Does vitamin D supplementation have a role in COVID-19?
A striking observation about COVID-19 is the greater severity among different populations. Indeed, statistics show that older age, non-Caucasian individuals, male gender, obesity and patients with multiple comorbidities have poorer outcomes. Moreover, most respiratory viruses peak during winter. Vitamin D deficiency, which is more prevalent in all these conditions, has become a unifying hypothesis as a mediator of poorer outcomes. Thus, its repletion could be interesting for COVID-19 patients.
- Vitamin D has multiple extraskeletal roles including the modulation of innate and adaptive immune response. While boosting mucosal defenses, it also limits excessive inflammatory process.1-3
- In a large review and meta-analysis of randomised controlled trials (RCTs), daily or weekly vitamin D supplements was safe and reduced the risk of acute respiratory infections overall, especially among patients having very deficient baseline 25-OH-vitamin-D levels (< 25 nmol/L).
- Subgroup analyses found a reduced rate of asthma exacerbation requiring systemic corticosteroids.
- Repletion of vitamin D deficient patients offered a strong protection against chronic obstructive pulmonary disease (COPD) exacerbations requiring antibiotics and/or systemic corticosteroids.
- The preventive effect of vitamin D against influenza is still controversial, deserving further investigation. The present literature suggests that the vitamin D dose-effect relationship is probably not linear, and future studies could focus on treatment of vitamin D deficient patients only.1
- In a large RCT, early administration of a single high-dose vitamin D3 (540 000 IU) in vitamin D-depleted patients did not reduce 90-day mortality in patients admitted in the intensive care unit (ICU) for pathologies with risk factors for death or lung injury.5
During COVID-19 outbreak
- Most countries that lie above 35o North latitude show higher mortality, and this is the latitude at which sunlight during winter does not provide enough UVB for vitamin D synthesis by skin.
- Moderate negative correlations have been found between mean levels of vitamin D in a country and its number of cases of COVID-19, as well as the number of deaths caused by COVID-19.7
- A recent study showed that lower 25-OH-Vitamin D levels predicted higher COVID-19 infection rate but these findings were not significant when adjusted for potential confounding factors (male sex, socioeconomic level, self-reported health status, age, obesity, non-white ethnicity).8
In conclusion, there is a rationale behind the protective effect of vitamin D in preventing cytokine storm in acute infections. It is still unclear if vitamin D deficiency is a distinct mediator for poorer outcomes. Low-dose vitamin D supplementation (ex. 1000 IU-4000 IU/day3) in depleted patients is safe and its role to reduce mortality in COVID-19 is worth investigating in a dedicated RCT.
This data comes from analysis of multiple publications consisting of epidemiologic studies, editorials, reviews ± meta-analysis, in vivo experimental studies and RCTs.
- Gruber-Bzura, B. M. (2018). Vitamin D and Influenza-Prevention or Therapy? International Journal of Molecular Sciences, 19(8). https://doi.org/10.3390/ijms19082419
Review of studies from 2010-2018, examining the role of vitamin D in the prevention and treatment of Influenza infection.
2. Hansdottir, S., Monick, M. M., Lovan, N., et al. (2010). Vitamin D decreases respiratory syncytial virus induction of NF-kappaB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state. Journal of Immunology, 184(2), 965-974. https://doi.org/10.4049/jimmunol.0902840
In vivo experimental study, examining the effect (regarding NF-κB signalling pathway) of vitamin D on respiratory syncytial virus-infected human airway epithelial cells.
3. Marik, P. E., Kory, P., & Varon, J. (2020). Does vitamin D status impact mortality from SARS-CoV-2 infection? Med Drug Discov, 100041. https://doi.org/10.1016/j.medidd.2020.100041
Study that assessed associations between the case fatality rate for each of the 50 states of United States of America and their latitude (30o South to 50o North).
4. Martineau, A. R., Jolliffe, D. A., Greenberg, L., et al. (2019). Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis. Health Technology Assessment, 23(2), 1-44. https://doi.org/10.3310/hta23020
Meta-analysis of 25 RCTs of high quality about supplementation with vitamin D on acute respiratory infection.
5. Ginde, A. A., Brower, R. G., Caterino, J. M., et al. (2019). Early High-Dose Vitamin D3 for Critically Ill, Vitamin D-Deficient Patients. New England Journal of Medicine, 381(26), 2529-2540. https://doi.org/10.1056/NEJMoa1911124
Multicenter, double blind, placebo-controlled phase 3 RCT that studied the effect of a single high-dose vitamin D administration on adverse outcomes among 1360 vitamin-D-depleted ICU patients.
6. Rhodes, J. M., Subramanian, S., Laird, E., & Kenny, R. A. (2020). Editorial: low population mortality from COVID-19 in countries south of latitude 35 degrees North supports vitamin D as a factor determining severity. Alimentary Pharmacology and Therapeutics. https://doi.org/10.1111/apt.15777
Editorial that plotted the mortality of COVID-19 in the world against latitude in all countries that had more than 150 cases.
7. Ilie, P. C., Stefanescu, S., & Smith, L. (2020). The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clinical and Experimental Research. https://doi.org/10.1007/s40520-020-01570-8
Epidemiologic study that assessed the associations between the mean levels of vitamin D in various European countries and the mortality and number of cases of COVID-19.
8. Hastie, C. E., Mackay, D. F., Ho, F., et al. (2020). Vitamin D concentrations and COVID-19 infection in UK Biobank. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. https://doi.org/10.1016/j.dsx.2020.04.050
Cohort study that examined univariate and multivariate regression analyses between 25-OH-Vitamin D levels collected from UK Biobank (2006-2010) and COVID-19 test results. Its main objective was to find out whether vitamin D deficiency explained the higher incidence of COVID-19 in black and South Asian people.