Vitamin D Deficiency Meets Hill's Criteria for Causation in SARS-CoV-2 Susceptibility, Complications, and Mortality:...

Clinical trials consistently demonstrate an inverse correlation between serum 25-hydroxyvitamin D [25(OH)D; calcifediol] levels and the risk of symptomatic SARS-CoV-2 disease, complications, and mortality. This systematic review (SR), guided by Bradford Hill's causality criteria, analyzed 294 peer-reviewed manuscripts published between December 2019 and November 2024, focusing on plausibility, consistency, and biological gradient. Evidence confirms that cholecalciferol (D₃) and calcifediol significantly reduce symptomatic disease, complications, hospitalizations, and mortality, with optimal effects above 50 ng/mL. While vitamin D requires 3-4 days to act, calcifediol shows effects within 24 h. Among 329 trials, only 11 (3%) showed no benefit due to flawed designs. At USD 2/patient, D₃ supplementation is far cheaper than hospitalization costs and more effective than standard interventions. This SR establishes a strong inverse relationship between 25(OH)D levels and SARS-CoV-2 vulnerability, meeting Hill's criteria. Vitamin D₃ and calcifediol reduce infections, complications, hospitalizations, and deaths by ~50%, outperforming all patented, FDA-approved COVID-19 therapies. With over 300 trials confirming these findings, waiting for further studies is unnecessary before incorporating them into clinical protocols. Health agencies and scientific societies must recognize the significance of these results and incorporate D₃ and calcifediol for prophylaxis and early treatment protocols of SARS-CoV-2 and similar viral infections. Promoting safe sun exposure and adequate vitamin D₃ supplementation within communities to maintain 25(OH)D levels above 40 ng/mL (therapeutic range: 40-80 ng/mL) strengthens immune systems, reduces hospitalizations and deaths, and significantly lowers healthcare costs. When serum 25(OH)D levels exceed 70 ng/mL, taking vitamin K₂ (100 µg/day or 800 µg/week) alongside vitamin D helps direct any excess calcium to bones. The recommended vitamin D dosage (approximately 70 IU/kg of body weight for a non-obese adult) to maintain 25(OH)D levels between 50-100 ng/mL is safe and cost-effective for disease prevention, ensuring optimal health outcomes.