Authors' reply: the biologic importance of the vitamin D binding protein polymorphism in pediatric COVID-19 patients.

What is Known? • Vitamin D has multiple roles in the immune system that can modulate the body reaction to an infection • Vitamin D binding protein (DBP) is the key transport protein which, along with albumin, binds over 99% of the circulating vitamin D metabolites What is New? • Lower 25 OH vitamin D levels were associated with higher inflammation markers, suggesting an important role of vitamin D in the clinical course of COVID-19 in children and adolescents probably by regulating the systemic inflammatory response • Further studies are warranted to investigate the possible causal association of DBP levels and polymorphism with vitamin D status (total and bioavailable vitamin D) in COVID-19 patients.

We would like to thank Speeckaert et al. for their interest in our study and for providing an insightful perspective on vitamin D binding protein (DBP) level or polymorphism as a possible explanation for the association between vitamin D status and COVID-19 outcomes.

The authors mentioned their previous study that the DBP1 allele frequency, which affects DBP concentration, was associated with lower prevalence and mortality due to SARS-COV-2 infection [1, 2]. Total 25(OH)D is defined by the DBP-bound fraction [approximately 85–90% of total 25(OH)D], the albumin-bound fraction [10–15% of total 25(OH)D], and the free circulating fraction [<1% of total 25(OH)D]. According to the free hormone hypothesis, vitamin D, which can enter the cell and have a biological effect, is in free form. It has been reported that DBP level and polymorphism affect the serum 25 OH vitamin D levels by changing the binding affinity to vitamin D, and also DBP may have an effect on 25 (OH) vitamin D related intracrine responses. Bioavailable vitamin D (not bound to DBP) is thought to be more biologically active in target tissues [3].

We agree with Speeckaert et al. that DBP polymorphism or concentration along could be a possible link for the association between vitamin D status and COVID-19 outcomes. Although there are opinions that measuring the bioavailable vitamin D is more reliable to evaluate vitamin D activity and adequacy, serum 25 OH vitamin D level has been measured in most of the studies. As PTH increases in vitamin D deficiency, it is thought that PTH is a useful indicator of low vitamin D level [4, 5]. In our retrospective study, we evaluated the vitamin D status with 25 OH vitamin D. The vitamin D-deficient group had significantly lower calcium, phosphorus, and higher PTH levels. In addition, 25 OH vitamin D levels were positively correlated with calcium and phosphorus levels and negatively with the PTH levels demonstrating the reliability of 25 OH vitamin D levels to assess vitamin D bioactivity (deficiency) in our cohort (Table 1). There can be several reasons of the low 25 OH vitamin D level such as decreased intake, decreased biosynthesis due to lack of sun exposure, or as Speeckaert et al. stated DBP level or polymorphism.

Table 1

Correlations of 25 OH vitamin D with calcium, phosphorus, and parathormone

	r	p Value
Calcium (mg/dL)	0.330	0.001
Phosphorus (mg/dL)	0.431	<0.001
Parathormone (pg/mL)	−0.287	0.023

In summary, our study shows the relationship between vitamin D deficiency and the clinical severity of COVID-19 and inflammatory markers. Further studies are warranted to investigate the possible causal association of DBP levels and polymorphism with vitamin D status (total and bioavailable vitamin D) in COVID-19 patients, as suggested by Speeckaert et al.

What is Known? • Vitamin D has multiple roles in the immune system that can modulate the body reaction to an infection • Vitamin D binding protein (DBP) is the key transport protein which, along with albumin, binds over 99% of the circulating vitamin D metabolites

What is New? • Lower 25 OH vitamin D levels were associated with higher inflammation markers, suggesting an important role of vitamin D in the clinical course of COVID-19 in children and adolescents probably by regulating the systemic inflammatory response • Further studies are warranted to investigate the possible causal association of DBP levels and polymorphism with vitamin D status (total and bioavailable vitamin D) in COVID-19 patients