

relative SOFA score @day 7, 45.5% better, RR 0.55, p < 0.001, treatment 30, control 30.

Excluded in meta analysis: combined treatments may contribute more to the effect seen.

Beigmohammadi et al., 11/14/2021, Single Blind Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 6 authors, this trial uses multiple treatments in the treatment arm (combined with vitamins A, B, D, E) - results of individual treatments may vary.

An investigation into the Effects of Intravenous Vitamin C on Pulmonary CT Findings and Clinical Outcomes of Patients with COVID 19 Pneumonia A Randomized Clinical Trial

Tehrani et al., Urology Journal, doi:10.22037/uj.v18i.6863

RCT 54 late stage patients, 18 treated with IV vitamin C (2g every 6h for 5 days), showing significant relative improvements in oxygen saturation and respiratory rate.

risk of death, 87.1% lower, RR 0.13, p = 0.13, treatment 0 of 18 (0.0%), control 4 of 26 (15.4%), NNT 6.5, relative risk is not 0 because of continuity correction due to zero events.

hospitalization time, 17.6% lower, relative time 0.82, p = 0.23, treatment 18, control 26.

Tehrani et al., 11/8/2021, Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 10 authors, average treatment delay 9.0 days.

Hepatic and gastrointestinal disturbances in Egyptian patients infected with coronavirus disease 2019: A multicentre cohort study

Shousha et al., World Journal of Gastroenterology, doi:10.3748/wjg.v27.i40.6951

Retrospective 547 hospitalized COVID+ patients in Egypt, showing lower mortality with vitamin C treatment. Treatment was applied according to the official guidelines, indicating that vitamin C was co-administered with HCQ. Actual treatment counts suggest that vitamin C treatment was typically co-administered with CQ or HCQ, with CQ being more common. The strong efficacy may be partly due to HCQ/CQ which may not be fully accounted for in analysis due to the split between HCQ/CQ and the use of HCQ/CQ without vitamin C for severe cases.

risk of death, 94.2% lower, RR 0.06, p = 0.003, treatment 22 of 340 (6.5%), control 31 of 207 (15.0%), adjusted, OR converted to RR, multivariable.

Shousha et al., 10/28/2021, retrospective, Egypt, Africa, peer-reviewed, 18 authors, study period 15 April, 2020 - 29 July, 2020.

Effect of a Nutritional Support System to Increase Survival and Reduce Mortality in Patients with COVID-19 in Stage III and Comorbidities: A Blinded Randomized Controlled Clinical Trial

Leal-Martínez et al., International Journal of Environmental Research and Public Health, doi:10.3390/ijerph19031172 (preprint 10/25/2021)

80 patient RCT with 40 patients treated with a comprehensive regimen of nutritional support, showing significantly lower mortality with treatment. Treatment contained cholecalciferol, vitamin C, zinc, spirulina maxima, folic acid, glutamine, vegetable protein, selenium, resveratrol, omega-3 fatty acids, l-arginine, magnesium, probiotics, and B-complex IV. Adherence was strictly monitored. NCT04507867.

risk of death, 85.7% lower, RR 0.14, p = 0.03, treatment 1 of 40 (2.5%), control 7 of 40 (17.5%), NNT 6.7.

risk of mechanical ventilation, 57.1% lower, RR 0.43, p = 0.31, treatment 3 of 40 (7.5%), control 7 of 40 (17.5%), NNT 10.0.

Excluded in after exclusion results of meta analysis: combined treatments may contribute more to the effect seen.

Leal-Martínez et al., 10/25/2021, Randomized Controlled Trial, Mexico, North America, peer-reviewed, 7 authors, study period 1 September, 2020 - 28 February, 2021, this trial uses multiple treatments in the treatment arm (combined with comprehensive nutritional support) - results of individual treatments may vary, trial NCT04507867.

Nutritional risk factors for SARS-CoV-2 infection: prospective study from the NutriNet-Santé cohort

Deschasaux-Tanguy et al., European Journal of Public Health, doi:10.1093/eurpub/ckab165.243

Analysis of 7,766 adults in France, showing higher intakes of vitamin C, folates, vitamin K, dietary fibre, and fruit and vegetables associated with a lower seroprevalence of anti-SARS-CoV-2 antibodies.

Deschasaux-Tanguy et al., 10/20/2021, peer-reviewed, 9 authors.

Effects of high dose vitamin C administration in Covid-19 patients

Simsek et al., Annals of Medical Research, doi:10.5455/annalsmedres.2020.10.1043

Retrospective 139 hospitalized patients in Turkey, 58 treated with high dose vitamin C, showing improved kidney functioning with treatment. Mortality was lower with treatment, but not reaching statistical significance with the small sample size.

risk of death, 44.1% lower, RR 0.56, p = 0.18, treatment 6 of 58 (10.3%), control 15 of 81 (18.5%), NNT 12.

risk of ICU admission, 10.2% lower, RR 0.90, p = 0.66, treatment 18 of 58 (31.0%), control 28 of 81 (34.6%), NNT 28.

Simsek et al., 9/27/2021, retrospective, Turkey, Europe, peer-reviewed, 16 authors.

No significant benefit of moderate-dose vitamin C on severe COVID-19 cases

Zheng et al., Open Medicine, doi:10.1515/med-2021-0361

Retrospective 397 severe COVID-19 patients in China, showing worse outcomes with vitamin C treatment, without statistical significance. IV vitamin C 2-4g/day. Subject to confounding by indication and immortal time bias. Exclusion criteria were (a) the duration of hospitalization was less than 3 days; (b) vitamin C treatment started before admission; and (c) the length of vitamin C use was less than 3 days. Includes vitamin C use started at any time during hospitalization, for many patients this was >15 days later (Figure A2). Duration of treatment varied widely (Figure A1). Treatment was determined by clinicians according to the condition of each patient.

risk of death, 157.0% higher, HR 2.57, p = 0.33, treatment 12 of 70 (17.1%), control 7 of 327 (2.1%), adjusted, propensity score matching.

risk of death, 169.0% higher, HR 2.69, p = 0.07, treatment 12 of 70 (17.1%), control 7 of 327 (2.1%), adjusted, IPTW.

clinical improvement ≥ 2 points, 35.1% worse, HR 1.35, p = 0.17, treatment 18 of 70 (25.7%), control 16 of 327 (4.9%), adjusted, propensity score matching.

clinical improvement ≥ 2 points, 31.6% worse, HR 1.32, p = 0.11, treatment 18 of 70 (25.7%), control 16 of 327 (4.9%), adjusted, IPTW.

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely, immortal time bias may significantly affect results, treatment start times unknown, treatment may not have started at baseline.

Zheng et al., 9/22/2021, retrospective, China, Asia, peer-reviewed, 10 authors, study period 13 February, 2020 - 29 February, 2020.

High-dose vitamin C ameliorates cardiac injury in COVID-19 pandemic: a retrospective cohort study

Xia et al., Aging, doi:10.18632/aging.203503

Retrospective 113 severe and critical patients in China with cardiac injury, 51 treated with high dose vitamin C, showing treatment associated with improvement of myocardial injury.

Xia et al., 9/7/2021, China, Asia, peer-reviewed, 5 authors.

Characterization of Critically Ill COVID-19 Patients at a Brooklyn Safety-Net Hospital

Capone et al., Cureus, doi:10.7759/cureus.9809

Retrospective 102 ICU patients in the USA, 73 receiving vitamin C and zinc, showing a negative correlation of treatment with mortality, but not reaching statistical significance (p = 0.31).

Capone et al., 8/17/2021, USA, North America, peer-reviewed, 11 authors.

Do body mass index (BMI) and history of nutritional supplementation play a role in the severity of COVID-19? A retrospective study

Mohseni et al., Nutrition & Food Science, doi:10.1108/NFS-11-2020-0421

Retrospective 603 patients in Iran, 34 taking vitamin C supplements, showing increased risk of COVID-19 cases in unadjusted results. IR.SHOUSHTAR.REC.1399.015.

risk of case, 44.2% higher, RR 1.44, p = 0.002, treatment 34 of 43 (79.1%), control 307 of 560 (54.8%).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Mohseni et al., 8/4/2021, retrospective, Iran, Middle East, peer-reviewed, 4 authors.

Efficacy of diammonium glycyrrhizinate combined with vitamin C for treating hospitalized COVID-19 patients: a retrospective, observational stud

Tan et al., QJM, doi:10.1093/qjmed/hcab184

PSM retrospective 207 hospitalized patients in China, 46 treated with diammonium glycyrrhizinate and vitamin C, showing lower risk of ARDS with treatment.

risk of death/intubation, 24.5% lower, RR 0.75, p = 0.74, treatment 1 of 46 (2.2%), control 14 of 115 (12.2%), NNT 10.0, OR converted to RR, primary outcome.

risk of ARDS, 73.3% lower, RR 0.27, p = 0.002, treatment 7 of 46 (15.2%), control 41 of 115 (35.7%), NNT 4.9, OR converted to RR.

Tan et al., 7/26/2021, retrospective, China, Asia, peer-reviewed, 7 authors, this trial uses multiple treatments in the treatment arm (combined with diammonium glycyrrhizinate) - results of individual treatments may vary.

Nutritional and lifestyle changes required for minimizing the recovery period in home quarantined COVID-19 patients of Punjab, Pakistan

Rabail et al., Food Science & Nutrition, doi:10.1002/fsn3.2458

Survey of 80 recovered COVID-19 patients in Pakistan, showing faster recovery with vitamin C, vitamin D, and zinc supplementation.

Rabail et al., 7/9/2021, Pakistan, South Asia, peer-reviewed, survey, 11 authors, study period November 2020 - February 2021.

20-Week Study of Clinical Outcomes of Over-the-Counter COVID-19 Prophylaxis and Treatment

Margolin et al., Journal of Evidence-Based Integrative Medicine, doi:10.1177/2515690X211026193

Retrospective 113 outpatients, 53 (patient choice) treated with zinc, quercetin, vitamin C/D/E, l-lysine, and quina, showing lower cases with treatment. Results are subject to selection bias and limited information on the groups is provided. See [journals.sagepub.com].

1. journals.sagepub.com, https://journals.sagepub.com/doi/full/10.1177/2515690X211058417.

risk of case, 94.4% lower, RR 0.06, p = 0.003, treatment 0 of 53 (0.0%), control 9 of 60 (15.0%), NNT 6.7, relative risk is not 0 because of continuity correction due to zero events.

risk of COVID-19 or flu-like illness, 81.1% lower, RR 0.19, p = 0.01, treatment 2 of 53 (3.8%), control 12 of 60 (20.0%), NNT 6.2.

Margolin et al., 7/6/2021, retrospective, USA, North America, peer-reviewed, 5 authors, this trial uses multiple treatments in the treatment arm (combined with zinc, quercetin, vitamin D/E, l-lysine, and quina) - results of individual treatments may vary.

The use of vitamin C in the intensive care unit during the COVID-19 pandemic

Özgünay et al., The European Research Journal, doi:10.18621/eurj.938778

Retrospective 160 ICU patients, 32 with raised neutrophil/lymphocyte ratio treated with vitamin C, showing no significant differences.

risk of death, 9.3% lower, RR 0.91, p = 0.69, treatment 17 of 32 (53.1%), control 75 of 128 (58.6%), NNT 18.

risk of mechanical ventilation, 1.1% higher, RR 1.01, p = 1.00, treatment 23 of 32 (71.9%), control 91 of 128 (71.1%).

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely.

Özgünay et al., 7/4/2021, retrospective, Turkey, Europe, peer-reviewed, 7 authors.

Role of high dose oral liposomal vitamin C in reducing mortality in patients with COVID-19

Vishnuram et al., Indian Journal of Basic and Applied Medical Research, doi:10.36848/IJBAMR/2020/29215.55599

Retrospective 8,634 hospitalized patients in India, showing lower mortality with high-dose vitamin C in unadjusted results. No group details are provided, the text and table appear to show different results, and some numbers do not match.

risk of death, 54.2% lower, RR 0.46, p = 0.03, treatment 164 of 8,634 (1.9%), control 10 of 241 (4.1%), NNT 44.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details, minimal details of groups provided.

Vishnuram et al., 6/30/2021, retrospective, India, South Asia, peer-reviewed, 5 authors.

Use of Intravenous Vitamin C in Critically Ill Patients With COVID-19 Infection

Li et al., Journal of Pharmacy Practice, doi:10.1177/08971900211015052

PSM retrospective 8 ICU patients treated with vitamin C and 24 matched controls, showing no significant difference. Authors note that "it is possible for the delayed timing of IV vitamin C to have blunted the beneficial effects as these patients may have already progressed to the late fibroproliferative phase or ARDS". IV vitamin C 1.5 grams every 6 hours.

risk of death, 10.5% higher, RR 1.11, p = 1.00, treatment 7 of 8 (87.5%), control 19 of 24 (79.2%), PSM.

Excluded in after exclusion results of meta analysis: very late stage, ICU patients.

Li et al., 6/8/2021, retrospective, propensity score matching, USA, North America, peer-reviewed, 6 authors.

Therapeutic potential of megadose vitamin C to reverse organ dysfunction in sepsis and COVID-19

May et al., British Journal of Pharmacology, doi:10.1111/bph.15579 (Review)

Review of data supporting the use of megadose vitamin C as a treatment for sepsis and COVID-19.

May et al., 6/1/2021, peer-reviewed, 3 authors.

Case Characteristics, Clinical Data, And Outcomes of Hospitalized COVID-19 Patients In Qom Province, Iran: A Prospective Cohort Study

Pourhoseingholi et al., Research Square, doi:10.21203/rs.3.rs-365321/v2 (Preprint)

Prospective study of 2,468 hospitalized COVID-19 patients in Iran, showing no significant difference with vitamin C treatment. IR.MUQ.REC.1399.013.

risk of death, 13.0% lower, HR 0.87, p = 0.38, treatment 54 of 199 (27.1%), control 285 of 2,269 (12.6%), adjusted, multivariable, Cox proportional hazards.

Pourhoseingholi et al., 5/26/2021, prospective, Iran, Middle East, preprint, mean age 57.9, 11 authors, study period 2 February, 2020 - 20 July, 2020, average treatment delay 7.4 days.

Effect of high-dose intravenous vitamin C on prognosis in patients with SARS-CoV-2 pneumonia

Suna et al., Med. Clin. (Barc.), doi:10.1016/j.medcli.2021.04.010

Retrospective 323 hospitalized patients, 153 treated with vitamin C, showing no significant differences. Patients in each group were in different time periods, with the vitamin C group first. Time based confounding is possible due to improvements in SOC.

risk of death, 21.3% lower, RR 0.79, p = 0.52, treatment 17 of 153 (11.1%), control 24 of 170 (14.1%), NNT 33.

risk of ICU admission, 1.9% higher, RR 1.02, p = 1.00, treatment 11 of 153 (7.2%), control 12 of 170 (7.1%).

Excluded in after exclusion results of meta analysis: substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.

Suna et al., 5/11/2021, retrospective, Turkey, Europe, peer-reviewed, 5 authors.

Vitamin C inhibits SARS coronavirus-2 main protease essential for viral replication

Malla et al., bioRxiv, doi:10.1101/2021.05.02.442358 (Preprint)

In Vitro study showing that vitamin C inhibits SARS-CoV-2 3CL^pro. Authors note that the different clinical results may be explained in part by the widely varying dosages used, and they conclude that vitamin C and/or derivatives may become an important treatment for COVID-19 and other viral infections.

Malla et al., 5/3/2021, preprint, 9 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Epidemiology, outcomes, and utilization of intensive care unit resources for critically ill COVID-19 patients in Libya: A prospective multi-center cohort study

Elhadi et al., PLOS ONE, doi:10.1371/journal.pone.0251085

Prospective study of 465 COVID-19 ICU patients in Libya showing no significant differences with treatment.

risk of death, 12.0% higher, RR 1.12, p = 0.15, treatment 175 of 277 (63.2%), control 106 of 188 (56.4%).

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Elhadi et al., 4/30/2021, prospective, Libya, Africa, peer-reviewed, 21 authors, study period 29 May, 2020 - 30 December, 2020.

High Dose Intravenous Vitamin C for Preventing The Disease Aggravation of Moderate COVID-19 Pneumonia. A Retrospective Propensity Matched Before-After Study

Zhao et al., Frontiers in Pharmacology, doi:10.3389/fphar.2021.638556

PSM retrospective 110 patients, 55 treated with high-dose IV vitamin C, showing lower progression to severe disease with treatment. Patients in each group were in different time periods, time based confounding is likely due to SOC improving over time. ChiCTR2000033050.

risk of progression, 72.0% lower, RR 0.28, p = 0.03, treatment 4 of 55 (7.3%), control 12 of 55 (21.8%), NNT 6.9, adjusted, PSM.

time to viral-, 7.7% higher, relative time 1.08, p = 0.79, treatment 55, control 55, PSM.

Excluded in after exclusion results of meta analysis: substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.

Zhao et al., 4/22/2021, retrospective, propensity score matching, China, Asia, peer-reviewed, 15 authors, average treatment delay 4.0 days.

The effect of vitamin E and vitamin C in patients with COVID-19 pneumonia; a randomized controlled clinical trial

Hakamifard et al., Immunopathologia Persa, doi:10.34172/ipp.2021.xx

RCT with 38 patients treated with vitamin C and vitamin E, and 34 control patients, showing lower ICU admission with treatment, but not statistically significant.

risk of ICU admission, 46.3% lower, RR 0.54, p = 0.46, treatment 3 of 38 (7.9%), control 5 of 34 (14.7%), NNT 15.

hospitalization time, 1.0% lower, relative time 0.99, p = 0.82, treatment 38, control 34.

Hakamifard et al., 4/14/2021, Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 8 authors, this trial uses multiple treatments in the treatment arm (combined with vitamin E) - results of individual treatments may vary.

COVID-19 severity in relation to sociodemographics and vitamin D use

Abdulateef et al., Open Medicine, doi:10.1515/med-2021-0273

Survey of 428 recovered COVID-19 patients in Iraq, showing fewer hospital visits for patients on prophylactic vitamin C or D. Hospitalization was lower for those on vitamin C, D, or zinc, without statistical significance.

risk of hospitalization, 18.7% lower, RR 0.81, p = 0.69, treatment 8 of 132 (6.1%), control 22 of 295 (7.5%), NNT 72, unadjusted.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Abdulateef et al., 4/8/2021, retrospective, Iraq, Middle East, peer-reviewed, 7 authors, study period July 2020 - August 2020.

Clinical characteristics of hospitalised patients with COVID-19 and the impact on mortality: a single-network, retrospective cohort study from Pennsylvania state

Gadhiya et al., BMJ Open, doi:10.1136/bmjopen-2020-042549

Retrospective 283 patients in the USA showing higher mortality with all treatments (not statistically significant). Confounding by indication is likely. In the supplementary appendix, authors note that the treatments were usually given for patients that required oxygen therapy. Oxygen therapy and ICU admission (possibly, the paper includes ICU admission for model 2 in some places but not others) were the only variables indicating severity used in adjustments.

risk of death, 0.7% higher, RR 1.01, p = 0.98, treatment 19 of 55 (34.5%), control 36 of 226 (15.9%), adjusted, OR converted to RR, multivariate logistic regression.

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely.

Gadhiya et al., 4/8/2021, retrospective, USA, North America, peer-reviewed, 4 authors.

3219 hospitalised patients with COVID-19 in Southeast Michigan: a retrospective case cohort study

Mulhem et al., BMJ Open, doi:10.1136/bmjopen-2020-042042

Retrospective database analysis of 3,219 hospitalized patients in the USA. Very different results in the time period analysis (Table S2), and results significantly different to other studies for the same medications (e.g., heparin OR 3.06 [2.44-3.83]) suggest significant confounding by indication and confounding by time.

risk of death, 32.2% higher, RR 1.32, p = 0.01, treatment 157 of 794 (19.8%), control 359 of 2,425 (14.8%), adjusted, OR converted to RR, logistic regression.

Excluded in after exclusion results of meta analysis: substantial unadjusted confounding by indication likely, substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.

Mulhem et al., 4/7/2021, retrospective, database analysis, USA, North America, peer-reviewed, 3 authors.

Ascorbic Acid as an Adjunctive Therapy in Critically Ill Patients with COVID-19: A Multicenter Propensity Score Matched Study

Al Sulaiman et al., Research Square, doi:10.21203/rs.3.rs-354711/v1 (Preprint)

Retrospective 158 critically ill patients receiving vitamin C and propensity matched controls, showing mortality OR 0.77 [0.48-1.23], and statistically significantly lower thrombosis, OR 0.42 [0.18-0.94]. 1000mg of vitamin C was given daily.

risk of death, 14.9% lower, RR 0.85, p = 0.27, treatment 46 of 142 (32.4%), control 59 of 142 (41.5%), NNT 11, OR converted to RR, PSM.

Al Sulaiman et al., 4/2/2021, retrospective, propensity score matching, Saudi Arabia, Middle East, preprint, 12 authors.

Risk factors for developing COVID-19: a population-based longitudinal study (COVIDENCE UK)

Holt et al., Thorax, doi:10.1136/thoraxjnl-2021-217487

Prospective survey-based study with 15,227 people in the UK, showing lower risk of COVID-19 cases with vitamin A, vitamin D, zinc, selenium, probiotics, and inhaled corticosteroids; and higher risk with metformin and vitamin C. Statistical significance was not reached for any of these. Except for vitamin D, the results for treatments we follow were only adjusted for age, sex, duration of participation, and test frequency. NCT04330599. COVIDENCE UK.

risk of case, 2.9% higher, RR 1.03, p = 0.86, treatment 49 of 1,580 (3.1%), control 397 of 13,647 (2.9%), adjusted, OR converted to RR, minimally adjusted, group sizes approximated.

Excluded in after exclusion results of meta analysis: significant unadjusted confounding possible.

Holt et al., 3/30/2021, prospective, United Kingdom, Europe, peer-reviewed, 34 authors, study period 1 May, 2020 - 5 February, 2021, trial NCT04330599.

Methylene blue for treatment of hospitalized COVID-19 patients: a randomized, controlled, open-label clinical trial, phase 2

Hamidi-Alamdari et al., Clinical and Translational Investigation, doi:10.24875/RIC.21000028

RCT 80 hospitalized patients with severe COVID-19, 40 treated with methylene blue + vitamin C + N-acetylcysteine, showing lower mortality, shorter hospitalization, and significantly improved SpO₂ and respiratory distress with treatment. NCT04370288.

risk of death, 44.4% lower, RR 0.56, p = 0.38, treatment 5 of 40 (12.5%), control 9 of 40 (22.5%), NNT 10.0.

hospitalization time, 37.6% lower, relative time 0.62, p = 0.004, treatment 40, control 40.

Hamidi-Alamdari et al., 3/8/2021, Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 23 authors, this trial uses multiple treatments in the treatment arm (combined with methylene blue and N-acetyl cysteine) - results of individual treatments may vary, trial NCT04370288.

Vitamin C may increase the recovery rate of outpatient cases of SARS-CoV-2 infection by 70%: reanalysis of the COVID A to Z Randomized Clinical Trial

Hemilä et al., Research Square, doi:10.21203/rs.3.rs-289381/v1 (Preprint) (meta analysis)

Reanalysis of Thomas et al. showing that vitamin C increased the recovery rate by 70%, p = 0.025.

Hemilä et al., 3/2/2021, preprint, 3 authors.

The efficiency and safety of high-dose vitamin C in patients with COVID-19: a retrospective cohort study

Gao et al., Aging, doi:10.18632/aging.202557

Retrospective 76 COVID-19 patients, 46 treated with intravenous high-dose vitamin C, showing lower mortality and improved oxygen requirements with treatment. Dosage was 6g intravenous infusion per 12hr on the first day, and 6g once for the following 4 days.

risk of death, 86.0% lower, HR 0.14, p = 0.04, treatment 1 of 46 (2.2%), control 5 of 30 (16.7%), NNT 6.9, adjusted, KM.

Gao et al., 2/26/2021, retrospective, China, Asia, peer-reviewed, 14 authors.

Seroprevalence of IgG against SARS-CoV-2 and its determinants among healthcare workers of a COVID-19 dedicated hospital of India

Mahto et al., American Journal of Blood Research, 11:1

Retrospective 689 healthcare workers in India, showing no significant difference in IgG positivity with vitamin C prophylaxis.

risk of IgG positive, 25.9% higher, RR 1.26, p = 0.49, treatment 34 of 140 (24.3%), control 59 of 549 (10.7%), adjusted, OR converted to RR, multivariable.

Mahto et al., 2/15/2021, retrospective, India, South Asia, peer-reviewed, 6 authors.

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

Thomas et al., JAMA Network Open, doi:10.1001/jamanetworkopen.2021.0369

Small 214 low-risk outpatient RCT showing non-statistically significant faster recovery with zinc and with vitamin C. NCT04342728. A secondary analysis concludes that vitamin C increases recovery rate by 71% (p = 0.036) [pubpeer.com]. See also [patrickholford.com].

1. patrickholford.com, https://www.patrickholford.com/blog/vitamin-c-speeds-up-covid-recovery.

2. pubpeer.com, https://pubpeer.com/publications/6DFC3BD2E1DAA79A9BBD1DAF5D9BB4#1.

risk of death, 204.2% higher, RR 3.04, p = 0.49, treatment 1 of 48 (2.1%), control 0 of 50 (0.0%), continuity correction due to zero event.

risk of hospitalization, 30.6% lower, RR 0.69, p = 1.00, treatment 2 of 48 (4.2%), control 3 of 50 (6.0%), NNT 55.

recovery time, 17.9% lower, relative time 0.82, p = 0.15, treatment mean 5.5 (±3.7) n=48, control mean 6.7 (±4.4) n=50, mean time to a 50% reduction in symptoms, primary outcome.

Thomas et al., 2/12/2021, Randomized Controlled Trial, USA, North America, peer-reviewed, 11 authors, trial NCT04342728.

Case Cluster of RT-PCR COVID-19 Positive Patients with an Unexpected Benign Clinical Course With Vitamin D, Melatonin, Vitamin C, and Viscum Album

Hancock et al., SSRN, doi:10.2139/ssrn.3779211 (Preprint)

Case series of 24 COVID-19 patients (12 confirmed PCR+) treated with vitamin D, vitamin C, and melatonin, showing positive outcomes with no patient having worse than a mild case, including 7 high risk patients.

Hancock et al., 2/9/2021, preprint, 4 authors.

Deficiency of antioxidants and increased oxidative stress in COVID-19 patients: A cross-sectional comparative study in Jigawa, Northwestern Nigeria

Muhammad et al., SAGE Open Medicine, doi:10.1177/2050312121991246

Case control study with 50 symptomatic COVID-19 patients and 21 healthy controls in Nigeria, showing that COVID-19 patients had significantly lower levels of selenium and zinc, and vitamins A, C, and E. Control patients were younger than COVID-19 patients. The p value for zinc in Table 2 appears to be a typo.

Muhammad et al., 2/1/2021, Nigeria, Africa, peer-reviewed, 8 authors.

Beneficial aspects of high dose intravenous vitamin C on patients with COVID-19 pneumonia in severe condition: a retrospective case series study

Zhao et al., Ann. Palliat. Med., doi:10.21037/apm-20-1387

Retrospective case study of 12 severe/critical COVID-19 patients finding that high dose IV vitamin C improved inflammatory response, immune and organ function. There was no control group.

Zhao et al., 2/1/2021, peer-reviewed, 14 authors.

Vitamin C supplementation is necessary for patients with coronavirus disease: An ultra-high-performance liquid chromatography-tandem mass spectrometry finding

Xing et al., Journal of Pharmaceutical and Biomedical Analysis, doi:10.1016/j.jpba.2021.113927

Prospective study with 31 COVID-19 patients and 60 controls reporting on a new method to assess plasma vitamin C concentrations. Vitamin C was deficient (11.4µmol/l vs. 52µmol/l for healthy controls), and returned to a normal range (76µmol/l) with intravenous vitamin C. Authors recommend high dose intravenous vitamin C for COVID-19 patients at a dose of 100mg/kg/day.

Xing et al., 1/27/2021, peer-reviewed, 13 authors.

Vitamin C and COVID-19

Hemilä et al., Frontiers in Medicine, doi:10.3389/fmed.2020.559811 (Review)

Review of the use of vitamin C for infections and the potential benefit for COVID-19.

Hemilä et al., 1/18/2021, peer-reviewed, 2 authors.

Safety and Effectiveness of High-Dose Vitamin C in Patients with COVID-19; A Randomized Controlled open-label Clinical Trial

JamaliMoghadamSiahkali et al., Research Square, doi:10.21203/rs.3.rs-139942/v1 (Preprint)

Small late stage RCT for the addition of vitamin C to HCQ and lopinavir/ritonavir, with 30 treatment and 30 control patients, finding a significant reduction in temperature and a significant improvement in oxygenation after 3 days in the vitamin C group. However, hospitalization time was longer and there was no significant difference in mortality.

risk of death, no change, RR 1.00, p = 1.00, treatment 3 of 30 (10.0%), control 3 of 30 (10.0%).

risk of mechanical ventilation, 25.0% higher, RR 1.25, p = 1.00, treatment 5 of 30 (16.7%), control 4 of 30 (13.3%).

hospitalization time, 30.8% higher, relative time 1.31, p = 0.03, treatment 30, control 30.

JamaliMoghadamSiahkali et al., 1/9/2021, Randomized Controlled Trial, Iran, Middle East, preprint, 17 authors.

Efficacy of High Dose Vitamin C, Melatonin and Zinc in Iranian Patients with Acute Respiratory Syndrome due to Coronavirus Infection: A Pilot Randomized Trial

Darban et al., Journal of Cellular & Molecular Anesthesia, doi:10.22037/jcma.v6i2.32182

Small RCT in Iran with 20 ICU patients, 10 treated with high-dose vitamin C, melatonin, and zinc, not showing significant differences. IRCT20151228025732N52.

risk of progression, 33.3% lower, RR 0.67, p = 1.00, treatment 2 of 10 (20.0%), control 3 of 10 (30.0%), NNT 10.

ICU time, 6.0% lower, relative time 0.94, p = 0.30, treatment 10, control 10.

Darban et al., 12/15/2020, Randomized Controlled Trial, Iran, Middle East, peer-reviewed, 8 authors, this trial uses multiple treatments in the treatment arm (combined with melatonin and zinc) - results of individual treatments may vary.

Risk Factors Associated With In-Hospital Mortality in a US National Sample of Patients With COVID-19

Rosenthal et al., JAMA Network Open, doi:10.1001/jamanetworkopen.2020.29058

Retrospective database analysis of 64,781 hospitalized patients in the USA, showing lower mortality with vitamin C or vitamin D (authors do not distinguish between the two), and higher mortality with zinc and HCQ, statistically significant for zinc. Authors excluded hospital-based outpatient visits, without explanation. Confounding by indication is likely, adjustments do not appear to include any information on COVID-19 severity at baseline.

risk of death, 11.0% lower, OR 0.89, p = 0.005, adjusted, vitamin C or vitamin D, multivariable, RR approximated with OR.

Excluded in meta analysis: results are only provided for use of one or more treatments within a class of treatments, results for each treatment are not provided, confounding by indication is likely and adjustments do not consider COVID-19 severity at baseline.

Rosenthal et al., 12/10/2020, retrospective, database analysis, USA, North America, peer-reviewed, 5 authors.

Vitamin C—An Adjunctive Therapy for Respiratory Infection, Sepsis and COVID-19

Holford et al., Nutrients, doi:10.3390/nu12123760 (Review)

Review of vitamin C use for respiratory infections including COVID-19 and the mechanisms of action. Authors note that evidence to date indicates oral vitamin C (2–8 g/day) may reduce the incidence and duration of respiratory infections, and intravenous vitamin C (6–24 g/day) has been shown to reduce mortality, intensive care unit (ICU) and hospital stays, and time on mechanical ventilation for severe respiratory infections. Authors conclude that given the favourable safety profile and low cost of vitamin C, and the frequency of vitamin C deficiency in respiratory infections, it may be worthwhile testing patients’ vitamin C status and treating them accordingly with intravenous administration within ICUs and oral administration in hospitalised COVID-19 patients.

Holford et al., 12/7/2020, peer-reviewed, 7 authors.

The Role of Vitamin C as Adjuvant Therapy in COVID-19

Kumari et al., Cureus 12(11): e11779, doi:10.7759/cureus.11779

RCT 150 hospitalized patients in Pakistan showing 26% faster recovery, p < 0.0001. 36% lower mortality, not statistically significant due to the small number of events. Dosage was 50 mg/kg/day of intravenous vitamin C.

risk of death, 36.4% lower, RR 0.64, p = 0.45, treatment 7 of 75 (9.3%), control 11 of 75 (14.7%), NNT 19.

risk of mechanical ventilation, 20.0% lower, RR 0.80, p = 0.67, treatment 12 of 75 (16.0%), control 15 of 75 (20.0%), NNT 25.

recovery time, 26.0% lower, relative time 0.74, p < 0.001, treatment 75, control 75, days to symptom-free.

hospitalization time, 24.3% lower, relative time 0.76, p < 0.001, treatment 75, control 75, days spent in hospital.

Kumari et al., 11/30/2020, Randomized Controlled Trial, Pakistan, South Asia, peer-reviewed, 10 authors.

Modest effects of dietary supplements during the COVID-19 pandemic: insights from 445 850 users of the COVID-19 Symptom Study app

Louca et al., BMJ Nutrition, Prevention & Health, doi:10.1136/bmjnph-2021-000250 (preprint 11/30/20)

Survey analysis of dietary supplements showing no significant difference in PCR+ cases with vitamin C usage in the UK, however significant reductions were found in the US and Sweden. These results are for PCR+ cases only, they do not reflect potential benefits for reducing the severity of cases. A number of biases could affect the results, for example users of the app may not be representative of the general population, and people experiencing symptoms may be more likely to install and use the app.

risk of case, no change, RR 1.00, p = 1.00, OR converted to RR, United Kingdom, all adjustment model.

Louca et al., 11/30/2020, retrospective, United Kingdom, Europe, peer-reviewed, 26 authors.

Role of ivermectin in the prevention of SARS-CoV-2 infection among healthcare workers in India: A matched case-control study

Behera et al., PLoS ONE, doi:10.1371/journal.pone.0247163 (preprint 11/3)

Retrospective matched case-control prophylaxis study for HCQ, ivermectin, and vitamin C with 372 healthcare workers, showing lower COVID-19 incidence for all treatments, with statistical significance reached for ivermectin.

HCQ OR 0.56, p = 0.29
Ivermectin OR 0.27, p < 0.001
Vitamin C OR 0.82, p = 0.58

risk of case, 18.0% lower, OR 0.82, p = 0.58, treatment 29 of 67 (43.3%) cases, 38 of 148 (25.7%) controls, adjusted, case control OR, model 2 conditional logistic regression.

risk of case, 29.0% lower, OR 0.71, p = 0.24, treatment 29 of 67 (43.3%) cases, 38 of 148 (25.7%) controls, adjusted, case control OR, matched pair analysis.

Behera et al., 11/3/2020, retrospective, India, South Asia, peer-reviewed, 13 authors.

The significance of oral ascorbic acid in patients with COVID-19

Patel et al., Chest Infections, doi:10.1016/j.chest.2020.08.322

Retrospective 176 hospitalized patients, 96 treated with oral vitamin C (from 500mg to 1500mg daily), showing lower mortality with treatment.

risk of death, 29.5% lower, RR 0.71, p = 0.18, treatment 22 of 96 (22.9%), control 26 of 80 (32.5%), NNT 10.

risk of death, 15.6% lower, RR 0.84, p = 0.60, treatment 15 of 30 (50.0%), control 16 of 27 (59.3%), NNT 11, ICU patients.

Patel et al., 10/1/2020, retrospective, USA, North America, peer-reviewed, 8 authors.

Effects of high dose vitamin c on patient outcomes in ARDS patients admitted to intensive care with COVID-19; multi-center retrospective study

Yüksel et al., Intensive Care Medicine Experimental, 9:S1, 001458, doi:10.1186/s40635-021-00413-8 (Preprint)

PSM retrospective 86 ICU patients on mechanical ventilation in Turkey, showing lower mortality with high dose vitamin C treatment (≥200mg/kg for 4 days).

risk of death, 18.8% lower, RR 0.81, p = 0.04, treatment 31 of 42 (73.8%), control 40 of 44 (90.9%), NNT 5.8, propensity score matching.

Yüksel et al., 9/20/2020, retrospective, Turkey, Europe, preprint, 13 authors.

Serum Levels of Vitamin C and Vitamin D in a Cohort of Critically Ill COVID-19 Patients of a North American Community Hospital Intensive Care Unit in May 2020: A Pilot Study

Arvinte et al., Med. Drug Discov, doi:10.1016/j.medidd.2020.100064

Pilot study with 21 ICU patients finding low serum levels of vitamin C and vitamin D in most patients. Older age and low vitamin C level appeared to be co-dependent risk factors for mortality.

Arvinte et al., 9/8/2020, peer-reviewed, 3 authors.

Vitamin C levels in patients with SARS-CoV-2-associated acute respiratory distress syndrome

Chiscano-Camón et al., Critical Care, doi:10.1186/s13054-020-03249-y

Small study of 18 COVID-19 ARDS patients showing that vitamin C levels were very low - 17 patients had undetectable levels and one had a low level (2.4 mg/L).

Chiscano-Camón et al., 8/26/2020, peer-reviewed, mean age 59.0, 5 authors.

Pilot Trial of High-dose vitamin C in critically ill COVID-19 patients (preprint 8/10/2020)

Zhang et al., Annals of Intensive Care, doi:10.1186/s13613-020-00792-3

Small RCT for high dose vitamin C for ICU patients showing reduced (but not statistically significant) mortality. Dosage was 12g of vitamin C/50ml every 12 hours for 7 days at a rate of 12ml/hour.

risk of death, 50.0% lower, RR 0.50, p = 0.20, treatment 6 of 27 (22.2%), control 11 of 29 (37.9%), NNT 6.4, adjusted, ICU mortality.

risk of death, 80.0% lower, RR 0.20, p = 0.04, treatment 5 of 27 (18.5%), control 11 of 29 (37.9%), NNT 5.2, adjusted, ICU mortality for SOFA>=3.

risk of death, 50.0% lower, RR 0.50, p = 0.31, treatment 6 of 27 (22.2%), control 10 of 29 (34.5%), NNT 8.2, adjusted, 28 day mortality.

risk of death, 70.0% lower, RR 0.30, p = 0.07, treatment 5 of 27 (18.5%), control 10 of 29 (34.5%), NNT 6.3, adjusted, 28 day mortality for SOFA>=3.

Zhang et al., 8/10/2020, Randomized Controlled Trial, China, Asia, peer-reviewed, 11 authors.

The use of IV vitamin C for patients with COVID-19: a case series

Hiedra et al., Expert Review of Anti-infective Therapy, doi:10.1080/14787210.2020.1794819

Case study of 17 patients receiving IV vitamin C for COVID-19, finding a significant decrease in inflammatory markers, including ferritin and D-dimer, and a trend to decreasing FiO₂ requirements, after vitamin C administration. There was no control group.

Hiedra et al., 8/1/2020, peer-reviewed, 8 authors.

Vitamin C as prophylaxis and adjunctive medical treatment for COVID-19?

Feyaerts et al., Nutrition, doi:10.1016/j.nut.2020.110948 (Review)

Review concluding that there is clear evidence that vitamin C in high doses can reduce interleukin-6 and endothelin-1 mediators. Authors suggest a relatively low dose as prophylaxis, and in cases of severe COVID-19, an (intravenous) high-dose regimen may be beneficial.

Feyaerts et al., 7/25/2020, peer-reviewed, 2 authors.

Clinical comorbidities, characteristics, and outcomes of mechanically ventilated patients in the State of Michigan with SARS-CoV-2 pneumonia

Krishnan et al., J Clin Anesth., doi:10.1016/j.jclinane.2020.110005

Retrospective 152 mechanically ventilated patients in the USA showing unadjusted lower mortality with vitamin C, vitamin D, HCQ, and zinc treatment, statistically significant only for vitamin C.

risk of death, 30.7% lower, RR 0.69, p = 0.04, treatment 40 of 79 (50.6%), control 52 of 73 (71.2%), NNT 4.9, OR converted to RR.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Krishnan et al., 7/20/2020, retrospective, USA, North America, peer-reviewed, 13 authors.

Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19)

Biancatelli et al., Frontiers in Immunology, doi:10.3389/fimmu.2020.01451 (Review)

Review of the evidence for the use of vitamin C and quercetin both for prophylaxis in high-risk populations and for the treatment of COVID-19 patients.

Biancatelli et al., 6/19/2020, peer-reviewed, 4 authors.

In silico virtual screening-based study of nutraceuticals predicts the therapeutic potentials of folic acid and its derivatives against COVID-19

Kumar et al., VirusDisease, doi:10.1007/s13337-020-00643-6 (preprint 5/27)

In Silico analysis finding that magnesium ascorbate, a form of Vitamin C, was found to be the top compound among 106 nutraceuticals for binding to M^pro of SARS-CoV-2.

Kumar et al., 5/27/2020, peer-reviewed, 3 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Antiandrogens	(meta)	Melatonin	(meta)
Aspirin	(meta)	Metformin	(meta)
Bamlaniv../e..	(meta)	Molnupiravir	(meta)
Bebtelovimab	(meta)	N-acetylcys..	(meta)
Bromhexine	(meta)	Nigella Sativa	(meta)
Budesonide	(meta)	Nitazoxanide	(meta)
Cannabidiol	(meta)	Paxlovid	(meta)
Casirivimab/i..	(meta)	Peg.. Lambda	(meta)
Colchicine	(meta)	Povidone-Iod..	(meta)
Conv. Plasma	(meta)	Probiotics	(meta)
Curcumin	(meta)	Proxalutamide	(meta)
Diet	(meta)	Quercetin	(meta)
Ensovibep	(meta)	Remdesivir	(meta)
Exercise	(meta)	Sleep	(meta)
Famotidine	(meta)	Sotrovimab	(meta)
Favipiravir	(meta)	Tixagev../c..	(meta)
Fluvoxamine	(meta)	Vitamin A	(meta)
Hydroxychlor..	(meta)	Vitamin C	(meta)
Iota-carragee..	(meta)	Vitamin D	(meta)
Ivermectin	(meta)	Zinc	(meta)
Lactoferrin	(meta)

Other Treatments		Global Adoption