Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), disproportionately affects the elderly, African Americans, individuals with obesity (BMI > 30), and those who are institutionalized (i.e. nursing home residents). In addition, belonging to any one of these groups indicates “high-risk” for vitamin D deficiency (and probable liver and/or kidney dysfunction, the drivers of Vitamin D activation). They go hand in hand. This is why it’s thought that low storage levels of vitamin D contribute to higher COVID-19 morbidity and mortality rates in the most high-risk populations.
You may have heard in the national news recently that Vitamin D supplementation is ineffective at preventing SARS-CoV-2 infection. In short, to say vitamin D is ineffective is hogwash since the evidence on its protective role for other respiratory viral infections or critical illness is well established (de Haan et al., 2014; Martineau et al., 2017).
In a recent cross-sectional study of around 300 COVID-19 patients hospitalized at the Boston University Medical Center, Charoenngam and colleagues (2021) found that among 136 patients aged 65 years and older, most were found to have vitamin D deficiency. When Vitamin D supplementation was given to jumpstart their storage levels to “sufficient” levels, it led to statistically significant lower rates of death, acute respiratory distress syndrome (ARDS), and severe sepsis/septic shock.
The association remained even after adjustment for potential confounders. Note: “Sufficiency” was defined as vitamin D [25(OH)D] levels greater than 30 ng/mL. Personally, I like to see my patients’ levels at least ≥ 100 ng/mL since it safeguards them against most infections. Regardless, this study shows that the higher the blood concentration of vitamin D, the better the outcome, even if vitamin D isn’t at functional concentrations.
How Does Vitamin D Fight Against COVID-19 Morbidity and Mortality?
Circulating 25(OH)D is further metabolized by the enzyme 1α-hydroxylase in the kidneys into its active form known as 1,25-dihydroxyvitamin D or [1,25(OH)2D]. Interestingly, the vitamin D activation enzyme is expressed by many bodily tissues—not just the kidneys. The activation enzyme is also found in activated macrophages of the immune system, microglia (the primary innate immune cells of the brain), parathyroid glands, breast cells, colon cells, and the outermost layer of the skin (keratinocytes) where 1,25(OH)2D is synthesized on site. Please note vitamin D activation can only occur when the blood is alkaline and then directly controls many endocrine functions (Holick, 2007; Charoenngam & Holick, 2020).
Thus, you can see that if the liver and kidney are down for the count, then the body’s ability to fully activate vitamin D and fight infection-induced inflammation is extremely limited.
Now, similar to Melatonin and its role in quelling inflammatory damage caused by SARS-CoV-2, vitamin D is believed to work on multiple cellular pathways simultaneously:
Since ACE2 is expressed all over the body, it sheds light on myriad infection routes of SARS-CoV-2. After infection, some patients go on to develop acute respiratory distress syndrome which quickly leads to multiple organ failure. Hence, closing the “ACE2 door”, which vitamin D has been shown to do, prevents SARS-CoV-2 entry into various cells (Lin et al., 2016; Ali et al., 2018).
Finally, it has been shown that upon viral infection, inactive vitamin D can be converted to the active form by the lungs’ epithelial cells and cause the expression of a host defense gene that turns on the production of cathelicidin (Hansdottir et al., 2008). Cathelicidins are known to have protective effects against lung damage due to hyperoxia (Jiang et al. 2020). Theoretically, vitamin D could reduce the risk of SARS-CoV-2 infection by enhancing the production of cathelicidin and defensins which lead to decreased the ability for the virus to survive and replicate.
Clearly, vitamin D plays a powerful role in quelling inflammation, but the extent to which it's helpful depends on one’s underlying disease factor(s). This is what is so hard for everyone to understand, and why so many conflicting results exist. Let’s go back to the results of those hospitalized at the Boston University Medical Center, showing that vitamin D sufficiency was associated with statistically significantly decreased rates of death, ARDS, and severe sepsis.
All in all, do remember that vitamin D deficiency (measured by functional medicine physicians to be less than 100) is directly related to underlying liver and kidney damage. The treatment and prevention of cOVID-19 infections and their associated complications are directly caused by other pre-existing organ damage which has never been adequately investigated and addressed.
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Ali, R. M., Al-Shorbagy, M. Y., Helmy, M. W., & El-Abhar, H. S. (2018). Role of Wnt4/β-catenin, Ang II/TGFβ, ACE2, NF-κB, and IL-18 in attenuating renal ischemia/reperfusion-induced injury in rats treated with Vit D and pioglitazone. European journal of pharmacology, 831, 68-76.
American Thoracic Society, & Infectious Diseases Society of America. (ATS-IDSA, 2005). Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. American journal of respiratory and critical care medicine, 171(4), 388.
Ardizzone, S., Cassinotti, A., Trabattoni, D., Manzionna, G., Rainone, V., Bevilacqua, M., ... & Porro, G. B. (2009). Immunomodulatory effects of 1, 25-dihydroxyvitamin D3 on TH1/TH2 cytokines in inflammatory bowel disease: an in vitro study. International Journal of Immunopathology and Pharmacology, 22(1), 63-71.
Aygun, H. (2020). Vitamin D can prevent COVID-19 infection-induced multiple organ damage. Naunyn-schmiedeberg's Archives of Pharmacology, 393(7), 1157-1160.
Boonstra, A., Barrat, F. J., Crain, C., Heath, V. L., Savelkoul, H. F., & O’Garra, A. (2001). 1α, 25-Dihydroxyvitamin D3 has a direct effect on naive CD4+ T cells to enhance the development of Th2 cells. The Journal of Immunology, 167(9), 4974-4980.
Cantorna, M. T., & Mahon, B. D. (2005). D-hormone and the immune system. The Journal of rheumatology Supplement, 76, 11-20.
Charoenngam, Nipith, and Michael F. Holick. (2020). "Immunologic effects of vitamin D on human health and disease." Nutrients 12(7), 2097.
Chastre, J., & Fagon, J. Y. (2002). Ventilator-associated pneumonia. American journal of respiratory and critical care medicine, 165(7), 867-903.
Charoenngam, N., Shirvani, A., Reddy, N., Vodopivec, D. M., Apovian, C. M., & Holick, M. F. (2021). Association of vitamin D status with hospital morbidity and mortality in adult hospitalized COVID-19 patients. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, S1530-891X(21)00057-4.
de Haan, K., Groeneveld, A. J., de Geus, H. R., Egal, M., & Struijs, A. (2014). Vitamin D deficiency as a risk factor for infection, sepsis and mortality in the critically ill: systematic review and meta-analysis. Critical care, 18(6), 1-8.
Hansdottir, S., Monick, M. M., Hinde, S. L., Lovan, N., Look, D. C., & Hunninghake, G. W. (2008). Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. The Journal of Immunology, 181(10), 7090-7099.
Holick, M. F. (2007). Vitamin D deficiency. New England Journal of Medicine, 357(3), 266-281.
Holick, M. F., Binkley, N. C., Bischoff-Ferrari, H. A., Gordon, C. M., Hanley, D. A., Heaney, R. P., ... & Weaver, C. M. (2011). Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism, 96(7), 1911-1930.
Jiang, J. S., Chou, H. C., & Chen, C. M. (2020). Cathelicidin attenuates hyperoxia-induced lung injury by inhibiting oxidative stress in newborn rats. Free Radical Biology and Medicine, 150, 23-29.
Kaufman, H. W., Niles, J. K., Kroll, M. H., Bi, C., & Holick, M. F. (2020). SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels. PLoS One, 15(9), e0239252.
Lemire, J. M., Archer, D. C., Beck, L., & Spiegelberg, H. L. (1995). Immunosuppressive actions of 1, 25-dihydroxyvitamin D3: preferential inhibition of Th1 functions. The Journal of nutrition, 125(suppl_6), 1704S-1708S.
Lin, M., Gao, P., Zhao, T., He, L., Li, M., Li, Y., ... & Wu, X. (2016). Calcitriol regulates angiotensin-converting enzyme and angiotensin converting-enzyme 2 in diabetic kidney disease. Molecular biology reports, 43(5), 397-406.
Liu, P. T., Stenger, S., Li, H., Wenzel, L., Tan, B. H., Krutzik, S. R., ... & Modlin, R. L. (2006). Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science, 311(5768), 1770-1773.
Martineau, A. R., Jolliffe, D. A., Hooper, R. L., Greenberg, L., Aloia, J. F., Bergman, P., ... & Camargo, C. A. (2017). Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. bmj, 356.
Meltzer, D. O., Best, T. J., Zhang, H., Vokes, T., Arora, V., & Solway, J. (2020). Association of vitamin D status and other clinical characteristics with COVID-19 test results. JAMA network open, 3(9), e2019722-e2019722.
Ortega, J. T., Serrano, M. L., Pujol, F. H., & Rangel, H. R. (2020). Role of changes in SARS-CoV-2 spike protein in the interaction with the human ACE2 receptor: An in silico analysis. EXCLI journal, 19, 410.
Palmer, M. T., Lee, Y. K., Maynard, C. L., Oliver, J. R., Bikle, D. D., Jetten, A. M., & Weaver, C. T. (2011). Lineage-specific effects of 1, 25-dihydroxyvitamin D3 on the development of effector CD4 T cells. Journal of Biological Chemistry, 286(2), 997-1004.
Peterson, C. A., & Heffernan, M. E. (2008). Serum tumor necrosis factor-alpha concentrations are negatively correlated with serum 25 (OH) D concentrations in healthy women. Journal of inflammation, 5(1), 1-9.
Provvedini, D. M., Tsoukas, C. D., Deftos, L. J., & Manolagas, S. C. (1983). 1, 25-dihydroxyvitamin D3 receptors in human leukocytes. Science, 221(4616), 1181-1183.
Schleithoff, S. S., Zittermann, A., Tenderich, G., Berthold, H. K., Stehle, P., & Koerfer, R. (2006). Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. The American journal of clinical nutrition, 83(4), 754-759.
Shahmiri, M., Enciso, M., Adda, C. G., Smith, B. J., Perugini, M. A., & Mechler, A. (2016). Membrane core-specific antimicrobial action of cathelicidin LL-37 peptide switches between pore and nanofibre formation. Scientific reports, 6(1), 1-11.
Talmor, Y., Bernheim, J., Klein, O., Green, J., & Rashid, G. (2008). Calcitriol blunts pro‐atherosclerotic parameters through NFκB and p38 in vitro. European journal of clinical investigation, 38(8), 548-554.
Tang, J., Zhou, R. U., Luger, D., Zhu, W., Silver, P. B., Grajewski, R. S., ... & Caspi, R. R. (2009). Calcitriol suppresses antiretinal autoimmunity through inhibitory effects on the Th17 effector response. The Journal of Immunology, 182(8), 4624-4632.
Tsoukas, C. D., Provvedini, D. M., & Manolagas, S. C. (1984). 1, 25-dihydroxyvitamin D3: a novel immunoregulatory hormone. Science, 224(4656), 1438-1440.
Xu, H., Zhong, L., Deng, J., Peng, J., Dan, H., Zeng, X., ... & Chen, Q. (2020). High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. International journal of oral science, 12(1), 1-5.
Zou, X., Chen, K., Zou, J., Han, P., Hao, J., & Han, Z. (2020). Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Frontiers of medicine, 1-8.