Prognostic and Therapeutic Role of Vitamin D in COVID-19: Systematic Review and Meta-analysis

Abstract

Purpose Vitamin D deficiency/insufficiency may increase the susceptibility to COVID-19. We aimed to determine the association between vitamin D deficiency/insufficiency and susceptibility to COVID-19, its severity, mortality and role of vitamin D in its treatment. Methods We searched CINHAL, Cochrane library, EMBASE, PubMED, Scopus, and Web of Science up to 30.05.2021 for observational studies on association between vitamin D deficiency/insufficiency and susceptibility to COVID-19, severe disease and death among adults, and, randomized controlled trials (RCTs) comparing vitamin D treatment against standard care or placebo, in improving severity or mortality among adults with COVID-19. Risk of bias was assessed using Newcastle-Ottawa scale for observational studies and AUB-KQ1 Cochrane tool for RCTs. Study-level data were analyzed using RevMan 5.3 and R (v4∙1∙0). Heterogeneity was determined by I 2 and sources were explored through pre-specified sensitivity analyses, subgroup analyses and meta-regressions. Results Of 1877 search results, 76 studies satisfying eligibility criteria were included. Seventy-two observational studies were included in the meta-analysis (n=1976099). Vitamin D deficiency/insufficiency increased the odds of developing COVID-19 (OR 1∙46, 95% CI 1∙28–1∙65, p<0∙0001, I 2=92%), severe disease (OR 1∙90, 95% CI 1∙52–2∙38, p<0.0001, I 2=81%) and death (OR 2∙07, 95% CI 1∙28–3∙35, p=0.003, I 2=73%). 25-hydroxy vitamin D (25(OH)D) concentration were lower in individuals with COVID-19 compared to controls (mean difference [MD] -3∙85 ng/mL, 95% CI -5∙44,-2∙26, p=<0.0001), in patients with severe COVID-19 compared to controls with non-severe COVID19 (MD -4∙84 ng/mL, 95% CI -7∙32,-2∙35, p=0∙0001) and in non-survivors compared to survivors (MD -4∙80 ng/mL, 95%-CI -7∙89,-1∙71, p=0∙002). The association between vitamin D deficiency/insufficiency and death was insignificant when studies with high risk of bias or studies reporting unadjusted effect estimates were excluded. Risk of bias and heterogeneity were high across all analyses. Discrepancies in timing of vitamin D testing, definitions of severe COVID-19 and vitamin D deficiency/insufficiency partly explained the heterogeneity. Four RCTs were widely heterogeneous precluding meta-analysis. Conclusion Multiple observational studies involving nearly two million adults suggest vitamin D deficiency/insufficiency increases susceptibility to COVID-19 and severe COVID-19, although with a high risk of bias and heterogeneity. Association with mortality was less robust. Heterogeneity in RCTs precluded their meta-analysis.

The Role of Nutrients in Prevention, Treatment and Post-Coronavirus Disease-2019 (COVID-19)

“…However, for some of them, such as vitamin D, diet alone cannot increase serum 25 (OH) D concentrations to provide optimal protection from SARS-CoV-2. In addition, further randomized trials with an early administration of high doses of vitamin D after the onset of COVID-19 should be conducted in order to identify the right time to start vitamin D administration to achieve a significant effectiveness [ 45 ].…”

Vitamin D Intake May Reduce SARS-CoV-2 Infection Morbidity in Health Care Workers

“…The bolus vitamin D supplementation also was associated with decreased mortality in hospitalized COVID-19 patients in Turkey [ 20 ], and an improved 3-month survival in geriatric patients [ 21 ]. This information was confirmed in a meta-analysis that included data from observational and randomized controlled trials that reported reduced severity risk with higher 25(OH)D, and some benefit from vitamin D in treating COVID-19 [ 22 ].…”

“…Our previous results also showed that severe vitamin D deficiency is associated with severity and death in COVID-19 patients [ 29 ], and were comparable to recent findings [ 4 , 30 ]. Dissanayake and colleagues, whose meta-analysis included 72 COVID-19 observational and 4 interventional randomized studies, have shown not only correlations between 25(OH)D level and severity or mortality, but also some clinical benefits and improvement in inflammatory markers of vitamin D supplementation in treating COVID-19 [ 22 ].…”

Vitamin D’s Role in Reducing Risk of SARS-CoV-2 and COVID-19 Incidence, Severity, and Death

“…A recent meta-analysis involving 76 studies reported inverse correlations for COVID-19 risk with respect to serum 25(OH)D concentrations for risk of developing the disease, its severity, and risk of death [ 3 ], thus offering support for the role of vitamin D in reducing risk of COVID-19.…”

“…However, because of the concern that having an acute inflammatory illness could lower serum 25(OH)D concentrations [ 4 ], observational studies of COVID-19 using 25(OH)D concentrations measured at or near time of diagnosis have been questioned. The data in Figure 3 of reference [ 3 ] can be used to address that concern. The 19 studies can be divided into four categories: 25(OH)D at time of diagnosis (seven studies); within 1 year prior (eight); preceding 10 years (one); and 10–15 years prior (three).…”