Vitamin D axis status and the severity of COVID-19.

Dear Editor,

We read with great interest the article recently published in Journal of Medical Virology by Demir et al., examining the relationship between serum vitamin D levels and the laboratory findings and clinical outcomes of COVID‐19 positive patients. They found that COVID‐19 positive individuals with sufficient vitamin D levels had significantly lower d‐dimer and CRP levels, reduced frequencies of ground‐glass opacities on chest scanning, and shorter hospital stays. However, we would like to add some points which may be taken into consideration.

Vitamin D works together with the vitamin D‐binding protein (VDBP) and vitamin D receptor (VDR). VDBP is a highly polymorphic serum glycoprotein synthesized and secreted by the liver. It is the major carrier of vitamin D and its metabolites, including 25‐hydroxyvitamin D (circulating reservoir) and 1,25‐dihydroxyvitamin D (active form). VDBP is essential for vitamin D metabolism, as it binds 85%–90% of total circulating vitamin D. The non‐VDBP fraction (bioavailable vitamin D) consists primarily of albumin‐bound (10%–15%), leaving the remainder in the free form (<1%). Compared to the overall vitamin D status, serum 25‐hydroxyvitamin D levels before the COVID‐19 positivity, appear to have limited value to predict the severity in COVID‐19. Through the altered pharmacokinetics, insufficient circulating vitamin D may result in a greater concentration of bioavailable or free vitamin D of which the roles are not yet completely defined during critical illness. Also, the reduced VDBP biosynthesis mainly due to the disturbed liver function with the upregulation of proinflammatory cytokines may change its affinity for vitamin D, which can take a role in the clinical severity during the COVID‐19 pandemic.

Active vitamin D leads to multiple biological responses by binding to intracellular nuclear receptors, the VDRs, which are found on immune and pulmonary epithelial cells. VDR expression is very low in resting conditions but upon activation, possibly due to the inflammatory conditions, it is significantly upregulated. This upregulation allows the upregulated vitamin D responsive genes that promote differentiation and proliferation of immune system cells to produce more anti‐inflammatory cytokines. , Possible idea is that COVID‐19‐related proinflammatory state might induce a VDR overexpression tending to be accompanied by an increased potency of circulating vitamin D on target cells.

Considering the above, it seems that vitamin D, VDBP, and VDR, as a whole share complex mechanisms underlying the COVID‐19 severity. Large‐scale longitudinal studies measuring all three may give the insight to evaluate the contributions of these proteins in the development of vitamin D deficiency‐related poor clinical outcomes.

CONFLICT OF INTERESTS

The authors declare that there are no conflict of interests.