Risk of bias of the included studies in the meta-analysis
The Cochrane risk of bias tool for RCTs for evaluation of the risk of bias in Castillo et al25. Data showed in Figure S2. The risk of bias assessment of the two non-randomized interventional studies is shown in Table S1. The risk of bias in observational studies is detailed in Table S2.
Results of the estimated bias coefficient were from 0.014 to 0.141, giving a P-value > 0.05 for all analyses. Therefore, the tests provide weak evidence for the presence of publication bias.

DISCUSSION

This is the first systematic review with meta-analysis to show an association between low plasma vitamin D level and increased risk of death in inpatients with COVID-19 (1.41-fold). The results of this study also show an association between low plasma vitamin D levels in COVID-19 patients and increase ICU admission risk (1.76-fold) and ventilation requirement (3.50-fold).
Vitamin D deficiency is associated with an increased risk of developing viral and bacterial infections36. Several studies have linked the reduction of plasma vitamin D levels with increase respiratory infections37,38, as influenza infection, and vitamin D supplementation with the decrease of risk of these infections39–41. Others studies revealed a higher risk of ICU admission, sepsis, and death in hospitalized patients who had low levels of vitamin D in pre-admission42,43.
Vitamin D has a role in regulating mineral metabolism, an important role in the modulation of the immune response, and control the exacerbation of the cellular immune response36,44,45. Studies report that critically ill patients with COVID-19 have elevated in inflammatory cytokines such as IL-1 and IL-6, and chemokines associated with a Th1 response, corroborating the hypothesis of a cytokine storm in this disease46,47.Vitamin D regulates feedback control pathways that serve to decrease potential inflammatory damage from disproportionate activation of the immune response48
Others authors question the role of the cytokine storm in COVID-19, and that severity of the disease occurs due to direct viral injury, endovasculitis, and or viral-induced immunosuppression49. There is some evidence to support this question. The less pronounced cytokine elevations in COVID-19 could reflect a regulated, or inadequate, inflammatory response to infection from SARS-Cov2. In addition, non-cytokine biomarkers, such D-dimer, C-reactive protein, and ferritin, are elevated to a similar in patients with COVID-19 when comparing with patients of another disorders49,50.
Vitamin D has other roles in regulating the immune system. LL37 peptide, a component of the innate immune system that acts in the lungs against SARS-CoV-2, requires sufficient levels of vitamin D to be effective, which could indicate the preventive effect of vitamin D levels for the development of respiratory viruses51.
T lymphocytes are directly susceptible to SARS-CoV-2 infection and are depleted in clinical COVID-1952. Vitamin D modulates the function of immune cells, such as T and B cells, monocytes, and dendritic cells, in an interaction between the innate and adaptive immune systems53. Lachmann et al54conducted an RCT that showed that vitamin D deficiency is associated with an absolute lower CD4+ T cell count in HIV patients, however, that vitamin D supplementation increased the absolute recovery of CD4+ T cell count in these patients.
It has also been previously shown that vitamin D affects on blood coagulation parameters55. Hejazi et al56 where the treatment of the deficiency of vitamin D in patients with thromboembolism resulted in control of events with the lowest doses of warfarin. Although COVID-19 is a respiratory disease, many data have pointed to coagulopathy as a marker of mortality from this disease57. Thus, anticoagulant therapy seems to be associated with a better prognosis in critically ill patients with COVID-19 57. Therefore, it is possible to assume that the sufficient levels of vitamin D may be useful in the anticoagulant treatment of critically ill patients with COVID-19 or may prevent mild cases from becoming severe.
SARS- CoV-2 uses the angiotensin-converting enzyme receptor 2 to enter alveolar epithelial cells, which would lead to the deregulation of the Renin-Angiotensin System (RAS), accumulating the toxic product angiotensin II in alveolar cells and causing an acute lung injury58,59. Vitamin D regulates the balance between the expression of members of the RAS and their deficiency pointed to excessive activation of this system60. Therefore, vitamin D deficiency may exacerbate pulmonary RAS dysregulation induced by SARS-CoV-2 infection.
This study also showed that regular vitamin D supplementation was associated with a lower risk of death and vitamin D treatment of patients with COVID-19 was associated with a lower risk of ICU admission. Castilho et al and Tan et al showed that administration of calcifediol and cholecalciferol, respectively, reduced the need for ICU admission of patients with COVID-19 that requiring hospitalization. However, treatment with vitamin D in patients already diagnosed with COVID-19 needs to be further studied.
This study has several strengths. To our knowledge, this is the first meta-analysis using interventional studies associating vitamin D with COVID-19 patients, and that included analyzing the risk of mortality in hospitalized patients. This study informs physicians and patients regarding the importance of monitoring vitamin D levels. Some limitations of our study were the small number of interventional studies, the analysis that used different treatments for vitamin D supplementation, different cut-off plasma vitamin D levels, observational design of the selected studies, and sample size.
CONCLUSION
These results suggest that COVID-19 patients with sufficient plasma vitamin D levels is decreased risks of death, ICU admission, and ventilation requirement. However, randomized clinical trials are needed to confirm the benefits of vitamin D treatment in patients with COVID-19.

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