The coronavirus disease-19 (COVID-19) pandemic, caused by the severe acute respiratory
syndrome β-coronavirus (SARS-CoV-2), is one of the greatest challenges facing modern
medicine and public health systems worldwide [1]. Since its appearance in December
2019[2], it has caused nearly 7 million deaths, recognized, and confirmed worldwide
(https://www.worldometers.info/coronavirus/?), with high acute and post-acute morbidity
[3], making it one of the deadliest in human history, with a devastating impact on
national economies worldwide [4].

In the first outbreaks of COVID-19, although 80% were asymptomatic or had mild symptoms,
20% of patients developed severe symptoms, and 5% presented acute respiratory distress
syndrome (ARDS), septic shock and accompanied multi-organ organ failure. of a high risk
of death. Numerous risk factors have been described that influence the poor outcome of
these patients, such as age, sex, high blood pressure, chronic obstructive pulmonary
disease, diabetes, obesity, chronic lung and digestive diseases, asthma, chronic heart
disease and cancer, D-dimer. greater than 1000) or a high SOFA ( Sequential Organ Failure
Assessment Score). It has also been observed that patients with no a priori risk factors,
may have a poor outcome [5].

The scientific community immediately proposed strong social containment measures, quickly
developed effective vaccines to prevent the appearance of severe clinical forms of
COVID-19 [6], and new treatments against all aspects of the disease: antiviral agents,
anti-inflammatory agents, antithrombotic therapies, to hypoxemic acute respiratory
failure, therapies with anti-SARS-CoV-2 antibodies (neutralizing), modulators of the
renin-angiotensin-aldosterone system and vitamins [7], so that social and economic
activity has gradually recovered worldwide [4].

However, at the current time, there are some indications that hospital admissions for
COVID-19 are on the rise again, so the pandemic seems far from over and future waves of
infection are likely [8,9].

These indications update and highlight again the repositioning strategy used since the
beginning of the pandemic for the use of safe drugs, approved for another indication, and
redirected to improve symptoms and clinical outcomes in patients with COVID-19. Various
drugs have been investigated with this strategy and many studies have been published,
some of them successful [10].

In this sense, in the first months of the pandemic, on the basis of biological
plausibility, we thought that the activation of the vitamin D receptor (VDR) signalling
pathway of the vitamin D endocrine system (VDES) could produce beneficial effects in
COVID 19, [11], by improving innate antiviral effector mechanisms, facilitating the
induction of antimicrobial peptides/autophagy, mitigating the subsequent reactive
hyperinflammatory phase of the host, decreasing the cytokine/chemokine storm, modulating
the expression of the renin angiotensin system - (RAAS), and neutrophil activity,
maintaining the integrity of the pulmonary/intestinal epithelial barrier, stimulating
epithelial repair and directly and indirectly reducing the increase in coagulability and
prothrombotic tendency associated with a severe course of COVID- 19 and its complications
[12]. Available evidence suggests that VDES/VDR stimulation, while maintaining optimal
serum 25-hydroxyvitamin D (25(OH)D) status, in patients with SARS-CoV-2 infection may
significantly reduce the risk of distress syndrome. acute respiratory syndrome (ARDS) and
the development of severe COVID-19 [13].

We decided to use calcifediol, prohormone and cornerstone of the VDES, and substrate for
the synthesis of the system's hormone, calcitriol [14]. The poor availability of
calcifediol in the general population [15], most marked in patients affected by COVID
[16], means that the potential protection that VDR/VDES stimulation confers against
various aspects of the disease is lost.

Calcifediol provides pharmacokinetic advantages, which give it a certain functional
superiority over native vitamin D3 and even over the hormonal form of VDES, calcitriol,
for its use in COVID-19. It is very hydrophilic and, therefore, after oral ingestion, it
is absorbed through the portal venous system and does not require hydroxylation at the 25
position, immediately increasing optimal circulating concentrations of 25(OH)D3 [17].
Therefore, even administered orally, it is available at high concentrations within a few
hours, and in a stable manner, to be a substrate for calcitriol synthesis in kidney and
other target organs in COVID-19 [18].

The clinical trial pilot study and several observational intervention studies using
relatively high doses of calcifediol (0.532 µg on day 1 and 0.266 µg on days 3, 7, 14, 21
and 28 decreased the severity of the disease, dramatically reducing the need for ICU
admission, severity, and mortality rate [19,20,21] Therefore, using calcifediol at the
doses described for rapid correction of 25(OH)D deficiency in all patients in the early
stages of COVID-19, in association with the best available therapy, was assessed as a
good option. for the treatment of COVID. For this reason, on January 24, 2021, our
hospital CALCIFEDIOL was incorporated into the protocol "RECOMMENDATIONS FOR ACTION AND
TREATMENT OF THE CORONAVIRUS SARS-CoV-2 DISEASE (COVID-19) version 11.1.