Association Between Vitamin D Levels and Inflammatory Markers in COVID-19 Patients: A Meta-Analysis of Observational Studies

Abstract

Purpose: Vitamin D has immunomodulatory properties that can be useful in COVID-19 patients. We performed a meta-analysis of observational studies to analyze the association of vitamin D levels with the inflammatory markers in COVID-19 patients. Methods: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Database of Systematic Reviews, and ClinicalTrial.gov for any relevant studies with comparison data reporting vitamin D levels and inflammatory markers in COVID-19 patients. A literature search was conducted from December 1, 2019, to January 14, 2022. Vitamin D deficiency was defined by each individual study and ranged from <9.9 ng/mL to <30 ng/mL. The inflammatory markers of interest were interleukin-6 (IL-6), C-reactive protein (CRP), ferritin, procalcitonin, erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), fibrinogen and D-dimer. Weighted mean difference (WMD) and 95% confidence intervals (CIs) were pooled using random or fixed-effects models. Two independent investigators assessed study eligibility and synthesized the evidence. Results: Thirty-two observational studies were included comprising of 7,771 patients ranging from 40-81 years of age with 57.1% being male. Meta-analysis showed that patients that were vitamin D sufficient (levels >30ng/mL) had statistically significant lower levels of IL-6, CRP, ferritin, LDH, fibrinogen, and D-dimer compared to vitamin D deficient group. With the highest mean difference found in ferritin (95.62; 95% CI, 33.14-158.10); P=0.003; I²=99%). No significant reductions were found in ESR (P=0.97). All inflammatory markers analyzed were higher than the normal healthy reference ranges in both groups. Conclusions: Our results suggest that low vitamin D levels are associated with increased inflammatory marker levels. Vitamin D deficiency may potentially serve as an early identifier for COVID-19 patients at high risk of developing severe inflammatory conditions as well as thrombotic complications. Randomized controlled trials should be conducted to establish a causal relationship.