A literature search has been performed in PubMed, Embase, Web of science and MedRxiv for relevant publications about the vit D and Coronavirus infection and Kawasaki disease published up to 30^th December 2020. Keyword used were vit D in combination with coronavirus infection, SARS-CoV-2 infection, COVID-19, MIS-C, multisystem inflammatory syndrome, Kawasaki disease, Kawasaki-like syndrome. Information was derived from selected reviews and original articles published in peer-reviewed journals, from preliminary reports of works that have not yet been certified by peer review. Also, reference tracking was carried out to identify other relevant articles, which were not found during the initial searching. Additionally, current guidelines of International and National Health Organizations were retrieved and summarized. Almost all the published studies until now, regarding relationship between COVID-19 and vit D status included adult patients, and data referring to children and adolescents are extremely limited. Due to a reduce number of publications referring to vit D status in children infected by SARS-CoV-2, the authors also collected information from adults. The search using the words MIS-C and vitamin D revealed no studies in PubMed, Web of science, Embase and MedRxiv. Using the other keywords, the initial search yielded 73 articles, of which, after elimination of duplicates and screening of their titles and abstracts, 7 studies were considered relevant to this review.

Despite of low susceptibility to SARS-CoV-2 infection, especially those younger than 14 years, children are still at risk of infection (9).The prevalence of SARS-CoV-2 in children who are asymptomatic varied from 0 to 2.2% but there is a strong association between this prevalence and contemporaneous weekly incidence of COVID-19 in the general population (10). The children with SARS-CoV-2 infection usually are asymptomatic or suffer mild or moderate illness. It has been reported that the prevalence of severe or critical disease is 10.6, 7.3% and about 4% in children aged <1 year, 1–5years and 6–15 year, respectively (11). Few months after the onset of the pandemic, a series of reports around the world described clusters of children and adolescents presenting with a life-threatening, hyperinflammatory syndrome, named Kawasaki-like syndrome (8, 12), Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) (13) or Multisystem Inflammatory Syndrome in Children (MIS-C) (14). The pathogenesis of MIS-C is still unknown, although it has been suggested that this syndrome occurs while the immune system is activated against the SARS-CoV-2 virus (15). The host immune system in pediatric patients responses excessively to SARS-CoV-2 infections and lead to the multisystem inflammatory syndrome in children (MIS-C). MIS-C is a new childhood disease linked to SARS-CoV-2 infection. It is a dangerous systemic inflammation characterized by fever, abdominal symptoms, conjunctivitis, and rash which appear three to 4 weeks after the initial infection (16). The laboratory evidence of inflammation has been defined by one or more of the following biomarkers: an elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase (LDH), or interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes and low albumin (17). Testing for SARS-CoV-2 infection including RT-PCR, antigen test and IgM/IgG antibody is suggested when COVID-19 or MIS-C is suspected (9).

A recent published study demonstrated that MIS-C hyperinflammation differs from severe acute COVID-19 hyperinflammation of adults, as well from the original Kawasaki disease (18). Consiglio et al. found that elevated IL-6, IL-17A, CXCL10 contributed the most to the cytokine storm of MIS-C, while IL-17A an important cytokine in Kawasaki disease, was significantly lower in MIS-C (18).

A systematic review compared characteristics between MIS-C and pediatric confirmed COVID-19 cases, found that the level of inflammation experienced in MIS-C outweigh the inflammation related to COVID-19 (16).

Despite that its name is “vitamin,” in fact vit D is a fat-soluble steroid pre-hormone produced in skin from UV-B exposure (19). Hormones are defined as chemical signals synthesized and secreted into the bloodstream. They act on distant tissues usually in a regulatory fashion. Their action is often associated with binding soluble proteins (20). Steroid hormones are the sex steroids (estrogens, progesterone -female and androgens -male), the mineralo-corticoids, the glucocorticoids, and the vit D with its daughter metabolites (21).

Vit D3 (cholecalciferol) is synthetized in the skin under UV-B radiation from the sun but also derived from intake of animal food and vit D3 supplements, while vit D2 (ergochalciferol) is derived only from intake of vegetable food and vit D2 supplementation. Both are initially hydroxylated in the liver by (CYP2R1, CYP27A1, CYP3A4), resulting the inactive circulating form 25-hydroxyvitamin D [25(OH)D, calcidiol]. This form is then hydroxylated in the kidney by the 1α-hydroxylase enzyme [1α(OH)ase, CYP27B1] into calcitriol, the active form of vit D (22). The immune cells are able to locally convert 25(OH)D3 into its active form−1,25(OH)2D3 (19). 1,25(OH)2D3 (1,25-dihydroxyvitamin D3, calcitriol) acts as a circulating hormone and is the most potent natural ligand of the vit D receptor (VDR) of target cells. Also, 1,25(OH)2D3 has been described as an immunomodulator targeting various immune cells, including monocytes, macrophages, dendritic cells (DCs), as well as T-lymphocytes and B-lymphocytes. For that reason, 1,25(OH)2D3 has characterized as modulator of both innate and adaptive immune responses (23). Severe infections, including COVID-19, can lead to consumption of vit D intracellularly during the immune processes. As a result of that the utilization is faster than the production.

The risk factors for development of MIS-C (16) correspond with those for occurrence of low vit D levels in children of African American, Afro-Caribbean descent and those related to the children's obesity (33–35).

The more severe is the disease, the greater is the inflammatory process and subsequently the greater is the need for vit D (active form) with an anti-inflammatory role. Therefore, the consumption of vit D in the cells involved in immunomodulation is increased, resulting in reduced vit D level in serum (inactive form). Through this perspective, the low level of serum vit D in severe disease is a result of severity and not a predisposing factor for. Inflammatory reactions involved in the process of the diseases would reduce 25(OH)D, which would explain why low vit D levels are reported in a wide range of disorders (55, 56).

A recent study has been shown that the profiles of seven cytokines, indicated treatment responses, could be useful markers to monitor MIS-C patients undergoing treatment (18). Several of these cytokines could be decreased by vit D (45). It has yet to be shown in the clinical practice whether vit D level could be used as a biomarker for the severity of COVID-19 and MIS-C. Serial measurements during the progression of the disease could be useful in clinical practice. Additionally, the association of vit D levels with other inflammatory markers (CRP, ERS) and inflammatory cytokines (IL-6) would help clinicians to manage these.

The rational of vit D supplementation in SARS-CoV-2 infection in children is based on the impact of vit D status on infections due to influenza viruses. Studying the effect of 1,200 IU/day of vit D vs. placebo on the incidence of seasonal influenza A and B among children aged 6–15 years, Urashima et al. showed reduced incidence of influenza A but not of influenza B infection (38). It seems that depending on the type of virus, the alterations at the molecular level may differ, and consequently the effect of vit D supplementation. During the 2009 pandemic of the H1N1, vit D3 supplementation did not lower the overall incidence of influenza A despite the initial benefit during the first month of treatment (57). The relationship between vit D and MIS-C and the significance of the nutritional supplementation must be proven. Vit D status has already recommended to be determined (58) and correction of low levels has been suggested (59). For this purpose, it would be useful to measure a baseline vit D level as soon as the SARS-CoV-2 infection has been detected. Then, sequential measurements, during the disease would be performed and be compared to the other inflammatory indices and to the evolution of the disease.

Increased liver enzymes during MIS-C suggests to some degree that the disturbance of liver function may reflect in the reduction of vit D 25 hydroxylation at this level. Therefore, the direct administration of the 25(OH)D3 (calcifediol) rather than vit D3 can offer a rapidly improvement of vitamin D status overcoming this impediment. Providing 25(OH)D3 to cells of immune system may contribute to reducing the severity and favorable evolution of MIS-C, particularly in children with low vit D levels. Of 50 adult patients hospitalized with COVID-19 infection and treated with of a high dose of calcifediol, one required admission to the ICU, while of 26 untreated patients, 13 required ICU admission. All patients in this study received a combination of hydroxychloroquine and azithromycin (60). The therapeutic efficacy of rapidly correcting vit D deficiency with the use of 25-hydroxyvitamin D3 [25(OH)D3] is under investigation in a clinical trial (NCT04386850) in adult patients with COVID-19. It remains to be demonstrated whether the administration of vit D supplementation is related to a potentially favorable evolution of MIS-C.