Bone Metabolism Unit. Internal Medicine Service. Marquis de Valdecilla University Hospital. University of Cantabria. Santander

Vitamin D is a fundamental hormone for the maintenance of musculoskeletal health and the proper functioning of the immune system[1]. The new coronavirus pandemic, SARS-CoV-2, which emerged in Wuhan at the end of 2019, has hit the world with extraordinary virulence[2]. Several lines of evidence support a potential role for vitamin D in COVID-19. First, a recent meta-analysis has shown a beneficial effect of vitamin D in preventing viral respiratory diseases, especially in those subjects with greater deficiency of this hormone[3]. In addition, vitamin D is crucial in modulating the innate immune system (production of antimicrobial peptides such as cathelicidin and activation of autophagy) and adaptive (inhibition of the activation of Th1 lymphocytes, activation of Th2 lymphocytes, decrease of cells Th17/Treg and inhibition of the proliferation and differentiation of B lymphocytes). Vitamin D deficiency is especially conspicuous in the elderly, in obese individuals and those with chronic diseases such as cancer, diabetes or cardiovascular diseases, which also represent the groups with the highest severity of COVID-19. Finally, vitamin D inhibits proinflammatory cytokine production and its deficiency can induce activation of the renin-angiotensin system (RAS), leading to the production of profibrotic factors and lung damage. This dysregulation of the RAS in COVID-19, mediated by the ACE2 receptor, through which SARS-CoV-2 penetrates the host cell, is responsible for the cytokine storm that precedes the characteristic acute respiratory distress syndrome. of the most serious form of infection by this coronavirus[4].
In this sense, although the studies published to date are heterogeneous in terms of methodology, sample size, inclusion criteria, ethnicity, geographic factors, criteria for defining COVID-19 severity and statistical analysis, the results of the meta-analyses and systematic reviews indicate a significant relationship between vitamin D deficiency and increased risk of SARS-CoV-2 infection and greater severity and mortality of COVID-19[5-10].
The aim of this brief review is to analyze the published works on the potential effect of vitamin D administration (without combination with other nutritional or vitamin supplements) in patients with COVID-19. A PubMed/MEDLINE database search was carried out up to August 1, 2021, using the key terms and operators “COVID-19” OR “SARS-CoV-2” AND “vitamin D supplementation”. Observational studies and clinical trials were included, regardless of their design.

Vitamin D in the treatment of COVID-19
Observational studies and clinical trials
Table 1 summarizes the published studies on the use of vitamin D supplements in patients with COVID194,[11-25]. As can be seen, the studies have been mainly of a prospective and retrospective observational design, in varied populations (hospitalized patients, institutionalized patients), with a highly variable sample size and with a heterogeneous adjustment of the influence of the potential confounding variables on the primary objective. Most used cholecalciferol and three of them calcifediol. For the most part, data were not available on the time from the onset of symptoms of SARS-CoV-2 infection and the start of vitamin D supplementation, nor on baseline 25(OH)D levels or the degree of increase of these after treatment. In addition, the doses of vitamin D were varied considerably (between 25,000 and 400,000 IU) and the time of initiation was also diverse (at diagnosis, admission or in the first days of hospitalization). The therapeutic regimen was also very different between the available clinical studies. The main objectives most frequently analyzed were mortality and the need for admission to the Intensive Care Unit (ICU).
Among all these studies, the so-called GERIA17 yields some interesting results on the preventive role that could be associated with vitamin D treatment prior to contracting the infection. The GERIA study is a retrospective study that was carried out in 3 groups of geriatric patients with COVID-19 with a poor prognosis. Group 1 included patients who had been supplemented with cholecalciferol during the year prior to the diagnosis of the infection. In group 2, patients supplemented with cholecalciferol a few hours after being diagnosed. Group 3 patients did not receive any supplementation. In conclusion, hospitalized frail elderly patients with COVID-19 who had received regular vitamin D3 supplementation for at least the year prior to COVID-19 diagnosis (50,000 IU/month, or 80,000 – 100,000 IU/2-3 months) presented a less severe COVID-19 and better survival rate. Aware that confirmatory studies are needed, the authors commented that vitamin D3 supplementation may represent an effective, accessible, and well-tolerated method of adjuvant treatment for COVID-19.

Meta-analysis and systematic reviews
Despite the heterogeneity of the studies published to date, the results of the meta-analyses, in general, show a trend towards a beneficial effect of vitamin D supplementation, in terms of reducing the severity of COVID-19 and especially in patients with deficiency of this vitamin[26]. However, in all of them it is pointed out that many unknowns remain to be resolved, especially regarding the type of supplementation, the dose, the most appropriate time of use and the duration of treatment with vitamin D.
Recently, Pal et al.[27] carried out a systematic review and meta-analysis of 10 observational studies and 3 clinical trials, with a total of 2,933 patients with COVID-19. The most relevant finding of this study was that the improvement in the adverse events of the disease was only observed in the subgroup of patients who received the vitamin D supplement after the diagnosis of COVID-19, but not in those who had previously received it. Rawat et al.[28] carried out a systematic review of quasi-experimental studies and clinical trials only and found no relationship between vitamin D supplementation and the need for invasive ventilation, admission to the ICU or mortality in patients with COVID-19. In any case, they again point out that the aforementioned limitations of the different studies prevent solid conclusions. Clinical trials with uniform methodology need to be carried out with an adequate sample size to resolve this issue.
In the systematic review by Da Rocha et al.[29] only the 3 clinical trials were analyzed, concluding that the evidence for the use of vitamin D in COVID-19 is currently insufficient. Grove et al. reached the same conclusion in a systematic review that evaluated the effect of vitamin D supplementation and vitamin D levels on susceptibility to SARS-CoV-2 infection or COVID-19, including morbidity and mortality variables[30].
The recent review of the Cochrane collaboration[31] published in May 2021 analyzed several relevant aspects of the relationship between vitamin D supplementation and SARS-CoV-2 infection. According to this systematic review, only 2 studies with a total of 213 participants[11,12] compared the effect of vitamin D supplementation (cholecalciferol and calcidiol, respectively) versus placebo or standard treatment on all-cause mortality, in subjects with moderate or severe COVID-19, without finding a clear protective effect. Regarding the need for mechanical ventilation and the duration of admission in this same population, Murai et al.[12] showed a non-significant trend towards a benefit of cholecalciferol supplementation in the first case and no effect in terms of reduction of the average hospital stay. As already shown in table 1, Entrenas-Castillo et al.[11] observed a significant reduction in ICU admission with their calcifediol regimen, while Murai et al.[12] showed a non-significant trend towards the same beneficial effect with cholecalciferol. The authors of the review point out again the heterogeneity and the different methodology, type of supplement, guideline, etc., between the different works. Thus, they conclude that the evidence of a potential benefit of vitamin D supplementation in patients with COVID -19 is currently uncertain. Several clinical trials are underway that will make it possible to answer open questions regarding the usefulness of vitamin D supplementation both in the prevention and treatment of COVID-19 in different population groups (clinicaltrials.gov).

Conclusions
According to the data available to date, vitamin D supplementation could have a beneficial effect on the evolution of COVID-19, although the level of evidence from the studies is insufficient to draw solid conclusions in this regard. Severe COVID-19 particularly affects people at high risk of vitamin D deficiency (the elderly, institutionalized subjects, obese people and patients with comorbidities), so institutional policies aimed at achieving adequate levels of 25(OH) should be promoted. D in these populations. Pending ongoing clinical trials with adequate methodology, treatment with vitamin D supplements may be considered in patients with COVID-19 and vitamin D deficiency.

Conflict of interest: The author declares that he has no conflicts of interest.

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