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Vitamin D and COVID-19

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. The problem is the totality of evidence supporting vitamin D’s effectiveness against severe COVID-19 outcomes is misunderstood, especially by the conventional non-integrative functional medicine community. 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?

It’s important to remember that the vitamin D receptor is found virtually on all cell types, including immune and endothelial cells (Charoenngam & Holick, 2020). Upon synthesis in the skin after any amount of sunlight exposure over 10 minutes (or ingestion from vitamin D-containing foods/supplements), circulating vitamin D is metabolized into 25-hydroxyvitamin D [25(OH)D] by the liver. Please note, 25(OH)D is the major circulating metabolite of vitamin D that is routinely measured by blood test to determine storage vitamin D levels (Holick, 2007; et al., 2011); this does not represent that fully active form of vitamin D which goes into cells. 

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). So, in many ways, vitamin D acts more like a hormone regulator than just a vitamin. 

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, thereby enhancing immune modulation. I’ll briefly discuss a few ways vitamin D is assumed to function in COVID-19 infection. Keep in mind there are several more than the following listed here!

  1. Activated vitamin D [1,25(OH)2D] triggers macrophage production of the endogenously produced antimicrobial peptide cathelicidin LL-37, which protects against invading respiratory viruses. Basically, this antimicrobial protein is also an antiviral protein—it disrupts the viral envelopes and alters viability of host target cells (Liu et al., 2006; Shahmiri et al., 2016). 
  2. Active vitamin D [1,25(OH)2D} changes the expression of angiotensin converting enzyme-2 (ACE2). ACE2 is the main host cell receptor of  SARS-CoV-2 (Aygun, 2020; Ortega et al., 2020). ACE2 is expressed in: 
  3. Alveolar cells of the lungs (type II)
  4. Absorptive cells in the esophagus, small and large intestines 
  5. Kidney, bladder, and heart cells
  6. Inside the mouth (epithelial cells of the oral mucosa)

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). 

  1. Activated vitamin D [1,25(OH)2D] confers a fundamental shift in immune function, altering the activity of different types of white blood cells (lymphocytes). In short, vitamin D decreases the production of T helper 1 cells (Th1) (Cantorna & Mahon, 2005; Schleithoff et al., 2006; Ardizzone et al., 2009). This is extremely important because active vitamin D can suppress the development and progression of inflammation by reducing inflammatory cytokines such as: 
  2. IL-6, IL-8, IL-12, and IL-17 → all of which damage cells in excess (Chastre & Fagon, 2002; ATS-IDSA, 2005; Palmer et al., 2011).
  3. Tumor necrosis factor alpha (TNFα) and nuclear factor-κB (NFκB) (Peterson & Heffernan, 2008; Talmor et al., 2008).
  4. Gamma interferon (IFN-γ) and IL-2 (Provvedini et al., 1983; Tsoukas et al., 1984).

What happens when Th1 is dialed down by vitamin D? T helper 2 cells (Th2) are dialed up. Essentially, vitamin D enhances the shift from Th1 (and Th17) to a Th2 immune profile and promotes differentiation of regulatory T cells (Lemire et al., 1995; Boonstra et al., 2001; Tang et al., 2009). This one-two punch in the shift and differentiation of immune cells is thought to decrease the severity of the cytokine storm. With damaging and deadly cytokines kept at bay, vitamin D alleviates and reduces the systemic inflammatory response (I.e. “cytokine storm syndrome”) in patients with severe SARS-CoV-2 infection and thus prevent multiple organ damage. 

  1. 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. 

 These associations were not observed in younger COVID-19 patients, i.e. patients who typically have a lower inflammatory burden compared to older populations. The elderly often present with multiple underlying health conditions making them more susceptible to severe outcomes. The known inflammatory burden of COVID-19 in the elderly points to how vitamin D can amplify the immune system and provide protection from death, ARDS, and sepsis in varying health conditions. This is why there was a statistically significantly decreased odds of death in vitamin D-sufficient patients among those with a BMI less than 30, but not those with BMI ≥ 30 kg. Healthier weight populations fared better than heavier weight populations with greater underlying health conditions. This reinforces the idea that vitamin D goes a long way, but it isn’t a panacea. Yes, vitamin D influences immune function and it does so differently among those with and without underlying health conditions.

This isn’t new news.

The connection between circulating vitamin D status and risk of incident COVID-19 infection is clearer by the day. Another research team led by Kaufman and colleagues (2020) investigated the likelihood of a positive COVID-19 test in a national clinical laboratory database of almost 200,000 patients and found that SARS-CoV-2 positivity is strongly and inversely associated with circulating vitamin D levels. This is a relationship that holds across latitudes, races and ethnicities, between sexes, and even among vast age ranges. This finding was in line with Meltzer and their team (2020) showing that deficient 25(OH)D status was associated with an increased risk of testing positive for SARS-CoV-2 after adjustment in a multivariate analysis compared to those who were sufficient.

All in all, headlines are designed to be sensational. Don’t fall for the latest soundbite when the totality of evidence showcases that vitamin D may not only prevent you from getting sick, but it may also save your life. 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. 

Dr. Bhandari and the Advanced Health Team Are Here to Support Your Health.

Our expert team of integrative holistic functional medical practitioners work closely together to better understand the root cause of our patients’ ailment and how they are directly causing chronic diseases. By knowing exactly how to reshift the body into optimal functioning and providing each patient with personalized treatment plans based on their unique constitution and circumstances, our team is extremely effective at reversing any disease into wellness. To learn more and book an appointment, contact Advanced Health or call 1-415-506-9393.




References 

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‚Äźatherosclerotic 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.

Author
Payal Bhandari M.D. Dr. Payal Bhandari M.D. Dr. Payal Bhandari M.D. is one of U.S.'s top leading integrative functional medical physicians and the founder of San Francisco' top ranked medical center, SF Advanced Health. Her well-experienced holistic healthcare team collaborates together to deliver whole-person personalized care and combines the best in Western and Eastern medicine. By being an expert of cell function, Dr. Bhandari defines the root cause of illness and is able to subside any disease within weeks to months. She specializes in cancer prevention and reversal, digestive & autoimmune disorders. Dr. Bhandari received her Bachelor of Arts degree in biology in 1997 and Doctor of Medicine degree in 2001 from West Virginia University. She the completed her Family Medicine residency in 2004 from the University of Massachusetts and joined a family medicine practice in 2005 which was eventually nationally recognized as San Francisco’s 1st patient-centered medical home. To learn more, go to www.sfadvancedhealth.com.

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