COVID-19 Mortality Risk Correlates Inversely with Vitamin D3 Status, and a Mortality Rate Close to Zero Could Theoretically Be Achieved at 50 ng/mL 25(OH)D3: Results of a Systematic Review and Meta-Analysis

Abstract

Background: Much research shows that blood calcidiol (25(OH)D3) levels correlate strongly with SARS-CoV-2 infection severity. There is open discussion regarding whether low D3 is caused by the infection or if deficiency negatively affects immune defense. The aim of this study was to collect further evidence on this topic.

Methods: Systematic literature search was performed to identify retrospective cohort as well as clinical studies on COVID-19 mortality rates versus D3 blood levels. Mortality rates from clinical studies were corrected for age, sex, and diabetes. Data were analyzed using correlation and linear regression.

Results: One population study and seven clinical studies were identified, which reported D3 blood levels preinfection or on the day of hospital admission. The two independent datasets showed a negative Pearson correlation of D3 levels and mortality risk (r(17) = -0.4154, p = 0.0770/r(13) = -0.4886, p = 0.0646). For the combined data, median (IQR) D3 levels were 23.2 ng/mL (17.4-26.8), and a significant Pearson correlation was observed (r(32) = -0.3989, p = 0.0194). Regression suggested a theoretical point of zero mortality at approximately 50 ng/mL D3.

Conclusions: The datasets provide strong evidence that low D3 is a predictor rather than just a side effect of the infection. Despite ongoing vaccinations, we recommend raising serum 25(OH)D levels to above 50 ng/mL to prevent or mitigate new outbreaks due to escape mutations or decreasing antibody activity.

Keywords: ACE2; ARDS; COVID-19; CRS; D3; SARS-CoV-2; angiotensin; calcidiol; calcitriol; cytokine release syndrome; immune status; immunodeficiency; inflammation; mortality; renin; virus infection; vitamin D.

Figure 1

Metabolic pathway of vitamin D3: The chemical formula of calcitriol is used to illustrate the biochemistry of vitamin D and its metabilites using different colors. The vitamin D pathway is characterized by two subsequent hydroxylation steps. In the liver, 25-Hydroxylase produces 25(OH)D3 (calcidiol), which can be stored in fat tissue. 1-Alpha-hydroxylase generates the active steroid hormone 1,25(OH)2D3 (calcitriol), which regulates calcium metabolism as well as the innate and adaptive immune system.

Figure 2

Interaction of vitamin D3 with the renin-angiotensin system (RAS): The renin-angiotensin system (RAS) is an important regulator of blood volume and systemic vascular resistance for the adjustment of blood pressure. The balance between angiotensin II and angiotensin-(1,7) is a critical factor for the proper functioning of the system [87]. Angiotensin-converting enzyme 2 (ACE2) is responsible for converting angiotensin II to angiotensin-(1,7). Angiotensin II primarily triggers vasoconstriction but can also cause inflammation, fibrosis, and oxidative stress in the absence of its counterpart, angiotensin-(1,7). ACE2 is the primary receptor of SARS-CoV-2, which decreases its activity, leading to an increase in angiotensin II levels and a decrease in angiotensin-(1,7) levels. This effect ultimately triggers SARS-CoV-2-induced “acute respiratory distress syndrome” (ARDS) [85,86]. Calcitriol, the active metabolite of vitamin D3, minimizes this effect by inhibiting renin expression and thus angiotensin II synthesis and by stimulating ACE2 expression [88,89], enhancing the conversion of angiotensin II to angiotensin-(1,7). Thus, insufficient vitamin D blood levels lead to the development of severe courses of SARS-CoV-2 disease. In addition, it has been shown that high angiotensin II levels lead to downregulation of the enzyme 1-alpha-hydroxylase [93], which is required for the formation of calcitriol, thereby exacerbating the negative consequences of vitamin D deficiency.

Figure 3

Flowchart of the search strategy and selection process [158].

Figure 4

Frequency distribution of vitamin D levels of all evaluated study cohorts.

Figure 5

Scatter plot and OLS regressions of the individual and combined datasets.