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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!
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).
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.
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.
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