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Perspective: Vitamin D supplementation prevents rickets and acute respiratory infections when given as daily maintenance but not as intermittent bolus: implications for COVID-19

Griffin et al., Clinical Medicine, doi:10.7861/clinmed.2021-0035

Mar 2021

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Vitamin D for COVID-19

8th treatment shown to reduce risk in October 2020, now with p < 0.00000000001 from 122 studies, recognized in 9 countries.

Lower risk for mortality, ICU admission, hospitalization, progression, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine treatments.

5,100+ studies for 109 treatments. c19early.org

Review of evidence showing that low-dose daily vitamin D supplementation is more effective than intermittent high-dose bolus for preventing various conditions, with a plausible biological mechanism. Bolus treatment may be less effective than daily treatment because high-dose bolus vitamin D may induce a long-lasting increase in the catabolizing enzyme 24-hydroxylase and in fibroblast growth factor 23 (FGF23), both of which have vitamin D inactivating effects. 24-hydroxylase activity can remain elevated for several weeks after bolus dosing, paradoxically leading to reduced levels of activated vitamin D. FGF23 increases progressively for at least 3 months after a large bolus dose and suppresses activation of vitamin D.

Reviews covering vitamin D for COVID-19 include1-34.

Important missing comments or errors? Let us know.

1. Fazli et al., Possible Link between Gut Microbiota, Diet, and COVID-19 Infection, Journal of Medical Bacteriology, 12:4, jmb.tums.ac.ir/index.php/jmb/article/view/525.ac.ir.

2. Wimalawansa, S., Unveiling the Interplay—Vitamin D and ACE-2 Molecular Interactions in Mitigating Complications and Deaths from SARS-CoV-2, Biology, doi:10.3390/biology13100831.mdpi.com, doi.org.

3. Santa et al., Comparative analysis of COVID-19 responses in Japan and Africa: diet, phytochemicals, vitamin D, and gut microbiota in reducing mortality—A systematic review and meta-analysis, Frontiers in Nutrition, doi:10.3389/fnut.2024.1465324.frontiersin.org, doi.org.

4. Kaushal, A., Nutraceuticals and pharmacological to balance the transitional microbiome to extend immunity during COVID-19 and other viral infections, Journal of Translational Medicine, doi:10.1186/s12967-024-05587-9.biomedcentral.com, doi.org.

5. Mu et al., Anti-inflammatory and Nutritional Interventions Against SARS-CoV-2: A Comprehensive Review, Journal of Agriculture and Food Research, doi:10.1016/j.jafr.2024.101422.sciencedirect.com, doi.org.

6. Wimalawansa (B), S., Unlocking Insights: Navigating COVID-19 Challenges and Emulating Future Pandemic Resilience Strategies with Strengthening Natural Immunity, Heliyon, doi:10.1016/j.heliyon.2024.e34691.sciencedirect.com, doi.org.

7. Imran et al., Therapeutic Role of Vitamin D in COVID-19 Patients, Clinical Nutrition Open Science, doi:10.1016/j.nutos.2024.07.004.sciencedirect.com, doi.org.

8. Grant, W., Vitamin D and viral infections: Infectious diseases, autoimmune diseases, and cancers, Advances in Food and Nutrition Research, doi:10.1016/bs.afnr.2023.12.007.sciencedirect.com, doi.org.

9. Polonowita et al., Molecular Quantum and Logic Process of Consciousness—Vitamin D Big-Data in COVID-19—A Case for Incorporating Machine Learning In Medicine, European Journal of Biomedical and Pharmaceutical sciences, doi:10.5281/zenodo.10435649.zenodo.org, doi.org.

10. Gomaa et al., Pharmacological evaluation of vitamin D in COVID-19 and long COVID-19: recent studies confirm clinical validation and highlight metformin to improve VDR sensitivity and efficacy, Inflammopharmacology, doi:10.1007/s10787-023-01383-x.springer.com, doi.org.

11. Gotelli et al., Understanding the immune-endocrine effects of vitamin D in SARS-CoV-2 infection: a role in protecting against neurodamage?, Neuroimmunomodulation, doi:10.1159/000533286.karger.com, doi.org.

12. Cutolo et al., Involvement of the secosteroid vitamin D in autoimmune rheumatic diseases and COVID-19, Nature Reviews Rheumatology, doi:10.1038/s41584-023-00944-2.nature.com, doi.org.

13. Schloss et al., Nutritional deficiencies that may predispose to long COVID, Inflammopharmacology, doi:10.1007/s10787-023-01183-3.springer.com, doi.org.

14. Arora et al., Global Dietary and Herbal Supplement Use during COVID-19—A Scoping Review, Nutrients, doi:10.3390/nu15030771.mdpi.com, doi.org.

15. Nicoll et al., COVID-19 Prevention: Vitamin D Is Still a Valid Remedy, Journal of Clinical Medicine, doi:10.3390/jcm11226818.mdpi.com, doi.org.

16. Foshati et al., Antioxidants and clinical outcomes of patients with coronavirus disease 2019: A systematic review of observational and interventional studies, Food Science & Nutrition, doi:10.1002/fsn3.3034.wiley.com, doi.org.

17. Quesada-Gomez et al., Vitamin D Endocrine System and COVID-19: Treatment with Calcifediol, Nutrients, doi:10.3390/nu14132716.mdpi.com, doi.org.

18. DiGuilio et al., Micronutrient Improvement of Epithelial Barrier Function in Various Disease States: A Case for Adjuvant Therapy, International Journal of Molecular Sciences, doi:10.3390/ijms23062995.mdpi.com, doi.org.

19. Grant (B) et al., A Narrative Review of the Evidence for Variations in Serum 25-Hydroxyvitamin D Concentration Thresholds for Optimal Health, Nutrients, doi:10.3390/nu14030639.mdpi.com, doi.org.

20. Shah Alam et al., The role of vitamin D in reducing SARS-CoV-2 infection: An update, International Immunopharmacology, doi:10.1016/j.intimp.2021.107686.sciencedirect.com, doi.org.

21. Griffin et al., Perspective: Vitamin D supplementation prevents rickets and acute respiratory infections when given as daily maintenance but not as intermittent bolus: implications for COVID-19, Clinical Medicine, doi:10.7861/clinmed.2021-0035.sciencedirect.com, doi.org.

22. Kohlmeier et al., When Mendelian randomisation fails, BMJ Nutrition, Prevention & Health, doi:10.1136/bmjnph-2021-000265.bmj.com, doi.org.

23. Brenner, H., Vitamin D Supplementation to Prevent COVID-19 Infections and Deaths—Accumulating Evidence from Epidemiological and Intervention Studies Calls for Immediate Action, Nutrients, doi:10.3390/nu13020411.mdpi.com, doi.org.

24. Mercola et al., Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity, Nutrients 2020, 12:11, 3361, doi:10.3390/nu12113361.mdpi.com, doi.org.

25. Basha et al., Is the shielding effect of cholecalciferol in SARS CoV-2 infection dependable? An evidence based unraveling, Clinical Epidemiology and Global Health, doi:10.1016/j.cegh.2020.10.005.sciencedirect.com, doi.org.

26. Xu et al., The importance of vitamin d metabolism as a potential prophylactic, immunoregulatory and neuroprotective treatment for COVID-19, Journal of Translational Medicine, doi:10.1186/s12967-020-02488-5.biomedcentral.com, doi.org.

27. Alexander et al., Early Nutritional Interventions with Zinc, Selenium and Vitamin D for Raising Anti-Viral Resistance Against Progressive COVID-19, Nutrients, doi:10.3390/nu12082358.mdpi.com, doi.org.

28. Andrade et al., Vitamin A and D deficiencies in the prognosis of respiratory tract infections: A systematic review with perspectives for COVID-19 and a critical analysis on supplementation, SciELO preprints, doi:10.1590/SciELOPreprints.839.scielo.org, doi.org.

29. Grant (C) et al., Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths, Nutrients, 12:4, 988, doi:10.3390/nu12040988.mdpi.com, doi.org.

30. McCullough et al., Daily oral dosing of vitamin D3 using 5000 TO 50,000 international units a day in long-term hospitalized patients: Insights from a seven year experience, The Journal of Steroid Biochemistry and Molecular Biology, doi:10.1016/j.jsbmb.2018.12.010.sciencedirect.com, doi.org.

31. EFSA, Scientific Opinion on the substantiation of health claims related to vitamin D and normal function of the immune system and inflammatory response (ID 154, 159), maintenance of normal muscle function (ID 155) and maintenance of normal cardiovascular function (ID 159) pursuant to Article 13(1) of Regulation (E, EFSA Journal, doi:10.2903/j.efsa.2010.1468.wiley.com, doi.org.

32. EFSA (B), Scientific Opinion on the substantiation of a health claim related to vitamin D and contribution to the normal function of the immune system pursuant to Article 14 of Regulation (EC) No 1924/2006, EFSA Journal, doi:10.2903/j.efsa.2015.4096.europa.eu, doi.org.

33. Palacios et al., Is vitamin D deficiency a major global public health problem?, J Steroid Biochem Mol Biol., 2014, 144PA, 138–145, doi:10.1016/j.jsbmb.2013.11.003.nih.gov, doi.org.

34. Cannell et al., Epidemic influenza and vitamin D, Epidemiol Infect., 2006, 134:6. 1129-40, doi:10.1017/S0950268806007175.nih.gov, doi.org.

Griffin et al., 31 Mar 2021, peer-reviewed, 8 authors.

This Paper Vitamin D All

Perspective: Vitamin D supplementation prevents rickets and acute respiratory infections when given as daily maintenance but not as intermittent bolus: implications for COVID-19

George Griffin, Martin Hewison, Julian Hopkin, Rose Anne Kenny, Richard Quinton, Jonathan Rhodes, Sreedhar Subramanian, David Thickett

Clinical Medicine, doi:10.7861/clinmed.2021-0035

The value of vitamin D supplementation in the treatment or prevention of various conditions is often viewed with scepticism as a result of contradictory results of randomised trials. It is now becoming apparent that there is a pattern to these inconsistencies. A recent large trial has shown that high-dose intermittent bolus vitamin D therapy is ineffective at preventing rickets -the condition that is most unequivocally caused by vitamin D deficiency. There is a plausible biological explanation since high-dose bolus replacement induces long-term expression of the catabolic enzyme 24-hydroxylase and fibroblast growth factor 23, both of which have vitamin D inactivating effects. Meta-analyses of vitamin D supplementation in prevention of acute respiratory infection and trials in tuberculosis and other conditions also support efficacy of low dose daily maintenance rather than intermittent bolus dosing. This is particularly relevant during the current COVID-19 pandemic given the well-documented associations between COVID-19 risk and vitamin D deficiency. We would urge that clinicians take note of these findings and give strong support to widespread use of daily vitamin D supplementation.

Conflicts of interest Martin Hewison and David Thickett have received speaking honoraria from Thornton Ross.

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