Vitamin A for COVID-19: real-time analysis of all 21 studies

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

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvements are seen for recovery, cases, and viral clearance. 4 studies from 3 independent teams in 3 different countries show statistically significant improvements in isolation (2 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 50% [-9‑77%] improvement, without reaching statistical significance. Results are better for Randomized Controlled Trials, similar after exclusions, and better for peer-reviewed studies. Results are consistent with early treatment being more effective than late treatment.

• Sufficiency studies, analyzing outcomes based on serum levels, show 73% [51‑85%] improvement for patients with higher vitamin A levels (3 studies).

• While many treatments have some level of efficacy, they do not replace vaccines and other measures to avoid infection. Only 25% of vitamin A studies show zero events in the treatment arm. Multiple treatments are typically used in combination, and other treatments may be 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., 8/12/2022, preprint, 1 author.

A Retinol Derivative Inhibits SARS-CoV-2 Infection by Interrupting Spike-Mediated Cellular Entry

Tong et al., mBio, doi:10.1128/mbio.01485-22 (In Vitro)

In Vitro study showing all-trans retinoic acid, a vitamin A derivative, has potent antiviral activity against SARS-CoV-2 in both human cell lines and human organoids of the lower respiratory tract.

Tong et al., 7/13/2022, China, peer-reviewed, 14 authors.

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

In-silico screening and in-vitro assay show the antiviral effect of Indomethacin against SARS-CoV-2

Chakraborty et al., Computers in Biology and Medicine, doi:10.1016/j.compbiomed.2022.105788

In Silico study predicting indomethacin and vitamin A can bind critical host and viral proteins for SARS-CoV-2 interaction, and may be able to compensate for gene expressions changes related to SARS-CoV-2.

Chakraborty et al., 6/30/2022, peer-reviewed, 11 authors.

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

Retinol Depletion in COVID-19

RodanSarohan et al., Clinical Nutrition Open Science, doi:10.1016/j.nutos.2022.05.007

Comparison of 27 COVID-19 ICU patients and 23 control patients, showing significantly lower vitamin A levels in COVID-19 patients.

RodanSarohan et al., 5/28/2022, retrospective, Turkey, peer-reviewed, 5 authors.

Suboptimal Consumption of Relevant Immune System Micronutrients Is Associated with a Worse Impact of COVID-19 in Spanish Populations

Galmés et al., Nutrients, doi:10.3390/nu14112254

Ecological study in Spain, showing lower intake of vitamin D, A, B9, and zinc in regions with the highest COVID-19 incidence and mortality.

Vitamin D intake was associated with lower prevalence, incidence, and a combined incidence+mortality index. Vitamin A intake was correlated with lower incidence, ∆incidence, and combined incidence+mortality, while not reaching statistical significance (p = 0.09, 0.07, 0.06). Vitamin B9, B12, and zinc were associated with lower ∆incidence.

Authors analyze 10 vitamins and minerals endorsed by the European Food Safety Authority (EFSA) as having sufficient evidence for a causal relationship between intake and optimal immune system function: vitamins D, A, C, B6, B9, B12, zinc, copper, iron, and selenium.

The intake of all 10 showed an inverse correlation with ∆incidence and combined incidence+mortality (statistically significant only as shown).

Galmés et al., 5/27/2022, Spain, peer-reviewed, 3 authors.

Significantly Reduced Retinol Binding Protein 4 (RBP4) Levels in Critically Ill COVID-19 Patientshttps://www.mdpi.com/2072-6643/14/10/2007

Vollenberg et al., Nutrients, doi:10.3390/nu14102007

Prospective study of 59 hospitalized COVID-19 patients and 20 matched convalescent control patients in Germany, showing significantly lower vitamin A levels in COVID-19 patients.

Vollenberg et al., 5/10/2022, prospective, Germany, peer-reviewed, 4 authors.

Prevalence of Micronutrient Deficiencies in Patients Hospitalized with COVID-19: An Observational Cohort Study

Voelkle et al., Nutrients, doi:10.3390/nu14091862

Prospective study of 57 consecutive hospitalized COVID-19 patients in Switzerland, showing higher risk of mortality/ICU admission with vitamin A, vitamin D, and zinc deficiency, with statistical significance only for vitamin A and zinc. Adjustments only considered age.

risk of death/ICU, 76.2% lower, RR 0.24, p = 0.004, treatment 4 of 35 (11.4%), control 11 of 22 (50.0%), NNT 2.6, adjusted, OR converted to RR.

Voelkle et al., 4/30/2022, prospective, Switzerland, peer-reviewed, median age 67.0, 9 authors, study period 17 March, 2020 - 30 April, 2020.

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.

Micronutrient Improvement of Epithelial Barrier Function in Various Disease States: A Case for Adjuvant Therapy

DiGuilio et al., International Journal of Molecular Sciences, doi:10.3390/ijms23062995 (Review)

Review of epithelial and endothelial barrier compromise and associated disease risk including COVID-19, and the potential benefits of vitamin A, vitamin D, and zinc for improving barrier function.

DiGuilio et al., 3/10/2022, peer-reviewed, 8 authors.

13 cis retinoic acid improved the outcomes of COVID-19 patients. A randomized clinical trial

Elkazzaz et al., medRxiv, doi:10.1101/2022.03.05.22271959 (Preprint)

RCT with 20 13-cis-retinoic acid patients and 20 control patients, showing faster recovery and viral clearance with treatment. Aerosolized 13-cis-retinoic acid with increasing dose from 0.2 mg/kg/day to 4 mg/kg/day for 14 days, plus oral 13-cis-retinoic acid 20 mg/day. 13-cis retinoic acid is a synthetic vitamin A derivative, and is teratogenic. NCT04353180.

risk of death, 85.7% lower, RR 0.14, p = 0.23, treatment 0 of 20 (0.0%), control 3 of 20 (15.0%), NNT 6.7, relative risk is not 0 because of continuity correction due to zero events.

risk of ICU admission, 66.7% lower, RR 0.33, p = 0.24, treatment 2 of 20 (10.0%), control 6 of 20 (30.0%), NNT 5.0.

recovery time, 35.4% lower, relative time 0.65, p < 0.001, treatment mean 16.3 (±4.5) n=20, control mean 25.23 (±4.72) n=20.

time to viral-, 44.0% lower, relative time 0.56, p < 0.001, treatment mean 13.36 (±1.49) n=20, control mean 23.85 (±4.0) n=20.

Elkazzaz et al., 3/8/2022, Randomized Controlled Trial, Egypt, preprint, 4 authors, study period June 2020 - August 2020, trial NCT04353180 (history).

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 no significant differences in the risk of severity and hospitalization with vitamin A prophylaxis.

risk of hospitalization, 21.2% lower, RR 0.79, p = 0.40, treatment 15 of 144 (10.4%), control 204 of 2,004 (10.2%), adjusted, OR converted to RR, multivariable.

risk of severe case, 20.8% lower, RR 0.79, p = 0.36, treatment 17 of 144 (11.8%), control 243 of 2,004 (12.1%), adjusted, OR converted to RR, multivariable.

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

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.

Beigmohammadi et al., 11/14/2021, Single Blind Randomized Controlled Trial, Iran, 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 (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

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 = 0.048, 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, peer-reviewed, 8 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, 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, peer-reviewed, 34 authors, study period 1 May, 2020 - 5 February, 2021, trial NCT04330599 (history) (COVIDENCE UK).

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, 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, 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, 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)

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

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, 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)

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)

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, peer-reviewed, 7 authors.

Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework

Galmés et al., Nutrients, doi:10.3390/nu12092738

Ecological study of European countries analyzing 10 vitamins and minerals endorsed by the European Food Safety Authority as having sufficient evidence for a causal relationship between intake and optimal immune system function: vitamins D, A, C, B6, B9, B12, zinc, copper, iron, and selenium.

Intake levels of all 10 showed an inverse correlation with the relative mortality rate, while all except vitamin B6 and selenium showed an inverse correlation with incidence and mortality. Most individual correlations did not reach statistical significance. Authors note greater association in populations genetically predisposed towards lower micronutrient status.

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

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

Li et al., Aging, doi:10.18632/aging.103888

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)

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)	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)	Nitric Oxide	(meta)
Casirivimab/i..	(meta)	Paxlovid	(meta)
Colchicine	(meta)	Peg.. Lambda	(meta)
Conv. Plasma	(meta)	Povidone-Iod..	(meta)
Curcumin	(meta)	Probiotics	(meta)
Diet	(meta)	Proxalutamide	(meta)
Ensitrelvir	(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