Title: Understanding a Low Vitamin D State in the Context of COVID-19

Abstract

While a low vitamin D state has been associated with an increased risk of infection by SARS-CoV-2 in addition to an increased severity of COVID-19 disease, a causal role is not yet established. Here, we review the evidence relating to i) vitamin D and its role in SARS-CoV-2 infection and COVID-19 disease ii) the vitamin D status in the Irish adult population iii) the use of supplemental vitamin D to treat a deficient status and iv) the application of the Bradford-Hill causation criteria. We conclude that reverse causality probably makes a minimal contribution to the presence of low vitamin D states in the setting of COVID-19. Applying the Bradford-Hill criteria, however, the collective literature supports a causal association between low vitamin D status, SARS-CoV-2 infection, and severe COVID-19 (respiratory failure, requirement for ventilation and mortality). A biologically plausible rationale exists for these findings, given vitamin D's role in immune regulation. The thresholds which define low, deficient, and replete vitamin D states vary according to the disease studied, underscoring the complexities for determining the goals for supplementation. All are currently unknown in the setting of COVID-19. The design of vitamin D randomised controlled trials is notoriously problematic and these trials commonly fail for a number of behavioural and methodological reasons. In Ireland, as in most other countries, low vitamin D status is common in older adults, adults in institutions, and with obesity, dark skin, low UVB exposure, diabetes and low socio-economic status. Physiological vitamin D levels for optimal immune function are considerably higher than those that can be achieved from food and sunlight exposure alone in Ireland. A window exists in which a significant number of adults could benefit from vitamin D supplementation, not least because of recent data demonstrating an association between vitamin D status and COVID-19. During the COVID pandemic, we believe that supplementation with 20-25ug (800-1000 IU)/day or more may be required for adults with apparently normal immune systems to improve immunity against SARS-CoV-2. We expect that higher monitored doses of 37.5-50 ug (1,500-2,000)/day may be needed for vulnerable groups (e.g., those with obesity, darker skin, diabetes mellitus and older adults). Such doses are within the safe daily intakes cited by international advisory agencies.

Keywords: Bradford-Hill criteria; SARS-CoV-2 infection; causation; disease severity; immunity; older adults; vitamin D; vitamin D supplementation.

FIGURE 1

Vitamin D Metabolism: UVB radiation penetrates the skin, converting 7-dehydrocholesterol to pre-vitamin D_3, which is rapidly converted to vitamin D₃. Vitamin D₃ is transported through the circulation to the liver. Dietary vitamin D₂ and D₃ are transported from the intestine to the liver by chylomicrons (plasma and lymph). In the liver, vitamin D is hydroxylated to 25(OH)D, mediated by CYP2R1 (cytochrome P450 [CYP] enzyme). Once released into the circulation 25(OH)D binds to vitamin D binding protein and is transported to the kidneys and other tissues. In the proximal tubules of the kidney, 1α-hydroxylation (CYP27B1) of 25(OH)D results in the production of the active vitamin calcitriol (1.25(OH)₂D). 1.25(OH)₂D induces the expression of the enzyme 24-hydroxylase encoded by the CYP24A1 gene which catalyses the conversion of 25(OH)D and 1.25(OH)₂D to the inactive 24-hydroxylated products, 24.25(OH)₂D and 1,24,25(OH)₃D respectively. Reproduced with permission from: Griffin TP, Bell M, Robinson S et al. (2017) Vitamin D and vitamin D deficiency in Ireland - a call to action. UPDATE Endocrinology and Diabetology [Internet]. 2017[37–40 pp.]. Available from: https://www.medicalindependent.ie/100980/update_ endocrinology__diabetology. Accessed 10.01.22).

FIGURE 2

Molecular pathways in the pathology of Covid-19 thought to be affected by vitamin D (adapted from McCartney et al., 2020).

FIGURE 3

Prevalence of vitamin D deficiency and vitamin D levels <50 nmol/L in Irish adults (n = 36,466) (Adapted from Scully et al., 2020).

FIGURE 4

Prevalence of Vitamin D levels <50 nmol/L in Irish adult population groups. Adapted from Scully et al., 2020 (https://doi.org/10.3390/nu12092663); Griffin et al., 2020 (https://doi.org/10.1093/gerona/glaa010), Laird et al., 2020b (DOI: 10.3390/nu12123674).