Study: Vitamin D deficiency link to COVID-19 patient fatality

1.1. Vitamin D effects

The skeletal and extra skeletal effects of vitamin D have recently been described in an extensive review [¹⁴]. Vitamin D exerts a genomic and non-genomic effect on gene expression. The genomic effect is mediated by the nuclear vitamin D receptor (VDR), which acts as a ligand activated transcription factor. The active form 1,25(OH)₂D binds to the VDR and in most cases heterodimerizes with the retinoid X receptor (RXR), whose ligand is one of the active metabolites of vitamin A, 9-cis retinoic acid.

The interaction of this complex with the vitamin D responsive element can regulate the expression of target genes either positively or negatively [¹⁵]. The non-genomic effects involve the activation of a variety of signaling molecules that interact with Vitamin D responsive element (VDRE) in the promoter regions of vitamin D dependent genes [¹⁶]. Vitamins A and D are also of particlular importance for the barrier function of mucous membranes in the respiratory tract [^17,18].

1.2. Vitamin D and immune system

Vitamin D plays an essential role in the immune system [¹⁹]. Vitamin D interferes with the majority of the immune systems cells such as macrophages, B and T lymphocytes, neutrophils and dendritic cells, which express VDR (for details [²⁰] and Fig. 3). Cathelicidin, a peptide formed by vitamin D stimulated expression, has shown antimicrobial activity against bacteria, fungi and enveloped viruses, such as corona viruses [^21,22]. Furthermore Vitamin D inhibits the production of pro-inflammatory cytokines and increases the production of anti-inflammatory cytokines [²³].

The active metabolite of vitamin D in macrophages and dendritic cells, derived from the precursor 25(OH)D, leads to the activation of VDR, which, after RXR heterodimerization, results in the expression of various proteins of the innate and adaptive immune system (Treg cells, cytokines, defensins, pattern recognition receptors etc.) [²⁴]. Vitamin D exerts opposite effects on the adaptive (inhibition) and innate (promotion) immunsystem This correlates with an anti-inflammatory response and balances the immune response [²⁵].

The active metabolite of vitamin D, 1,25(OH)2D3 can be formed in T and B lymphocytes and inhibits T cell proliferation and activation [²⁶]. This way, vitamin D may suppress T-cell mediated inflammation and stimulate Treg cells proliferation, by increasing IL-10 formation in DC cells, and thus enhance their suppressive effect [^27,28].

1.3. Food sources

There are only few dietary sources of vitamin D (cod liver oil, fat fish) that could satisfy the recommended daily allowance (15–20 μg/day for adults). To reach such amount besides availability of dietary sources, vitamin D skin synthesis, which contributes to 80% in healthy individuals up to the age of 65, is important.

With the exception of mushrooms there are no plant sources of vitamin D. In particular wild mushrooms, which are grown in light. Sun-dried but not fresh mushrooms can contain between 7 and 25 μg/100 g of vitamin D2 [²⁹], which is an important source [³⁰] with a good shelf life [³¹] and comparable bioavailability to vitamin D3 [³²]. Vitamin D status can be significantly improved by fortified foods, as was shown in a meta-analysis [³³].

1.4. Vitamin D deficiency

Insufficient levels of vitamin D are caused by two main physiological causes: Low UVB exposure, especially in northern regions during the winter season [³⁴] and in case of strong pigmentation, as well as decreased vitamin synthesis in the skin with aging [³⁵]. In addition a poor diet, low in fish and fortified food (if available) are the major reason for deficiency in old age and people living in poverty. Major risk groups [³⁶], besides pregnant women and children under 5, include elderly, over 65 years, those with little or no sun exposure (full body coverage, little contact with the outside world) as well as people with dark skin, especially in Europe and the USA.

The vitamin D deficiency is a worldwide problem, which is not only observed in the northern countries, but increasingly also in the south. While in Europe, for example, deficits (< 30 nmol) are between 20 and 60% in all age groups, in Asia the figure for children is 61% (Pakistan, India) and 86% (Iran) [^37,38].

Particularly critical is the number of migrants from Southern countries with insufficient vitamin D status (<25 nmol/L) [³⁹]: e.g. Netherlands 51%, Germany 44% (in summer), UK 31% (end of summer) and 34% (autumn). In India, the number of adults with values < 25 nmol/L ranges from 20% to 96% depending on the region.

The half-life of 25(OH)D₃ is about 15 days and that of 25(OH)D₂ is between 13 and 15 days, due to the weaker affinity to the vitamin D binding protein [⁴⁰]. Consequently, longer periods of time indoor, e.g. in care homes or longer time in quarantine, pose risk for developing vitamin D deficiency.

1.5. Risk factors for severe courses of COVID-19

Older age and co-morbidities are linked to an insufficient vitamin D supply. Over 60 years of age, a reduction in the synthesis of vitamin D in the skin becomes apparent, which further increases getting older [⁴¹]. The precursor of vitamin D, 7-dehydrocholesterol in the skin declines about 50% from age 20 to 80 [⁴²], and the elevation of cholecalciferol levels in serum following UVB radiation of the skin shows more than a 4-fold difference in individuals aged 62–80 yrs. compared with controls (20–30 yrs) [⁴³]. This explains the high number of older individuals with an inadequate vitamin D status.  ….

…..

3. Conclusion

An inadequate supply of vitamin D has a variety of skeletal and non-skeletal effects. There is ample evidence that various non-communicable diseases (hypertension, diabetes, CVD, metabolic syndrome) are associated with low vitamin D plasma levels. These comorbidities, together with the often concomitant vitamin D deficiency, increase the risk of severe COVID-19 events. Much more attention should be paid to the importance of vitamin D status for the development and course of the disease. Particularly in the methods used to control the pandemic (lockdown), the skin’s natural vitamin D synthesis is reduced when people have few opportunities to be exposed to the sun. The short half-lives of the vitamin therefore make an increasing vitamin D deficiency more likely. Specific dietary advice, moderate supplementation or fortified foods can help prevent this deficiency. In the event of hospitalisation, the status should be urgently reviewed and, if possible, improved.

In the meantime, 8 studies have started to test the effect of supplementing vitamin D in different dosages (up to 200,000 IU) on the course of the COVID-19 disease. The aim is to clarify whether supplementation with vitamin D in different dosages has an influence on the course of the disease or, in particular, on the immune response, or whether it can prevent the development of ARDS or thromboses [¹⁹³].

Read the full paper (plus links) at www.ncbi.nlm.nih.gov

****