Dozens of clinical trials ongoing to investigate whether vitamin D prevents COVID-19; no firm evidence yet

Key takeaway

Several studies reported lower levels of vitamin D in COVID-19 patients. However, it remains unclear whether low vitamin D levels increase the risk of infection and severe outcomes from COVID-19. Alternatively, low vitamin D levels in patients could be a consequence of the disease or reflect a patient's poor health prior to COVID-19 infection. Several of the studies that found an association between vitamin D levels and COVID-19 infection or severity did not account for confounding factors such as ethnicity, body mass index, or underlying health condition, which are known risk factors for the disease. Further research is needed to determine whether vitamin D might play a role in the prevention of and treatment of COVID-19.

Reviewed content

Verdict:

Unsupported

Claim:

“Vitamin D insufficiency [...] may account for the majority of COVID-19 deaths”

Verdict detail

Overstates scientific confidence: Although several studies found correlations between low vitamin D levels and COVID-19 infection or severity, they do not provide direct evidence to establish a cause and effect relationship between both. Furthermore, different studies show mixed results that do not allow scientists to come to robust conclusions about the role of vitamin D in preventing COVID-19.

See our method of evaluation

Full Claim

“Vitamin D insufficiency [...] may account for the majority of COVID-19 deaths”; “There are cheap alternatives to prevent hospitalization and death. Why keep pushing for untested expensive drugs /vaccines?”

Claims that vitamin or mineral supplements, including zinc, selenium, and vitamins C and D can prevent or cure COVID-19 have circulated since the beginning of the pandemic. In late November 2020, numerous social media posts (examples here and here) repeated the claim that supplementation with vitamin D can prevent, cure, or reduce the severity of COVID-19. Posts including these claims received tens of thousands of interactions on Facebook and Instagram in early December, according to the social media analytics tool CrowdTangle. However, current scientific evidence is insufficient to assess whether vitamin D is useful for preventing or treating COVID-19, as this review explains below.

Many of these posts cite an October 2020 comment on an observational study published in the journal Nutrients in September 2020 that found an association between vitamin D deficiency and COVID-19 severity and mortality^[1,2]. Based on these results, the authors of the comment state, “87% of COVID-19 deaths may be statistically attributed to vitamin D insufficiency and could potentially be avoided by eliminating vitamin D insufficiency.” However, the authors of the observational study responded to this comment, warning that their results cannot establish a causal association between vitamin D levels and severity of COVID-19:

“[I]n an observational study design, it cannot be excluded that [vitamin D] deficiency represents a surrogate marker for a general micronutrient deficiency, which in turn reflects only the patient’s overall health status. For instance, obesity, which is associated with chronic low-grade inflammation and higher IL-6 levels and risk of hospitalization from respiratory tract infections, was recently also shown to be a determinant of COVID-19 severity and mortality. In addition, although evidence is accumulating that suggests COVID-19 mortality to be associated with poor [vitamin D] status, studies which found no association with disease outcomes or mortality also need to be acknowledged. Therefore, in the absence of a randomized controlled trial on [vitamin D] treatment, no causal association between [vitamin D] status and severity/outcome of COVID-19 can be inferred.”

Vitamin D is a fat-soluble vitamin involved in the absorption of calcium, a mineral necessary to maintain healthy bones, teeth, and muscles. Vitamin D deficiency can lead to a loss of bone density, which in turn contributes to osteoporosis and fractures. A few foods, including cod liver oil, fatty fish, mushrooms, egg yolks, and liver, are rich in vitamin D. However, the primary natural source of vitamin D is the skin, which produces the vitamin upon regular exposure to sunlight. Limited sunlight during wintertime or remaining indoors for excessive periods of time can lead to deficiencies, but other factors such as aging and skin pigmentation can also influence vitamin D production by the skin.

Growing scientific evidence suggests that vitamin D may also modulate the immune response and help against infections^[3]. Two systematic reviews of data from published clinical trials showed that vitamin D supplementation reduced the risk of acute upper respiratory tract infections. This effect, however, was most prominent in people who had vitamin D deficiency to begin with^[4,5], as Health Feedback explained in this previous review.

Early observational studies in different countries found an association between low vitamin D levels and higher rates of COVID-19 infection, severity, and mortality, suggesting that vitamin D supplementation might be beneficial for reducing COVID-19 infection and severe outcomes in vitamin D-deficient individuals ^[6-9]. However, such studies have a high risk of bias, as none of them adjusted for potential confounding factors, such as socio-demographic variables, ethnicity, body mass index, or underlying health conditions. These factors might influence vitamin D status or COVID‑19 infection or severity, causing a spurious association between both. Indeed, one retrospective study that analyzed 1,474 blood samples from the U.K. Biobank found that the correlation between vitamin D levels and COVID-19 infection vanished after adjustment for potential confounders such as ethnicity and body mass index^[10].

On the other hand, reverse causality might also explain the correlation between vitamin D deficiency and COVID-19 infection, severity, and mortality in patients, altering the conclusions of the studies. For example, people who are in ill health prior to COVID-19 infection, and therefore more likely to develop severe illness, may also be more likely to be vitamin D-deficient. Some researchers also point out that excessive inflammation, which is a common condition in COVID-19 patients, can reduce the levels of vitamin D in blood. Therefore, it could be the disease that leads to lower vitamin D levels rather than the other way around^[11].

Based on these early data, the U.K. National Institute of Clinical Excellence published a June 2020 evidence review concluding that there was “no evidence to support taking vitamin D supplements to specifically prevent or treat COVID‑19.”

More recently, an August 2020 cohort study conducted in a U.K. hospital showed that COVID-19 patients older than 65 were more likely to have vitamin D deficiency, which was associated with an increased risk of respiratory failure, but not with increased mortality^[12]. Similarly, a cohort study in Austria and a retrospective study in Spain also found that hospitalized COVID-19 patients had lower levels of vitamin D in the serum. These levels did not correlate with the need for intensive care, mechanical ventilation, or mortality[^13], nor with impairments in lung or heart function^[14].

Comparing the results of the above studies is difficult because different studies used different thresholds for defining vitamin D deficiency. This is because there is no consensus on how vitamin D deficiency is defined, nor a standard for what constitutes mild, moderate, or severe deficiency. Furthermore, observational studies can allow scientists to identify correlations between two variables, but generally not causal relationships.

About 28 clinical trials are now ongoing to assess whether there is a cause and effect relationship between vitamin D levels and COVID-19 infection or severity, but available data is still scarce. An October 2020 pilot clinical study found that early oral intake of vitamin D significantly reduced the need for intensive care in 50 hospitalized COVID-19 patients in Spain^[15]. However, the vitamin D treatment group included more patients with high blood pressure and diabetes, which are known risk factors for developing severe COVID-19. Also, the researchers did not assess vitamin D levels before treatment to account for potential deficiencies.

In November 2020, the results of the first randomized controlled trial were published as a preprint, which is a study that has not been peer-reviewed by other scientists yet. The study found no benefit from vitamin D supplementation in 240 patients hospitalized with severe COVID-19 in Brazil in terms of hospital stay duration, need for intensive care and ventilation, or mortality^[16]. These results, however, do not exclude the possibility that earlier vitamin D supplementation might have a beneficial effect.

In light of the contradictory results from scientific studies, there is currently not enough evidence to support the use of vitamin D supplements to prevent and/or treat COVID-19. Accordingly, as of December 2020, the World Health Organization and the U.S. National Institutes of Health have not issued guidance on the use of vitamin D or any other supplement specifically for COVID-19.

On the other hand, vitamin D deficiency is emerging as a widespread condition worldwide, and research studies suggest it may be associated with an increased risk of infections and higher severity for other diseases^[17]. While vitamin D deficiency is more prevalent in places that receive limited sunlight, it affects people from all populations, ethnicities, and age groups, including an estimated 40% of the U.S. population^[18]. For this reason, despite the lack of conclusive evidence about the benefit of vitamin D specifically in COVID-19, some health authorities recommend people use vitamin D supplementation to prevent deficiencies during wintertime and improve their overall health status.

However, experts warn that toxicity can occur in individuals who use excessive vitamin D supplementation over long time periods, leading to increased calcium accumulation in the blood (“hypercalcemia”) and potential damage to the bones, kidneys, and heart. Therefore, general recommendations irrespective of COVID-19 include a balanced diet rich in vitamins and minerals and regular sun exposure. Eventual supplementation with vitamin D or fortified foods can help people to reach daily recommended dietary amounts.

In summary, the claim that vitamin D supplementation can prevent or improve the clinical outcome of COVID-19 is unsupported by the scientific evidence at the moment. Mixed results from observational studies do not provide sufficient evidence to support the therapeutic use of vitamin D for COVID-19 beyond the daily dietary recommendation to prevent deficiencies. However, this may change, depending on the results from ongoing clinical trials, which may shed more light on the potential benefit of vitamin D in COVID-19.

REFERENCES

• 1 – Brenner and Schöttker. (2020) Vitamin D Insufficiency May Account for Almost Nine of Ten COVID-19 Deaths: Time to Act. Comment on: “Vitamin D Deficiency and Outcome of COVID-19 Patients”. Nutrients.
• 2 – Radujkovic et al. (2020) Vitamin D Deficiency and Outcome of COVID-19 Patients. Nutrients.
• 3 – Aranow. (2011) Vitamin D and the Immune System. Journal of Investigative Medicine.
• 4 – Martineau et al. (2017) Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ.
• 5 – Pham et al. (2020) Acute Respiratory Tract Infection and 25-Hydroxyvitamin D Concentration: A Systematic Review and Meta-Analysis. International Journal of Environmental Research and Public Health.
• 6 – D’Avolio et al. (2020) 25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2. Nutrients.
• 7 – Ilie et al. (2020) The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clinical and Experimental Research.
• 8 – Laird et al. (2020) Vitamin D and Inflammation: Potential Implications for Severity of Covid-19. Irish Medical Journal.
• 9 – Merzon et al. (2020) Low plasma 25(OH) vitamin D level is associated with increased risk of COVID‐19 infection: an Israeli population‐based study. FEBS Journal.
• 10 – Hastie et al. (2020) Vitamin D concentrations and COVID-19 infection in UK Biobank. Diabetes & Metabolic Syndrome: Clinical Research & Reviews.
• 11 – Smolders et al. (2020) Letter to the Editor: Vitamin D deficiency in COVID-19: Mixing up cause and consequence. Metabolism.
• 12 – Baktash et al. (2020) Vitamin D status and outcomes for hospitalised older patients with COVID-19. Postgraduate Medical Journal.
• 13 – Hernández et al. (2020) Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection. The Journal of Clinical Endocrinology and Metabolism.
• 14 – Pizzini et al. (2020) Impact of Vitamin D Deficiency on COVID-19-A Prospective Analysis from the CovILD Registry. Nutrients.
• 15 – Entrenas-Castillo et al. (2020) Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study. The Journal of Steroid Biochemistry and Molecular Biology.
• 16 – Murai et al. (2020) Effect of Vitamin D3 Supplementation vs Placebo on Hospital Length of Stay in Patients with Severe COVID-19: A Multicenter, Double-blind, Randomized Controlled Trial. medRxiv [Note: This is a pre-print that has not yet been peer-reviewed or published in a journal at the time of this review’s publication.]
• 17 –  Amrein et al. (2020) Vitamin D deficiency 2.0: an update on the current status worldwide. European Journal of Clinical Nutrition.
• 18 – Forrest and Stuhldreher. (2011) Prevalence and Correlates of Vitamin D Deficiency in US Adults. Nutrition Research.