Study: Pre-infection 25-hydroxyvitamin D3 levels and association with severity of COVID-19 illness. Image Credit: Kavun Halyna / Shutterstock

Are pre-existing Vitamin D deficiencies linked to COVID-19 severity and mortality?

Even as the coronavirus disease 20019 (COVID-19) pandemic continues to spread and new variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerge, much remains to be known about why severity varies so unpredictably between individuals.

Study: Pre-infection 25-hydroxyvitamin D3 levels and association with severity of COVID-19 illness. Image Credit: Kavun Halyna / Shutterstock

A new study by researchers from the Galilee Medical Center, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel, elucidates the relationship between vitamin D and COVID-19 severity. The researchers recently released their findings as a preprint on the medRxiv* server.


Vitamin D is a fat-soluble molecule that is important for bone metabolism and as an immunomodulator. Low levels of this vitamin have been linked to autoimmune disease, poor heart health, and infectious diseases.

Vitamin D deficiency (VDD) is a health problem worldwide, especially common in the Middle East. The major risk factors include low skin exposure, highly pigmented skin, and low consumption of fish and dairy products. Several researchers have found that influenza and respiratory virus infections are linked to VDD.

VDD is diagnosed at levels of less than 20 ng/mL. At 20 to 29.9 ng/mL, levels are insufficient. At or above 30 but below 40 ng/mL, levels are adequate, while above 40 ng/mL, they are high-normal.

It is an interesting fact that many risk factors such as temperate location, older age, increased skin pigmentation, Black, Asian or other minority ethnic origin, being male, obesity, diabetes and hypertension are associated with VDD on the one hand, and with COVID-19 severity, on the other.

Earlier studies point to a possible link between COVID-19 and VDD, therefore, but are based mostly on serum vitamin D levels in hospitalized COVID-19 patients. As a result, the low vitamin D levels could be either the cause or the result of the infection.

VDD associated with COVID-19 severity

In the current study, however, baseline vitamin D levels were examined dating from before the onset of COVID-19 to clarify the causality of this association. The last measured vitamin D levels came from 14 to 730 days before test positivity.

Interestingly, of the over 250 individuals in the study, with a mean age of 63 years, just over half had VDD. Mortality was 13 times higher in this group, occurring in 26% of patients vs. 2% in the vitamin D-sufficient group.

Of those with VDD, almost half developed severe illness, compared to less than a tenth in those with vitamin D levels above 20 ng/mL. The lower the vitamin D levels, the greater the risk of severe COVID-19, observed in 87% of people with VDD compared to 34% of the rest of the group.

In fact, VDD was found in 9% of mild COVID-19 patients, vs. 58% in those with moderate illness, but 87% of severely or critically ill patients. The odds that a patient with severe or critical disease would have VDD were 14 times higher compared to those with mild or moderate disease, even after adjusting for age, male sex, and the presence of other illnesses.

VDD is higher among those of Arab origin, perhaps due to a combination of lifestyle factors such as almost complete skin covering with darker skin and socioeconomic inequities, including less access to healthcare. In the current study, too, they made up 64% of the VDD cohort.

However, Arab ethnicity was not associated between ethnic origin and disease severity or mortality. This may indicate the overriding effect of vitamin D levels in determining COVID-19 severity.

The oldest patients, above 65 years, were most likely to have severe illness if they had VDD, with less strong, or still positive, correlations below 50 years of age. Younger patients with VDD may be at higher risk of hospitalization with COVID-19, but older patients share this increased risk even without such low levels.

What are the implications?

Earlier research has indicated that a low vitamin D level at admission, or a history of VDD, indicates higher chances of severe disease. Here, the investigators showed that VDD presents even before the onset of infection is linked to poorer outcomes during hospitalization.

These findings are not in complete congruence with all earlier studies. One reason may be the use of supplemental vitamin D in patients with low levels, the results being difficult to gauge. Genetic heterogeneity may also play a role in determining the risk posed by COVID-19 in the individual.

A large meta-analysis involving almost 50,000 patients with acute respiratory infections (ARIs) showed the safety of this measure and an overall reduction in ARIs compared to a placebo. The benefits of vitamin D supplementation in improving COVID-19 outcomes remain to be established, however.  

The findings thus support a link between VDD and severe COVID-19. “It should be emphasized that VitD represents only one piece of the complex puzzle that is COVID-19.” Further studies are required to assess the possible benefits of supplemental vitamin D in those with VDD in terms of mitigating the risk in case of COVID-19 infection.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.