Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 6 December 2020 / Approved: 7 December 2020 / Online: 7 December 2020 (19:43:48 CET)

How to cite: Janssen, R.; Walk, J.; van den Ouweland, J.M. 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. Preprints 2020, 2020120176 (doi: 10.20944/preprints202012.0176.v1). Janssen, R.; Walk, J.; van den Ouweland, J.M. 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. Preprints 2020, 2020120176 (doi: 10.20944/preprints202012.0176.v1).

Abstract

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.

Keywords

Vitamin D; COVID-19; SARS-CoV-2; endothelialithis; CYP27B1; vitamin D receptor; CYP24A1

Comments (1)

Comment 1
Received: 22 December 2020
The commenter has declared there is no conflict of interests.
Comment: In discussing the Castillo et al study, your preprint incorrectly states that, "comorbidities (i.e. diabetes and hypertension) were unevenly distributed between the intervention and control groups, and the differences lost significance after correcting for this". In fact, the study said the opposite, namely that after correcting for diabetes and hypertension the differences remained extremely significant. The corrected odds ratio was 0.03 (95%CI: 0.003- 0.25). In other words, with 95% confidence the treatment decreased the odds of requiring ICU care by at least a factor of 4, so the improvement is very statistically significant. I hope you will correct this misrepresentation of the results of Castillo et al.
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