A new paper published on the preprint server medRxiv* in May 2020 reports the first evidence that vitamin D deficiency and inadequate treatment could increase the chances of testing positive for COVID-19. This could shape the way for screening individuals at risk for vitamin D deficiency.
Classifying Vitamin D Deficiency
The study by researchers at the University of Chicago looked at over 4,300 patients with COVID-19 of whom 499 had been tested for vitamin D levels in the previous year. Based on this, they were divided into likely deficient (25%), likely adequate (58%), and uncertain (16%).
Vitamin D deficiency was diagnosed by “the most recent 25-hydroxycholecalciferol <20ng/ml or 1,25-dihydroxycholecalciferol <18pg/ml within one year before COVID-19 testing.”
Vitamin D Deficiency Linked to Positive COVID-19 Test
Multiple variables were analyzed in this study. The researchers found that people with vitamin D deficiency at the last testing, and who did not receive higher doses of vitamin D (keeping them deficient in all probability), are much more likely to be infected with the virus than those with probably sufficient levels. The corresponding rates of infection were 22% vs. 12%.
The prevalence of vitamin D deficiency decreased with higher vitamin D dosage, but the latter was not linked to positive testing for COVID-19.
Earlier trials and meta-analyses have already suggested that sufficient vitamin D can prevent COVID-19. Still, this study is the earliest direct connection between vitamin D deficiency and a higher risk of viral illness. Vitamin D treatment can reduce the risk of other respiratory infections as well, with coronaviruses playing a leading role in them.
The analysis failed to throw up a significant difference between patients with low vitamin D levels at last testing who were or were not treated. On the other hand, the study shows that few such patients actually receive high doses of vitamin D. In other words, the reluctance to treat this deficiency adequately is a significant contributor to the failure to detect an association.
Factors Underlying Vitamin D Deficiency
Vitamin D deficiency is more common in black Americans due to the dense concentration of the ultraviolet-blocking chemical in the skin. Since this community has been disproportionately affected by COVID-19, in terms of both sickness and death, it would be wise to offer vitamin D testing to them.
Genetic factors affect the incidence of vitamin D deficiency. This finding may indicate a heritable component of the risk for the viral illness. This could help determine whether to test for COVID-19 among relatives of people who have the infection.
Another question that is raised by this study is whether vitamin D supplementation could reduce the transmission of the virus. Vitamin D is an immunomodulator, acting through the innate immune cells called dendritic cells as well as the adaptive T cells. This leads to higher clearance of the virus from the body as well as suppression of the inflammatory responses which lead to symptomatic illness.
A higher level of vitamin D is linked to a reduction in IL-6 levels, the latter being a proinflammatory cytokine. This is a significant discovery since IL-6 inhibitors are a major drug target to suppress the cytokine storm that is thought to be linked to death and critical illness.
The vitamin may also influence the processing of zinc, which reduces coronavirus replication. All the above actions are beneficial and can help to control viral spread.
However, the anti-inflammatory or immunomodulatory activity of vitamin D could also increase the number of asymptomatic infections, and thus possibly increase the number of people infected by secondary contact. The absence of cough, fever, and other expected manifestations could confuse the issue by increasing the asymptomatic patient pool. Since this has the potential to increase community spread, it is difficult to gauge the degree of protection in individuals without deficiency.
Limitations and Implications
The study has its drawbacks. The observational nature of the study does not allow the conclusion that vitamin D deficiency causes an increased risk of COVID-19 infection. Indeed, vitamin D may be reduced because of multiple medical conditions and behavioral factors that quite possibly reduce the chance of adequate treatment while boosting the COVID-19 risk.
However, the findings remain unchanged over a wide range of other disease conditions and age groups.
The study also examined patients who had received vitamin D2 or calcitriol. The use of calcitriol was one of the factors that led to a definition of vitamin D deficiency since it is often used in patients with chronic renal disease or hypoparathyroidism. When these cases are excluded, the observed associations typically become stronger.
Another factor is the study location and base: a large number of people with chronic illness, health workers, and Black Americans, in a northern city in winter. This predisposes to a more significant number of people with vitamin D deficiency. In another population subgroup, this may be less important in determining COVID-19 risk.
The Case for Universal Vitamin D Supplementation
The findings are in support of the finding that a low vitamin D level boosts the risk of COVID-19, but treatment that adequately addresses the deficiency reduces the risk. This conclusion is strengthened by the finding that those who were treated with higher doses after having a low vitamin D level at their last test were not at higher risk. Their chances were comparable to those whose last test results and treatment history suggested adequate vitamin D levels at the time of COVID-19 testing.
The type and dosage of treatment are related to the rate of vitamin D deficiency, and this can be explained entirely by the administration of vitamin D3 at 2000 IU of ≥3000IU. This relationship shows that treatment is an important factor in determining this risk.
On the other hand, the relationship between treatments for vitamin D deficiency and the risk for COVID-19, and to the level of vitamin D and its deficiency, is intricate. It underlines the need to carry out randomized trials that can settle the matter with more significant evidence for or against the role of treatment of vitamin D deficiency in reducing this risk.
The importance of social distancing and restriction of movement in COVID-19 makes inexpensive home tests for vitamin D even more valuable against the background of its contribution to deciding the type of treatment. On the other hand, vitamin D may be blindly given at 4000IU or 5000IU a day because of its known safety, as long as the person is not known to have any contraindication to this supplement,.
Logically, the preventive effect of vitamin D treatment would be most significant among those who have low levels of the sunshine vitamin. Despite this expectation, the researchers argue for supplementation to be available to all, and if required, for testing directed at high-risk groups that are likely to have deficient levels of Vitamin D and/or for COVID-19.
This is the more feasible considering that vitamin D supplements are quite safe, COVID-19 tests are limited even today, tests are expensive and vitamin D levels fluctuate with the seasons due to variable exposure to the strong ultraviolet rays needed to convert the prodrug to its active form.
The type of analysis performed here is quite simple and lends itself to other situations, with every likelihood of achieving similar conclusions. This is especially so because vitamin D deficiency is so prevalent in the American population, and particularly in darker-skinned people, older individuals, and those living in nursing homes.
Given these findings, the researchers recommend “expanded population-level vitamin D treatment and testing and assessment of the effects of those interventions,” because of the strong possibility that vitamin D deficiency increases COVID-19 risk. This should, therefore, be followed up with more studies at once to understand whether positive measures to increase vitamin D levels in deficient people would help reduce the number of new COVID-19 cases. Large-scale interventions aimed at the people at large, as well as high-risk group-specific interventions, should be prioritized.
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.