Vitamin A for COVID-19: real-time analysis of all 11 studies

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 (Peer Reviewed)

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 [1].

[1] 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.

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 B, C, D, E) - results of individual treatments may vary.

All-Trans Retinoic Acid Exhibits Antiviral Effect against SARS-CoV-2 by Inhibiting 3CLpro Activity

Morita et al., Viruses, doi:10.3390/v13081669 (Peer Reviewed) (In Vitro)

In Vitro and In Silico study showing that all-trans retinoic acid is a potent SARS-CoV-2 3CL^pro inhibitor, inhibits SARS-CoV-2 replication in VeroE6/TMPRSS2 cells, and is effective against alpha, beta, gamma, and delta variants in Calu-3 cells.

Morita et al., 8/23/2021, peer-reviewed, 9 authors.

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

Vitamin A Plasma Levels in COVID-19 Patients: A Prospective Multicenter Study and Hypothesis

Tepasse et al., Nutrients, doi:10.3390/nu13072173 (Peer Reviewed)

Prospective analysis of 40 hospitalized patients and 47 age-matched convalescent patients, showing significantly lower vitamin A levels in critical patients, and significantly lower vitamin A levels in hospitalized patients vs. controls. Low vitamin A levels were significantly associated with ARDS and mortality in hospitalized patients.

risk of death, 69.7% lower, RR 0.30, p = 0.04, treatment 4 of 29 (13.8%), control 5 of 11 (45.5%), NNT 3.2, OR converted to RR, >2mg/L, logistic regression.

risk of progression, 45.2% lower, RR 0.55, p = 0.05, treatment 13 of 29 (44.8%), control 9 of 11 (81.8%), NNT 2.7, OR converted to RR, progression to ARDS, >2mg/L, logistic regression.

Tepasse et al., 6/24/2021, prospective, Germany, Europe, peer-reviewed, 8 authors.

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

Holt et al., medRxiv, doi:10.1101/2021.03.27.21254452 (Preprint)

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. Results are subject to confounding, with only the vitamin D result fully adjusted. NCT04330599. COVIDENCE UK.

risk of case, 56.3% lower, RR 0.44, p = 0.41, treatment 1 of 91 (1.1%), control 445 of 15,136 (2.9%), NNT 54, 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, preprint, 31 authors, 1 May, 2020 - 5 February, 2021.

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 (Peer Reviewed)

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.

Retinol Depletion in Severe COVID-19

Sarohan et al., medRxiv, doi:10.1101/2021.01.30.21250844 (Preprint)

Retrospective 27 severe COVID-19 patients and 23 non-COVID-19 patients, showing signifcantly lower vitamin A levels in COVID-19 patients (0.37mg/L vs. 0.52 mg/L, p<0.001). 10 of 27 COVID-19 patients received vitamin A, with higher mortality. Group details are not provided but authors note that 8 of 10 had comorbidities.

risk of death, 282.5% higher, RR 3.83, p = 0.001, treatment 9 of 10 (90.0%), control 4 of 17 (23.5%).

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

Sarohan et al., 2/1/2021, retrospective, Turkey, Europe, preprint, 4 authors.

Therapeutic effect of vitamin A on COVID-19 patients and its prophylactic effect on contacts

Al-Sumiadai, Systematic Reviews in Pharmacy, 12:1 (Preprint)

Treatment and prophylaxis studies of vitamin A in Iraq.

The treatment study contained 100 patients, 50 treated with 200,000IU vitamin A for two days, showing lower progression to severe disease, and shorter duration of symptoms.

The prophylaxis study contained 209 contacts of COVID-19 patients, 97 treated with vitamin A, showing significantly lower cases with treatment, and shorter duration of symptoms.

risk of progression, 66.7% lower, RR 0.33, p = 0.27, treatment 2 of 50 (4.0%), control 6 of 50 (12.0%), NNT 13, progression to severe disease.

recovery time, 37.5% lower, relative time 0.62, treatment 50, control 50.

Al-Sumiadai et al., 1/31/2021, prospective, Iraq, Middle East, preprint, 3 authors.

Vitamin A in resistance to and recovery from infection: relevance to SARS-CoV2

Stephensen et al., British Journal of Nutrition, doi:10.1017/S0007114521000246 (Review) (Peer Reviewed)

Review of the potential benefits of vitamin A for COVID-19, including maintaining innate and adaptive immunity, minimizing inflammation, supporting repair of respiratory epithelium and preventing fibrosis, and counteracting adverse effects of SARS-CoV-2 on the angiotensin system.

Stephensen et al., 1/20/2021, peer-reviewed, 2 authors.

Therapeutic effect of Vitamin A on severe COVID-19 patients

Al-Sumiadai et al., EurAsian Journal of Biosciences, 14:7347-7350 (Peer Reviewed)

Retrospective 70 severe condition patients treated with vitamin A (200,000IU for two days), salbutamol, and budesonide, and 70 patients not treated with vitamin A, showing significantly lower mortality with the addition of vitamin A.

risk of death, 85.7% lower, RR 0.14, p = 0.002, treatment 2 of 70 (2.9%), control 14 of 70 (20.0%), NNT 5.8.

Excluded in after exclusion results of meta analysis: minimal details of groups provided.

Al-Sumiadai et al., 12/31/2020, retrospective, Iraq, Middle East, peer-reviewed, 3 authors.

Mega doses of retinol: A possible immunomodulation in Covid-19 illness in resource-limited settings

Midha et al., Reviews in Medical Virology, doi:10.1002/rmv.2204 (Review) (Peer Reviewed)

Review of the potential benefits of vitamin A for COVID-19, including the effect of vitamin A on ACE2 expression in the respiratory tract, potentially improving the generation of protective immune responses to vaccines, and dosage and safety analysis.

Midha et al., 12/31/2020, peer-reviewed, 4 authors.

Low Levels of Few Micronutrients May Impact COVID-19 Disease Progression: An Observational Study on the First Wave

Tomasa-Irriguible et al., Metabolites, doi:10.3390/metabo11090565 (preprint 10/26/2020) (Peer Reviewed)

Retrospective 120 hospitalized patients in Spain showing vitamin A deficiency associated with higher ICU admission.

risk of mechanical ventilation, 71.4% lower, RR 0.29, p = 0.001, treatment 4 of 34 (11.8%), control 48 of 86 (55.8%), NNT 2.3, adjusted, OR converted to RR, ≥0.3 mg/L, multivariate logistic regression.

risk of ICU admission, 61.3% lower, RR 0.39, p = 0.004, treatment 6 of 34 (17.6%), control 54 of 86 (62.8%), NNT 2.2, adjusted, OR converted to RR, ≥0.3 mg/L, multivariate logistic regression.

Tomasa-Irriguible et al., 10/26/2020, retrospective, Spain, Europe, peer-reviewed, 7 authors.

Revealing the targets and mechanisms of vitamin A in the treatment of COVID-19

Li et al., Aging, doi:10.18632/aging.103888 (Peer Reviewed)

Bioinformatics and network pharmacology analysis identifying potential mechanisms of action of vitamin A for COVID-19.

Li et al., 8/15/2020, peer-reviewed, 7 authors.

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

Vitamin A and D deficiencies in the prognosis of respiratory tract infections: A systematic review with perspectives for COVID-19 and a critical analysis on supplementation

Andrade et al., SciELO preprints, doi:10.1590/SciELOPreprints.839 (Review) (Peer Reviewed)

Systematic review showing deficiencies of vitamins A and D negatively affecting the prognosis of respiratory tract infections.

Andrade et al., 6/24/2020, peer-reviewed, 6 authors.

Antiandrogens	(meta)	Metformin	(meta)
Aspirin	(meta)	Molnupiravir	(meta)
Bamlanivimab	(meta)	Nigella Sativa	(meta)
Bromhexine	(meta)	Nitazoxanide	(meta)
Budesonide	(meta)	Paxlovid	(meta)
Casirivimab/i..	(meta)	Povidone-Iod..	(meta)
Colchicine	(meta)	Probiotics	(meta)
Conv. Plasma	(meta)	Proxalutamide	(meta)
Curcumin	(meta)	Quercetin	(meta)
Favipiravir	(meta)	Remdesivir	(meta)
Fluvoxamine	(meta)	Sotrovimab	(meta)
Hydroxychlor..	(meta)	Vitamin A	(meta)
Iota-carragee..	(meta)	Vitamin C	(meta)
Ivermectin	(meta)	Vitamin D	(meta)
Melatonin	(meta)	Zinc	(meta)

Other Treatments		Global Adoption