The COVID-19 pandemic and its consequences have demonstrated that viral infections still pose great challenge to health systems worldwide. The immune system plays a primary role in fighting infections, and non-specific innate immunity, in particular, is a key defense mechanism engaged during the first phases of an infection. The subsequent triggered immune response, characterized by specific cytokine patterns, can be exaggerated and lead to a cytokine storm, causing multiorgan damage and intravascular disseminated coagulation. Calcitriol, the active form of vitamin D, a key player in mineral homeostasis, is able to control the immune response by favoring the production of antimicrobial peptides (e.g., cathelicidin), decreasing viral shedding, and modulating the inflammatory process. A poor vitamin D status has been demonstrated to be associated with increased risk of infections, especially in fragile subjects, as also recently shown in COVID-19 disease. Unfortunately, this does not demonstrate that supplementation with vitamin D is significantly linked to prevention or modulation of the course of viral infections. Large intervention trials are necessary to produce evidence that vitamin D supplementation is linked to decreased rates of infections and related complications. At present, cholecalciferol and calcidiol regimens commonly employed in clinical practice to prevent and correct musculoskeletal abnormalities are advisable, at least in fragile, vitamin D-deficient individuals, in order to reach a target of serum 25(OH)D of 30–50 ng/ml, avoiding large doses, which can be responsible for hypercalciuria-hypercalcemia or increased falls.
