First clinical trial: Vitamin D prevents Covid-19 complications in hospitalized patients
A lot has been written on the role of vitamin D in the prevention & management of SARS-CoV-2 infection & COVID-19 disease. Interest in Vitamin D therapy has increased multifold after the recent bradykinin hypothesis successfully answered the questions that had been left unanswered by the cytokine storm hypothesis. The bradykinin hypothesis also proposed that Vitamin D therapy may control the bradykinin storm. However, the literature lacked a clinical trial in this regard. This article covers the results of a preliminary trial that has shown promising results with Vitamin D therapy in preventing complications in hospitalized Covid-19 patients.
Severely sick Covid-19 patients require hospital admission, and among the hospitalized patients, about 20 % will develop Acute Respiratory Distress Syndrome (ARDS) and require intensive care unit (ICU) admission. 
Multiple studies [2- 6] have shown that the activation of the vitamin D receptor (VDR) signalling pathway may generate beneficial effects in (ARDS) by
- decreasing the cytokine/chemokine storm,
- regulating the renin‑angiotensin system (RAS),
- modulating neutrophil (PMN) activity,
- maintaining the integrity of the pulmonary epithelial barrier,
- stimulating epithelial repair,
- tapering down the increased coagulability
Also, the recently formulated bradykinin hypothesis  proposed vitamin D as a potential treatment for Covid-19. The biological basis for this proposal is that vitamin D regulates the Renin-Angiotensin System (RAS) and prevents bradykinin accumulation.
According to the bradykinin hypothesis , SARS-CoV-2 dysregulates the RAS via its interaction with the Angiotensin-Converting Enzyme 2 (ACE2) receptor. This interaction results in the accumulation of bradykinin, which makes blood vessels leaky. The hypothesis also says that SARS-CoV-2 upregulates ACE2 expression in organs where it is less expressed. This upregulation of receptors poses problems in multiple organs, e.g., it causes leakage of fluid and immune cells into the lungs and breakdown of the blood-brain-barrier.
Looking at the above mechanisms, vitamin D seems to play a very critical role in Covid-19 management.
To test the hypothesis of a possible link between Vitamin D Receptor activation and the severity of ARDS or COVID-19, researchers conducted a pilot study  to assess the clinical effectiveness of Calcifediol (25-hydroxyvitamin D3 or 25OHD) in early stages infection in Covid-19 hospitalized patients. Cholecalciferol is the native vitamin D3 form and nutritional substrate for Calcifediol. The study tested Calcifediol as it is known to increase serum 25OHD concentration rapidly.
The study, done as a preliminary step to a more extensive randomized clinical trial, evaluated whether such treatment can reduce the need for admission to ICU and the potential risk of death. 
The researchers divided a total of 76 patients into Calcifediol treated (test = 50) and untreated (control=26) groups. Both groups had similar baseline characteristics (e.g. age, sex, comorbidities) and clinical biomarkers of disease severity (oxygen levels, C-reactive protein, interleukin-6, ferritin, D-dimer, lactate dehydrogenase, and lymphocyte count). However, the control group had a higher prevalence (57.69%) of hypertension than the calcifediol group (24.19%).
They treated 50 patients with Calcifediol, out of which the only one (2%) required ICU admission. None died, and all were discharged, without complications.
Among the 26 untreated, 13 patients (50%) required ICU admission, out of which two died, and the remaining 11 were discharged.
This pilot study has some limitations - but it demonstrates that high dose Calcifediol can significantly reduce the need for ICU admission. Calcifediol seems to be effective in reducing the severity of the disease. However, larger sample size randomized controlled trials are needed to come up with a definitive answer.
 Chen N., Zhou M., Dong X., Qu J., Gong F., Han Y., Qiu Y., Wang J., Liu Y., Wei Y., Xia J., Yu T., Zhang X., Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395:507–513. doi: 10.1016/S0140-6736(20)30211-7.
 Quesada-Gomez J.M., Entrenas-Castillo M., Bouillon R. Vitamin D receptor stimulation to reduce acute respiratory distress syndrome (ARDS) in patients with coronavirus SARS-CoV-2 infections: Revised Ms SBMB 2020_166. J. Steroid Biochem. Mol. Biol. 2020;202 doi: 10.1016/j.jsbmb.2020.105719.
 Shi Y.Y., Liu T.J., Fu J.H., Xu W., Wu L.L., Hou A.N., Xue X.D. Vitamin D/VDR signalling attenuates lipopolysaccharide-induced acute lung injury by maintaining the integrity of the pulmonary epithelial barrier. Mol. Med. Rep. 2016;13:1186–1194. doi: 10.3892/mmr.2015.4685.
 Kong J., Zhu X., Shi Y., Liu T., Chen Y., Bhan I., Zhao Q., Thadhani R., Chun Li Y. VDR attenuates acute lung injury by blocking Ang-2-Tie-2 pathway and the renin-angiotensin system. Mol. Endocrinol. 2013;27:2116–2125. doi: 10.1210/me.2013-1146.
 Zheng S.X., Yang J.X., Hu X., Li M., Wang Q., Dancer R.C.A., Parekh D., Gao-Smith F., Thickett D.R., Jin S.W. Vitamin D attenuates lung injury via stimulating epithelial repair, reducing epithelial cell apoptosis and inhibits TGF-β induced epithelial to mesenchymal transition. Biochem. Pharmacol. 2020;177 doi: 10.1016/j.bcp.2020.113955.
 Martinez-Moreno J.M., Herencia C., De Oca A.M., Muñoz-Castañeda J.R., Rodríguez-Ortiz M.E., Diáz-Tocados J.M., Peralbo-Santaella E., Camargo A., Canalejo A., Rodriguez M., Velasco-Gimena F., Almaden Y. Vitamin D modulates tissue factor and protease-activated receptor 2 expression in vascular smooth muscle cells. FASEB J. 2016;30:1367–1376. doi: 10.1096/fj.15-272872.
 A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. eLife 2020;9:e59177 DOI: 10.7554/eLife.59177
 Castillo ME, Entrenas Costa LM, Vaquero Barrios JM, et al. "Effect of Calcifediol Treatment and best Available Therapy versus best Available Therapy on Intensive Care Unit Admission and Mortality Among Patients Hospitalized for COVID-19: A Pilot Randomized Clinical study" [published online ahead of print, 2020 Aug 29]. J Steroid Biochem Mol Biol. 2020;105751. doi:10.1016/j.jsbmb.2020.105751