Why Appreciation of Pulmonary Vitamin D Metabolism Should Temper Expectations for Vitamin D Supplementation to Reduce Disease Severity and Improve Clinical Outcome of COVID-19

Vitamin D is a nutrient with anti-inflammatory properties whose role is currently being evaluated in COVID-19. Although studies are conflicting, they seem to suggest a role for vitamin D in reducing disease susceptibility but not in improving clinical outcome. In order to understand why vitamin D does not seem to have much effect on decreasing disease severity, it is essential to appreciate pulmonary vitamin D metabolism. To reach the pulmonary compartment, vascular endothelial cells would need to take up vitamin D from the blood stream, but they lack vitamin D receptor (VDR) and the activating enzyme CYP27B1. Endothelialitis – an important disease manifestation of COVID-19 – is therefore not expected to be directly affected by vitamin D. Bronchial epithelial cells are usually among the first to be infected with SARS-CoV-2. They do express both VDR and CYP27B1, but circulating vitamin D may not reach bronchial epithelial cells without transportation from the blood stream through the blood vessel wall. Inhalation therapy with vitamin D has therefore been suggested as an alternative for oral administration to bypass endothelial cells and efficaciously target bronchial epithelium. In conclusion, based on the principles of pulmonary vitamin D metabolism, it is not expected that vitamin D administration has a significant effect on COVID-19 severity. Vitamin D is more likely to reduce SARS-CoV-2 susceptibility, but reaching the airways with oral supplementation will be difficult and vitamin D inhalation therapy should be considered.