Patients with low vitamin D are at greater risk for infection, hospitalization and death. However, High dose of vitamin D has no therapeutic effect in COVID-19 patients. This could be due to inadequate conversion of the inactive vitamin D (calcidiol) to the active calcitriol..

1. THE UNRESOLVED STATUS
OF
VITAMIN-D IN COVID-19
By
Kevin KF Ng, MD, PhD.
Former Associate Professor of Medicine
Division of Clinical Pharmacology
University of Miami, Miami, FL, USA.
Email: kevinng68@gmail.com
A Slide Presentation for HealthCare Providers Nov 2021

2. Presentation Outline
▪ Vitamin D and COVID-19 in the news.
▪ What is vitamin D?
▪ Different forms of vitamin D.
▪ Prevalence of Vitamin D deficiency among COVID-19
patients
▪ Mortality of COVID-19 patients with Vitamin D deficiency
▪ Treatment of COVID-19 patients with high dose of
25hydroxyvitamin D3 (calcidiol)
▪ A Pilot study of 1,25 hydroxyvitamin D3 (calcitriol) in
hospitalized COVID-19 patients shows favorable results.
▪ Comment

3. Vitamin D & COVID-19 in the news

4. What is Vitamin D
▪ Vitamin D is a group of fat-soluble secosteroids involved in calcium absorption,
immune functions and cardiovascular health.
Supplement

5. Classification of Vitamin D

6. Sources of Vitamin D
plant
synthetic
UV on skin
Food
Supplement

7. Different forms of Vitamin D
https://www.researchgate.net/figure/Chemical-structures-of-vitamin-
D-3-D-2-25OHD-and-1-25OH-2-D-Structural_fig1_344692424
(ergocalciferol)
(cholecalciferol)
(calcidiol) (calcitriol)
active form

8. Difference between vitamin D2 and vitamin D3
Vitamin D2 (ergosterol)
▪ Found in plants and mushrooms
▪ Synthetically derived supplements
▪ Molecular weight 397 g/mol
▪ Relatively unstatble compound
▪ Half-life of 2 days
Vitamin D3 (cholecalciferol)
▪ Synthesized in skin by UV light
▪ Naturally derived from foods
▪ Molecular weight 384.64 g/mol
▪ Relatively stable compound
▪ Half-life of 24 hours

9. PHYSIOLOGICAL ACTIONS OF VITAMIN D
Conversion of the inactive vitamin D to the active vitamin D

10. Conversion of Vitamin D to physiologically active molecule

11. Two enzymes are involved in the conversion of
Vitamin D (Cholecalciferol) to active molecule (1,25 hydroxyvitamin D3)
©DRKEVINKFNG

12. Functions of active 1,25 hydroxyvitamin D3
Calcium
absorption
Immune
function
Bone, muscle, heart
health
©DRKEVINKFNG
+

13. Mechanism of immuno-modulatory & anti-inflammatory actions of
active 1,25-hydroxyvitamin D3 (calcitriol)
▪ The physiologically active 1,25 hydroxyvitamin D3 (calcitriol) is bound in blood to
the vitamin D-binding protein.
▪ The action of calcitriol is mediated by the vitamin D receptor, a nuclear receptor
that regulates the synthesis of hundreds of proteins in every nucleated cell in the
body.
©DRKEVINKFNG
Immune cell

14. Immunologic Effects of Vitamin D on
Human Health and Disease (2020)
https://www.mdpi.com/2072-6643/12/7/2097/htm

15. PHARMACOKINETICS OF VITAMIN D AND
ITS METABOLITES

16. Assays of different forms of vitamin D in blood
▪ Blood level of 25-hydroxyvitamin D3 (calcidiol) reflects its storage in the body.
▪ Calcidiol is converted to the active form 1,25-hydroxyvitamin D3 (calcitriol) by the
kidneys and extra-renal tissues such as immune cells.
▪ Calcitriol is regulated primarily by parathyroid hormone and calcium levels.

17. Effect of a single dose of Vitamin D2 and Vitamin D3 on
plasma concentration of 25(OH)D2 and 25(OH)D3
https://drnealsmoller.com/blog/vitamin-d-not-what-we-think-it-is/

18. What is an Optimal 25(OH)D Level?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2912737/

19. Pharmacokinetics of a single, large dose (100,000 IU) of
calcidiol (25-hydroxyvitamin D3) (2008)
https://vitamindwiki.com/100%2C000+IU+single+dose+of+vitamin+D+-+2010

20. Biochemical measurements of a 52-year-old multiple sclerosis female
who received 40,000 international units per day of
vitamin D3 for 5 years. (2020)
https://www.mdpi.com/2072-6643/12/7/2097/htm

21. Metabolism of Vitamin D3 (cholecalciferol)
▪ Vitamin D3 is a fat-soluble vitamin
▪ Bioavailability range from 55% to 99%
▪ Storage of vitamin D3 in adipose tissue
▪ Half-life of vitamin D3 (cholecalciferol) ≈50 hours•
▪ Half-life of calcidiol (25-hydroxyvitamin D3) ≈ 15 days
▪ Half-life of calcitriol (1,25-hydroxyvitamin F3) ≈15 hours
▪ Rate of Conversion of calcidiol to calcitriol ?days ?weeks ?months
•https://www.nature.com/articles/222482a0
https://www.medscape.com/viewarticle/731722_2

22. PREVALENCE OF VITAMIN D DEFICIENCY IN COVID_19

23. Vitamin D3 (25(OH)D) in 107 COVID-19 patients
https://www.frontiersin.org/articles/10.3389/fpubh.2020.00513/full

24. COVID-19 Risk and Severity Is Increased in
Vitamin D Deficiency (2020)
Data from 212 hospitalized COVID-19 patients
https://www.frontiersin.org/articles/10.3389/fpubh.2020.00513/full

25. Low vitamin D status is associated with COVOD-19 outcomes:
a systematic review and meta-analysis (2021)
https://www.ijidonline.com/article/S1201-9712(20)32600-X/fulltext
low vit. D (higher mortality)
high vit. D

26. Overview of vitamin D deficiency in regions highly affected
by COVID-19. (2020)
European Journal of Clinical Nutrition
https://doi.org/10.1038/s41430-020-0661-0

27. Correlation between vitamin D levels and the number of COVID-19
cases and deaths/1 M population in 20 European countries (2020)
https://www.sciencedirect.com/science/article/pii/S1876034120305311#fig0005

28. Prevalence of Severe Vitamin D deficiency vs. COVID-19 Deaths
per Million in Europe (2020)
https://www.medrxiv.org/content/10.1101/2020.06.24.20138644v1.full-text

29. Recommendation for Vitamin D supplementation during
COVID-19 pandemic
(one author per country for each study)
https://www.frontiersin.org/articles/10.3389/fpubh.2020.00513/full
2000 IU

30. VITAMIN D DEFICIENCY IN COVID_19
• STUDIES WITH 25-HYDROXYVITAMIN D3 (CALCIDIOL)
● STUDY WITH 1,25-HYDROXYVITAMIN D3 (CALCITRIOL)

31. Low vitamin D levels independently associated with
severe COVID-19 cases, death (Sept 2020)
https://www.healio.com/news/endocrinology/20200911/low-vitamin-
d-levels-independently-associated-with-severe-covid19-cases-death

32. Effect of daily high dose oral vitamin D (60,000 IU) for 8 or 10 days
therapy on the inflammatory markers in patients with
COVID 19 disease (May 2021)
https://www.nature.com/articles/s41598-021-90189-4

33. Effect of daily high dose oral vitamin D (60,000 IU cholecalciferol)
for 8-10 days on the inflammatory markers in COVID-19 patients
(May 2021)
Adapted from https://www.nature.com/articles/s41598-021-90189-4#change-history

34. Effect of Vitamin D3 (300,000 IU) on critical Covid-19 patients
percentage of survivors and non-survivors belonging to groups (2021):
https://www.nature.com/articles/s41430-021-00984-5#Tab1
Mortality

35. Comorbid diseases of survivors and non-survivors. (2021)
https://www.nature.com/articles/s41430-021-00984-5#Tab1
Mortality

36. The effect of high-dose vitamin D3 (300,000 IU I/M) on mortality of
critical COVID-19 patients in intensive care unit :
an observational cohort study (2021)
▪ 175 COVID-19 patients
▪ vitamin D [25(OH) D <12 ng/mL
▪ hospitalized in the ICU.
▪ Vitamin D3 group (n = 113) received a single dose
of 300,000 IU vitamin D3 intramuscularly.
▪ Vitamin D3 was not administered to the control
group (n = 62).
https://www.nature.com/articles/s41430-021-00984-5#Tab1
Study #1

37. Effect of single dose of 25(OH)-D3 (300,000 IU I/M) on
length of hospital stay in COVID-19
No significant difference in vitamin D3 and control groups (2021)
https://www.nature.com/articles/s41430-021-00984-5#Tab1
Study #1

38. Effect of a High Dose of Vitamin D3 (200,000 IU) on
Patients With Moderate to Severe COVID-19 (2021)
Study #2
https://jamanetwork.com/journals/jama/fullarticle/2776738

39. Effect of a High Dose of Vitamin D3 (200,000 IU) on Patients
With Moderate to Severe COVID-19 (2021)
https://jamanetwork.com/journals/jama/fullarticle/2776738
7-day interval 8-day interval
Study #2

40. Hospital Discharge in a Study of the Effect of a High Dose of Vitamin D3
(200,000 IU)) on Patients With Moderate to Severe COVID-19
No significant difference (2021)
Study #2
https://jamanetwork.com/journals/jama/fullarticle/2776738

41. Why hospitalized COVID-19 patients do not respond to
25-hydroxyvitamin D3 (calcidiold) even though their
blood levels of calcidiol had increased?
▪ The studies were done using calciferol (vitamin D)and calcidiol (25-hydroxyvitamin
D3) which are not the active molecule of vitamin D.
▪ Calcidiol (25-hydroxyvitamine D3) is converted to the active calcitriol (1,25-
hydroxyvitamin D3) by an enzyme in the kidneys and the immune cells.
▪ The action of calcitriol is mediated by the vitamin D receptor, a nuclear receptor
that regulates the synthesis of hundreds of proteins in every nucleated cell in the
body.
▪ Could the lack of efficacy of calcidiol (25-hydroxyvitamin D3) on COVID-19 be due to
lack of conversion from calcidiol to calcitriol?

42. STUDY WITH CALCITRIOL ON COVID-19

43. Effect of calcitriol in oxygen saturation using SaO2/FIO2 ratio
on admission and discharge between the groups
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425676/

44. Clinical outcomes of a randomized pilot study using calcitriol in
hospitalized COVID-19 patients (Sep 2021)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425676/

45. Adverse effects of calcitriol (1,25-hydroxyvitamin D3)
in hospitalized COVID-19 patients (2021)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425676/
Adverse effects.

46. Conclusion
▪ There is a positive correlation between low Vitamin D and COVID-19.
▪ Patients with low vitamin D3 (25-hydroxyvitamin D3) are at greater risk for
infection, hospitalization and death.
▪ Treatment with vitamin D3 (25-hydroxyvitamin D3) did not show therapeutic
effect in hospitalized COVID-19 patients.
▪ Vitamin D3 (25-hydroxyvitamin D3) is an inactive molecule which needs to
be converted to the active 1,25 dihydroxyvitamin D3 by the kidneys and
the immune cells.
▪ The rate for the conversion of inactive vitamin D3 to the active 1,25
dihydroxyvitamin D3 in COVID-19 has not been reported.
▪ Lack of therapeutic effect of Vitamin D3 in COVID-19 could be due to its
slow or lack of converson to the active 1,25-hydroxyvitamin D3.
▪ A pilot study with the active 1,25-hydroxyvitamin D3 (cacitriol) showed
favorable outcomes in COVID-19 patients.
▪ Further research is needed to define if 25-hydroxycitamin D3 (calcidiol) is
converted to the active 1,25-hysroxyvitamin D3 (calcitriol) in COVID-19
patients.

47. ANY QUESTION?
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