The Role of Vitamin D in COVID-19 Survival and Prevention: A Meta-analysis

Background: COVID-19 is still ongoing with frequently discovered new strains, although vaccines are highly effective for prevention. Literature on vitamin D supplementation in COVID-19 prevention and its effect on survival is scarce. This meta-analysis assessed the role of vitamin D supplementation in COVID-19 prevention and survival. Methods: Four databases (Web of Science, SCOPUS, PubMed, MEDLINE, and the ﬁrst 100 articles of Google Scholar) were searched for articles published up to September 2023. The keywords used were COVID-19, mortality


Introduction
The Covid-19 pandemic has become the most dramatic event of the current century with more than 50 million confirmed cases and 18.2 million deaths during the period January 2020-December 2021 [1].In the aftermath of COVID-19, a great challenge is still present due to the long-COVID or postacute COVID-19 syndrome.The persistence of symptoms (fatigue, cognitive decline,cough, sputum, headache, chest pain, insomnia, wheeze, taste and smell disturbances) among those who recovered is called post-COVID-19 syndrome or long COVID-19.The prevalence of post-COVID-19 at 90 days is substantial with a great burden on the patients and the healthcare system [2].Vitamin D performs both skeletal and extra-skeletal functions, and vitamin D receptors are expressed in various tissues.Vitamin D receptors are expressed in the lung, brain, heart, and immune system.Therefore, vitamin D deficiency is associated with immune and inflammatory conditions, chest infections including COVID-19.In addition, vitamin D deficiency is associated with type 1 diabetes, demyelination, and rheumatoid arthritis [3].Importantly, enzyme 1 alpha-hydroxylase (CYP27B1) is expressed in many organs and can activate vitamin D to exert autocrine or paracrine effects [4].Evidence regarding the effects of vitamin D deficiency and vitamin D supplementations on COVID-19 is contradicting; some studies found a reduction in severity and mortality [5], while Hastei and colleagues who published a study with large population size and long follow-up study period showed no association of vitamin D deficiency, disease severity, and mortality [6].A meta-analysis with a high selection bias and heterogeneity showed no difference among patients who took vitamin D and their counterparts without supplementation regarding COVID-19 outcomes [7].On the other hand, Naguyen et al. found better outcomes among patients with normal vitamin D levels [8].The controversy is ongoing; Hu et al. found no association of vitamin D levels on severity, ventilation need, and mortality [9], and Tomaszewska et al.
concluded no evidence of vitamin D in treatment of COVID-19 [10].Moreover, new studies have been published covering this topic -Cannata-Andia et al. [11] showed no benefit of single oral dose of vitamin D on outcomes; Fernandes and colleagues [12] found no benefits of single 200,000 IU vitamin D3 on cytokines, growth factors, and chemokines among hospitalized patients with severe COVID-19, and Annweiler et al. [13] found the benefit of the early high-dose chemokinese vitamin D supplementation among patients with severe COVID-19.Therefore, a meta-analysis on the effects of vitamin D supplementation on COVID-19 mortality and prevention is justifiable.
Thus, this meta-analysis aimed to assess the same among patients with COVID-19.

Eligibility criteria according to PICOS
We included randomized controlled trials, prospective, and retrospective studies.The studies must assess the effects of vitamin D supplementation on COVID-19 prevention and mortality.Casecontrol studies, cross-sectional studies, experts' opinions, editorials, case reports, and series were not included.

Risk of bias assessment
The Newcastle Ottawa Scale risk of bias assessment, and a modified Cochrane risk of bias were used [14,15].All the included studies were of good quality.

Statistical analysis
RevMan, version 5.4 was used to analyze the dichotomous of 16 studies, 8 studies that assessed the effects of vitamin D on mortality, and 8 cohorts that assessed the effects on COVID-19 prevention.
The random effect was used (because of the significant heterogeneity).A P-value of <0.05 was considered significant.

Results
In the present meta-analysis, 5905,109 patients were included from 16 studies, and 186,500 events occurred.Eleven studies were from Europe, two were from the USA, two were published in South

Discussion
The present meta-analysis pooled 16  A previous meta-analysis with a limited number of studies [32] found no effects of vitamin D supplementation on primary COVID-19 prevention, in contradiction to the present findings, regarding mortality the authors found a positive effect in line with current findings.The current results were in agreement with a previous meta-analysis [33] which found a reduction in all-cause mortality and      [32], who included only five studies, and Bassatne et al. [37], who included only three, found no benefits, and contradicting the current findings, a Mendelian randomization study failed to support the use of vitamin D for COVID-outcomes [49].
Plausible explanation might be the difference in vitamin D dose, high intermittent doses of vitamin D paradoxically deplete intracellular vitamin D as a rebound in particular in immune cells [50].For now, doses of 4000 IU daily are recommended [37].The strength of this meta-analysis is that it is the first to assess the role of vitamin D in COVID-19 secondary prevention and included a large randomized controlled trials.However, the significant heterogeneity observed substantially limited our findings.Further randomized trials with large sample size focusing on the timing of vitamin D supplementations (before against hospital), the dose (continuous or intermittent, high versus low), comorbidities, and vaccination status are recommended.

Conclusion
Vitamin

Limitation
The study was limited by the inclusion of observational studies, and significant heterogeneity (due to the pooling of studies with different methodologies) was observed in the mortality arm.

Figure 1 :
Figure 1: Studies that assessed the effects of vitamin D supplementation on COVID-19 prevention and mortality (the PRISMA Chart).
America, and one was from Asia.Eight studies assessed vitamin D supplementation on COVID-19 mortality [15-23] and eight cohorts investigated the effects of vitamin D supplementation on COVID-19 prevention [24-31].Vitamin D supplementation reduced mortality among patients with COVID-19 patients, odd ratio, 2.31, 95% CI, 1.49-3.58.The Chi-square was 14.53, and the P-value for the overall effect was 0.0002.A significant heterogeneity was found, I 2 for heterogeneity = 52%, P-value, 0.04, and the standard difference = 7 (Figure2).Vitamin D supplementation was effective in COVID-19 prevention, odd ratio, 1.92, 95% CI, 1.01-3.64.The Chi-square was 204.46, and the Pvalue for the overall effect was 0.05.Significant heterogeneity was found, I 2 for heterogeneity = 97%, P-value < 0.001, and the standard difference = 7 (Figure3).The source of heterogeneity was the pooling of studies with different methodology.The significant heterogeneity in particular regarding Covid-19 prevention limited the current results.The random effect was used.
primary prevention.The authors pointed out that vitamin D supplementation improved outcomes of COVID-19 only when prescribed after COVID-19 diagnosis.The previous study was limited by pooling both randomized and observational studies and included in their results various studies published by the same authors [34, 17].Shah and colleagues [35] in their meta-analysis found no difference between vitamin D supplementation, placebo, and usual care.A big limitation of Shah et al. study is that they included only three underpowered studies with a high baseline heterogeneity.Nikniaz et al. [36] included only four studies with a limited number of patients (259) and found lower mortality among the vitamin D supplementation arm.The link between vitamin D Sudan Journal of Medical Sciences Begum, Mirghani

Figure 2 :
Figure 2: The effects of vitamin D supplementation on mortality among patients with moderate/severe COVID-19.

Figure 3 :
Figure 3: The effects of vitamin D supplementation on COVID-19 prevention.
D supplementation prevented COVID-19 and increased survival among patients admitted with moderate/severe COVID-19.Further randomized control trials assessing the time, duration, and doses of vitamin D are recommended.

.1. Literature search
analysis.A structured checklist was used to gather the author's name, country, year of publication, number of patients in vitamin D supplementation and control group, age and sex of the participants, the study duration, mortality, and comorbidities.Sudan Journal of Medical Sciences Begum, Mirghani

Table 1 :
Vitamin D supplementation and mortality reduction among patients with COVID-19.

Table 2 :
Basic characteristics of patients with COVID-19 and vitamin D supplementation.

Table 4 :
Basic characteristics of patients on vitamin D supplementation for COVID-19 prevention.

Table 5 :
Newcastle Ottawa risk of bias of observational studies.

Table 6 :
Risk of bias assessment of the included studies according to Cochrane risk of bias of randomized controlled trials.