Abstract
Vitamin D is a group of lipophilic hormones with pleiotropic actions. It has been traditionally related to bone metabolism, although several studies in the last decade have suggested its role in sarcopenia, cardiovascular and neurological diseases, insulin-resistance and diabetes, malignancies, and autoimmune diseases and infections. In the pandemic era, by considering the response of the different branches of the immune system to SARS-CoV-2 infection, our aims are both to analyse, among the pleiotropic effects of vitamin D, how its strong multimodal modulatory effect on the immune system is able to affect the pathophysiology of COVID-19 disease and to emphasise a possible relationship between the well-known circannual fluctuations in blood levels of this hormone and the epidemiological trend of this infection, particularly in the elderly population. The biologically active form of vitamin D, or calcitriol, can influence both the innate and the adaptive arm of the immune response. Calcifediol levels have been found to be inversely correlated with upper respiratory tract infections in several studies, and this activity seems to be related to its role in the innate immunity. Cathelicidin is one of the main underlying mechanisms since this peptide increases the phagocytic and germicidal activity acting as chemoattractant for neutrophils and monocytes, and representing the first barrier in the respiratory epithelium to pathogenic invasion. Furthermore, vitamin D exerts a predominantly inhibitory action on the adaptive immune response, and it influences either cell-mediated or humoral immunity through suppression of B cells proliferation, immunoglobulins production or plasma cells differentiation. This role is played by promoting the shift from a type 1 to a type 2 immune response. In particular, the suppression of Th1 response is due to the inhibition of T cells proliferation, pro-inflammatory cytokines production (e.g., INF-γ, TNF-α, IL-2, IL-17) and macrophage activation. Finally, T cells also play a fundamental role in viral infectious diseases. CD4 T cells provide support to B cells antibodies production and coordinate the activity of the other immunological cells; moreover, CD8 T lymphocytes remove infected cells and reduce viral load. For all these reasons, calcifediol could have a protective role in the lung damage produced by COVID-19 by both modulating the sensitivity of tissue to angiotensin II and promoting overexpression of ACE-2. Promising results for the potential effectiveness of vitamin D supplementation in reducing the severity of COVID-19 disease was demonstrated in a pilot clinical trial of 76 hospitalised patients with SARS-CoV-2 infection where oral calcifediol administration reduced the need for ICU treatment. These interesting results need to be confirmed in larger studies with available information on vitamin D serum levels.