Review the Research

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Influence of 25-hydroxy-cholecalciferol levels on SARS-CoV-2 infection and COVID-19 severity: A systematic review and meta-analysis.

Take Home Message

The results of this meta-analysis suggest a relationship between low serum vitamin D and COVID-19 onset and severity.


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.



  • Serum levels of 25(OH)D were significantly lower in patients with SARS-CoV-2 infection than in negative ones.
  • Vitamin D levels were significantly lower in patients with severe disease and in those who died of COVID-19.
  • Patients with vitamin D deficiency had an increased risk of developing severe disease but not a fatal outcome.


29 studies including adult participants

Things to Keep in Mind

  • It is important to consider that the studies included are limited to the inclusion exclusion criteria of the study design and therefore may miss important studies with slightly different design but meaningful data.
  • In addition, in order to conduct a meta-analysis the studies included must have similar endpoints to extract and in doing so researchers may group together studies that are not the same, but will be analyzed as the same which can lead to skewed conclusions.
  • A meta-analysis only includes studies that have been published and therefore information gathered may be subject to publication bias. This means that studies that show no effect or the opposite of the expected effect may not be published and therefore not included.
  • The studies consider in-hospital mortality without specifying which complication led to the patient death, therefore it is not certain whether the fatal event resulted from the infection or whether the disease severity was an aggravating condition of an already compromised baseline situation.
  • Many of the included studies did not adjust for confounding (related factors) like BMI, Age, etc.
  • The studies were observational, had no control and therefore cause and effect cannot be established.

Author’s Conclusions

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.

Study Design

  • This study was performed by applying the Meta-Analysis and Systematic Reviews of Observational Studies (MOOSE) guidelines. It also complies with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P).
  • The 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.
  • The search strategy included the combination of the following Medical Subjects Headings (MeSH) terms and keywords: “Vitamin D”, “25 hydroxy Vitamin D”, “25 hydroxycholecalciferol”, “cholecalciferol”, “COVID 19″, “SARS-CoV-2″.
  • Included studies were all observational, cohort, cross-sectional, and case-control studies that evaluated 1) the differences in 25(OH)D levels in patients who were positive or negative for the SARS-CoV-2, 2) the difference in 25(OH)D levels between patients with severe COVID-19 and patients with asymptomatic or paucisymptomatic (few symptoms) disease, and 3) analyzing the correlation between hypovitaminosis D and the risk of severe course of COVID-19 and in-hospital mortality. Studies that diagnosed COVID-19 by real-time polymerase chain reaction on a nasopharyngeal swab or with at least one positive test for SARS-CoV-2 infection, or with vitamin D deficiency diagnosed when the levels of 25(OH)D were lower than 20 ng/ml according to the Endocrine Society guidelines were included


Crafa A, Cannarella R, Condorelli RA, Mongioì LM, Barbagallo F, Aversa A, La Vignera S, Calogero AE. Influence of 25-hydroxy-cholecalciferol levels on SARS-CoV-2 infection and COVID-19 severity: A systematic review and meta-analysis. EClinicalMedicine. 2021 Jul;37:100967. doi: 10.1016/j.eclinm.2021.100967. Epub 2021 Jun 18. PMID: 34179737; PMCID: PMC8215557.

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Research Summaries

Association Between Vitamin D Supplementation and COVID-19 Infection and Mortality

Association Between Vitamin D Supplementation and COVID-19 Infection and Mortality Take Home Message Among VA (Veterans Administration) patients, vitamin D3 and vitamin D2 supplementation reduced the associated risk of COVID-19 infection