There is no miracle cure against COVID. The world had high hopes for drugs like remdesivir, favipiravir, ivermectine, and many others, but their effectiveness is limited or non-existent. There was more success with anti-inflamatory corticosteroids in later stages of the disease. Injected vaccines remain recommended to prevent either infection or worsening disease, yet it is hard to find an overview of their effectiveness on multiple outcomes and for various strains, as the effects of boosters on preventions may be short-lived, and the absolute risk reduction on hospitalisations is very limited. Sadly, outside of zero-COVID policies and border controls as in China, or Australia and New-Zealand, where the measure has been lifted, no NPI proves very effective. In Japan, for instance, similar rates of hospital admissions are observed compared to the west, despite more compliance with mask wearing.
From the onset of the epidemic, seasonality has been expected and linked to climatological aspects affecting the biology of either the virus (e.g. survival time in the air or on surfaces, dilution through ventilation) or the host (e.g. cyclical human susceptibility). As sunshine leads to the production of vitamin D in humans, its role in regulating the immune system, rather than in calcium uptake only, has been much discussed. Observational data has suggested a correlation between vitamin D deficiency and disease severity, which was also reflected in the increased risk for severe disease for dark-skinned people with low sun exposure (e.g. people from African descent in northern countries). Finally, we see alternating waves between the northern and the southern hemisphere.
However, the initial data was only suggestive. It may be that the same people who have vitamin D deficiency have a worse overall health and worse COVID outcomes - this is called a pseudo-correlation. It may also be that COVID lowers vitamin D levels to establish a relationship that was thought to causally run the other way. Further more, there are many possible confounders, for instance when poorer demographies turned out to be more at risk: it may be the effect of poverty and social exclusion on health, treatment inequality, characteristics of neighbourhoods, dwellings, or social interaction, etc. Finally, vitamins do not work on their own: with UV and IR exposure also comes (beneficial) melatonine production, with eating fruit comes fibers leading to a healthy state of the gut, and vitamins as well as minerals interact. We may observe a negative effect between vitamin D levels in the blood and disease severity, but that does not mean that supplementing vitamin D will work. This has lead to deception in the past, when vitamin C was hyped as a panacea, leading to scepsis around vitamins in general. Still, vitamin C is used in the treatment of sepsis (pun intended) and there is some effect in shortening a common cold. At the same time, it doesn't make you invincible and it doesn't take away the need for a healthy lifestyle and balanced diet. Any reductionism should be avoided. This should go without saying, but in 2022 nothing is obvious.
Yet two years down the road, it is no longer a matter of needing more research, but rather of consulting the research that has accumulated at this point. While modalities may be specific, for instance: what type of vitamin D can be administered, at what dose, to solve what degree of deficiency, at what time of the year and whether to prevent or to cure, my take on the matter is that vitamin D should become part of health policy to get thought he pandemic and minimise public health damage and costs.
Below are nine studies published in 2022, including meta-analyses, that were retrieved by searching Google Scholar articles for the query "vitamin D COVID". Skimming through the abstracts and conclusions, the clearest take-aways have been highlighted. Statistical results were left out. In general, odds ratios are rather promising: I would interpret them as on par with vaccine boosters and probably complementary. Nevertheless, high risks for biases were mentioned, which perhaps is unavoidable and not unlike other current research on COVID medicine.
Disclaimer: this is not medical advice to the population or any individual. It is an advice to policy makers to reconsider large scale interventions to monitor or administer vitamin D in the population, based on the research that is available.
Edit (7/10/2022): although the Google Scholar search reported below used a neutral query ("vitamin D COVID", not "vitamin D beneficial effects on COVID"), there may be a publication bias or studies that are cited more often may appear higher up in the search results. I don't know what algorithm is used. The studies I found point to beneficial effects, even if the types of outcome and intervention vary. This is why my call is to zoom in on what works (and for who) and what doesn't. There are always more sceptical minds that will highlight research to the contrary. This may be biased as well ("the moon doesn't exist, because I saw no moon last night"). Nevertheless, it is a body of research that should be contrasted with studies showing or suggesting beneficial effects, and it probably does tell us that the popular over the counter medicine does not work wonders.
On a personal note, I am very much in favour of vitamin D, not because it makes me invincible, but because it restores my sense of smell (albeit just for a day). Anyway, by all means check out the evidence of absence of an effect reported here: https://www.mcgill.ca/oss/article/covid-19-medical/vitamin-d-no-cure-covid.
Edit (2/2/2023): dr. John Campbell (who is a lecturer, nurse, and academic, not an MD) made a video about recent meta-analysis that did come to the conclusion that vitamin D has a protective effect. You can watch it here: https://youtu.be/x5sc7G4s4CY.
Bikle, D. D. (2022). Vitamin D regulation of immune function during covid-19. Reviews in Endocrine and Metabolic Disorders, 23(2), 279–285. https://doi.org/10.1007/s11154-021-09707-4
The adaptive immune system provides a more specific response, but takes longer to develop, although once developed provides a powerful response against invading organisms. However, this response if not controlled can also be destructive. Vitamin D, via its active metabolite 1,25(OH)2D, regulates adaptive immunity by limiting the maturation of DC, limiting their ability to present antigen to T cells, and shifting the T cell profile from the proinflammatory Th1 and Th17 subsets to Th4 and Treg subsets, which inhibit the proinflammatory processes.
di Filippo, L., Allora, A., Doga, M., Formenti, A. M., Locatelli, M., Rovere Querini, P., Frara, S., & Giustina, A. (2022). Vitamin D Levels Are Associated With Blood Glucose and BMI in COVID-19 Patients, Predicting Disease Severity. The Journal of Clinical Endocrinology & Metabolism, 107(1), e348–e360. https://doi.org/10.1210/clinem/dgab599
Patients with both hypovitaminosis D and diabetes mellitus, as well those with hypovitaminosis D and overweight, were more frequently affected by a severe disease with worse inflammatory response and respiratory parameters, compared to those without or just one of these conditions.
We showed, for the first-time, a strict association of VD levels with blood GLU and BMI in COVID-19 patients. VD deficiency might be a novel common pathophysiological mechanism involved in the detrimental effect of hyperglycemia and adiposity on disease severity.
Dissanayake, H. A., de Silva, N. L., Sumanatilleke, M., de Silva, S. D. N., Gamage, K. K. K., Dematapitiya, C., Kuruppu, D. C., Ranasinghe, P., Pathmanathan, S., & Katulanda, P. (2022). Prognostic and Therapeutic Role of Vitamin D in COVID-19: Systematic Review and Meta-analysis. The Journal of Clinical Endocrinology & Metabolism, 107(5), 1484–1502. https://doi.org/10.1210/clinem/dgab892
Vitamin D deficiency/insufficiency increased the odds of developing COVID-19, severe disease, and death. The 25-hydroxy vitamin D concentrations were lower in individuals with COVID-19 compared with controls, in patients with severe COVID-19 compared with controls with nonsevere COVID-19 and in nonsurvivors compared with survivors.
Multiple observational studies involving nearly 2 million adults suggest vitamin D deficiency/insufficiency increases susceptibility to COVID-19 and severe COVID-19, although with a high risk of bias and heterogeneity. Association with mortality was less robust.
Hariyanto, T. I., Intan, D., Hananto, J. E., Harapan, H., & Kurniawan, A. (2022). Vitamin D supplementation and Covid-19 outcomes: A systematic review, meta-analysis and meta-regression. Reviews in Medical Virology, 32(2), e2269. https://doi.org/10.1002/rmv.2269
Our data suggested that vitamin D supplementation was associated with reduction in intensive care unit admission rate; reduction of the need for mechanical ventilation and reduction of mortality from Covid-19. Further analysis showed that the associations were influenced by age. Our study suggests that vitamin D supplementation may offer beneficial effects on Covid-19 outcomes.
Oristrell, J., Oliva, J. C., Casado, E., Subirana, I., Domínguez, D., Toloba, A., Balado, A., & Grau, M. (2022). Vitamin D supplementation and COVID-19 risk: A population-based, cohort study. Journal of Endocrinological Investigation, 45(1), 167–179. https://doi.org/10.1007/s40618-021-01639-9
Cholecalciferol supplementation was associated with slight protection from SARS-CoV2 infection.
Patients on cholecalciferol treatment achieving 25OHD levels ≥ 30 ng/ml had lower risk of SARS-CoV2 infection, lower risk of severe COVID-19 and lower COVID-19 mortality than unsupplemented 25OHD-deficient patients.
Calcifediol use was not associated with reduced risk of SARS-CoV2 infection or mortality in the whole cohort. However, patients on calcifediol treatment achieving serum 25OHD levels ≥ 30 ng/ml also had lower risk of SARS-CoV2 infection, lower risk of severe COVID-19, and lower COVID-19 mortality compared to 25OHD-deficient patients not receiving vitamin D supplements.
In this large, population-based study, we observed that patients supplemented with cholecalciferol or calcifediol achieving serum 25OHD levels ≥ 30 ng/ml were associated with better COVID-19 outcomes.
Pereira, M., Dantas Damascena, A., Galvão Azevedo, L. M., de Almeida Oliveira, T., & da Mota Santana, J. (2022). Vitamin D deficiency aggravates COVID-19: Systematic review and meta-analysis. Critical Reviews in Food Science and Nutrition, 62(5), 1308–1316. https://doi.org/10.1080/10408398.2020.1841090
Vitamin D deficiency was not associated with a higher chance of infection by COVID-19, but we identified that severe cases of COVID-19 present 64% more vitamin D deficiency compared with mild cases. A vitamin D concentration insufficiency increased hospitalization and mortality from COVID-19. We observed a positive association between vitamin D deficiency and the severity of the disease.
Povaliaeva, A., Bogdanov, V., Pigarova, E., Dzeranova, L., Katamadze, N., Malysheva, N., Ioutsi, V., Nikankina, L., Rozhinskaya, L., & Mokrysheva, N. (2022). Impaired Vitamin D Metabolism in Hospitalized COVID-19 Patients. Pharmaceuticals, 15(8), Article 8. https://doi.org/10.3390/ph15080906
Overall, hospitalized patients with an acute course of COVID-19 have not only very low levels of 25OH-D but also profound abnormalities in the metabolism of vitamin D regardless of the clinical course of the disease. These alterations might exacerbate existing vitamin D deficiency and its negative impact.
Rastogi, A., Bhansali, A., Khare, N., Suri, V., Yaddanapudi, N., Sachdeva, N., Puri, G. D., & Malhotra, P. (2022). Short term, high-dose vitamin D supplementation for COVID-19 disease: A randomised, placebo-controlled, study (SHADE study). Postgraduate Medical Journal, 98(1156), 87–90. https://doi.org/10.1136/postgradmedj-2020-139065
Fibrinogen levels significantly decreased with cholecalciferol supplementation unlike other inflammatory biomarkers.
Greater proportion of vitamin D-deficient individuals with SARS-CoV-2 infection turned SARS-CoV-2 RNA negative with a significant decrease in fibrinogen on high-dose cholecalciferol supplementation.
Seal, K. H., Bertenthal, D., Carey, E., Grunfeld, C., Bikle, D. D., & Lu, C. M. (2022). Association of Vitamin D Status and COVID-19-Related Hospitalization and Mortality. Journal of General Internal Medicine, 37(4), 853–861. https://doi.org/10.1007/s11606-021-07170-0
After adjusting for all covariates, including race/ethnicity and poverty, there was a significant independent inverse dose-response relationship between increasing continuous 25(OH)D concentrations and decreasing probability of COVID-19-related hospitalization and mortality. In modeling 25(OH)D as a log-transformed continuous variable, the greatest risk for hospitalization and death was observed at lower 25(OH)D concentrations.
Continuous blood 25(OH)D concentrations are independently associated with COVID-19-related hospitalization and mortality in an inverse dose-response relationship in this large racially and ethnically diverse cohort of VA patients. Randomized controlled trials are needed to evaluate the impact of vitamin D supplementation on COVID-19-related outcomes.
