Influence of 25-hydroxy-cholecalciferol Levels on SARS-CoV-2 Infection and COVID-19 Severity: A Systematic Review and Meta-analysis

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of coronavirus disease 19 (COVID-19), a respiratory infection that, starting from December 2019, has spread around the world in a few months, becoming a pandemic. The lack of initial knowledge on its management has led to a great effort in developing vaccines and in finding therapeutic weapons capable of improving the clinical outcome of the affected patients. In particular, the possible role of vitamin D status in the management of COVID-19 has been widely analysed, resulting in a great amount of data. This systematic review and meta-analysis aimed to assess whether hypovitaminosis D is a risk factor for developing SARS-CoV-2 infection and whether it affects the worsening of the clinical course of COVID-19.

Methods: Data were extracted through extensive searches in the Pubmed, MEDLINE, Cochrane, Academic One Files, Google Scholar, and Scopus databases from December 2019 to January 2021, using the keywords: "Vitamin D", "25 hydroxy Vitamin D", "25 hydroxycholecalciferol", "cholecalciferol", "COVID 19″, "SARS-CoV-2″. We included observational cohort, cross-sectional, and case-control studies that evaluated differences in serum levels of 25‑hydroxy-cholecalciferol [25(OH)D] in patients who were positive or negative for SARS-CoV-2, in patients with mild or severe forms of COVID-19, and in patients who died or were discharged from the hospital. Finally, studies that evaluated the risk of developing severe illness or death in patients with vitamin D deficiency (VDD), defined as levels of 25(OH) <20 ng/ml, were also included. We calculated the mean difference (MD) and the 95% confidence intervals (CI) for quantitative variables such as 25(OH)D levels in patients with or without SARS-CoV-2 infection, in those with mild vs. severe COVID-19, or those who have died vs. those who have been discharged. Instead, we calculated odds ratios and 95% CI for qualitative ones, such as the number of patients with severe illness/death in the presence of VDD vs. those with normal serum 25(OH)D levels. A p-value lower than 0.05 was considered statistically significant. The study was registered on PROSPERO (CRD42021241473).

Findings: Out of 662 records, 30 articles met inclusion criteria and, therefore, were included in the meta-analysis We found that the serum levels of 25(OH)D were significantly lower in patients with SARS-CoV-2 infection than in negative ones [MD -3.99 (-5.34, -2.64);  <0.00001; I= 95%]. Furthermore, its levels were significantly lower in patients with severe disease [MD -6.88 (-9.74, -4.03); <0.00001; I=98%] and in those who died of COVID-19 [MD -8.01 (-12.50, -3.51);  = 0.0005; I=86%]. Finally, patients with VDD had an increased risk of developing severe disease [OR 4.58 (2.24, 9.35); <0.0001; I=84%] but not a fatal outcome [OR 4.92 (0.83, 29.31);  = 0.08; I=94%].

Interpretation: This meta-analysis revealed a large heterogeneity of the studies included due to the different enrolment criteria of patient samples (age, body mass index, ethnicity, comorbidities), the country where they live, all factors influencing serum 25(OH)D levels, and the different criteria used to define the severity of COVID-19. Furthermore, the observational nature of these studies does not allow to establish a cause-effect relationship, even taking into account that 25(OH)D represents a marker of acute inflammation. Treatment with vitamin D might be considered for the primary prevention of SARS-CoV-2 infection and the management of patients with COVID-19. However, further intervention studies are needed to prove this hypothesis.