As the global struggle against COVID-19 continues, scientists have questioned why some people are better protected from the illness than others. Identifying the differences between severe and mild COVID-19 patients and those who seem to be safeguarded from its effects altogether could change the world’s approach to aiding the population during the ongoing pandemic. One nutrient that captured the attention of researchers early on was vitamin D. As it turns out, vitamin D exerts biological effects that extend far beyond its well-known role in calcium and bone health.
Observations from a Raging Pandemic
Epidemiological data emerging early in the pandemic began to hint at vitamin D’s role in COVID-19. First, there appeared to be a seasonal dependence where both case and death rates were lowest in summer. Furthermore, they noticed a north-south gradient, where those farther from the equator appeared to suffer more than those close to it. A study published in June of 2020 found a statistically significant correlation between a country’s latitude and its COVID-19 mortality, with a positive correlation found between lower death rates and a country’s proximity to the equator.
Why does this matter? Both trends show an inverse correlation with illness and solar UVB doses and, potentially, vitamin D production. Vitamin D, also known as the “sunshine vitamin,” can be made in the skin from exposure to sunlight. Due to the limited amounts of foods that contain vitamin D, sunlight is the primary resource for many people.
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In addition to the sunlight factor, there was a recognizable overlap between populations at high risk for COVID-19 and those at high risk for vitamin D deficiency. People older than age 65 and people of non-White race are two groups that face an increased risk for COVID-19 and increased risk for vitamin D deficiency. Although the reasons for vulnerability in these populations are multifaceted, the link to vitamin D could not be ignored. So, is this coincidence or evidence that vitamin D serves to mitigate the risk and outcomes of COVID-19?
Vitamin D Deficiency Increases the Risk of COVID-19
Due to the observations listed above, researchers set out to determine the relationship between vitamin D and COVID-19. Even though the evidence that vitamin D status affects the risk of COVID-19 comes primarily from observational and ecological research, the studies are plenty.
One retrospective cohort study found that testing positive for COVID-19 was associated with increased age, non-White race, and low vitamin D status. These results were confirmed in another cohort study finding that lower vitamin D levels (<20 ng/mL) are associated with an increased risk of a positive COVID-19 test. Another Israeli population-based study concluded that low plasma vitamin D (<20 ng/mL) appears to be an independent risk factor for COVID-19 infection and hospitalization.
Kaufman et al. performed a huge retrospective, observational analysis on over 190,000 people. They found that COVID-19 positivity is strongly and inversely associated with circulating vitamin D levels. The relationship persisted across latitudes, races/ethnicities, both sexes, and age ranges. The data indicated that COVID-19 positivity was 40% lower for those with serum vitamin D levels >50 ng/mL than those with 20 ng/mL. The risk of COVID-19 positivity continued to decline until the serum levels reached 55 ng/mL. Overall, these studies suggest that low vitamin D levels are associated with increased COVID-19 incidence.
Vitamin D Deficiency Increases the Severity of COVID-19
Multiple studies have found that vitamin D does more than affect the incidence of COVID-19; it also impacts the severity. A study recently conducted in Italy found that vitamin D levels were lower in hospitalized, severely-symptomatic COVID-19 patients than in mildly-symptomatic-COVID-19 patients and in non-COVID-19 infected controls.
Moreover, in severely symptomatic COVID-19 patients, vitamin D levels at hospital admission were associated with increased inflammatory markers, the severity of respiratory distress, and mortality. Overall, the authors concluded that vitamin D deficiency is associated with the clinical outcomes of COVID-19, independent of inflammatory markers, age, and the presence of major comorbidities.
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This was confirmed in another study that measured ICU admission and mortality on over 800 COVID-19 hospital patients in Spain. They found that in patients hospitalized with COVID-19, vitamin D treatment significantly reduced ICU admission and mortality compared to the control group.
Moreover, multiple meta-analyses have established similar conclusions since the pandemic began. One meta-analysis published in April of 2021 concluded that vitamin D deficiency seems to be associated with increased COVID-19 infection severity and mortality.
A second meta-analysis published in June of 2021 established that vitamin D deficiency is associated with greater severity of COVID-19 infection.
Finally, the most comprehensive and recent systematic review concluded that vitamin D deficiency might increase the risk of COVID-19 infection and the potential for severe disease outcomes. The authors ended the paper by stating that considering all the evidence; vitamin D supplementation may be added to prevention and treatment protocols for COVID-19.
The Argument Between Association and Causation
Although most of these findings suggest that vitamin D plays a role in COVID-19 incidence and severity, it’s important to recognize that most of these studies are retrospective and observational. This means that the investigators look backward in time and examine a naturally occurring relationship (in this case, between vitamin D and COVID-19 disease and severity) with no active intervention.
The argument has been made that the association between low serum vitamin D concentrations and COVID-19 is due to “reverse causation,” where the disease state itself lowers vitamin D concentrations in the host. While this may be possible, most prospective observational studies used vitamin D level data from blood draws before COVID-19 onset. So, while it appears the theories suggested in these studies are substantial, randomized controlled trials need to be performed to determine the true effects of vitamin D supplementation on COVID-19 outcomes.
Vitamin D’s Role in COVID-19 Immunity
Vitamin D plays several roles in both innate and adaptive immunity. Vitamin D receptors are found throughout the immune system and may reduce COVID-19 risk through the regulation of (i) cellular innate and adaptive immunity, (ii) physical barriers, and (iii) the renin-angiotensin system (RAS).
Vitamin D activates immune cells to produce antimicrobial peptides (AMPs), including essential defense molecules such as cathelicidins and defensins. AMPs have a broad spectrum of immune action, including antiviral activity. They have even been found to inactivate the influenza virus. AMPs, such as cathelicidins, can destroy viral proteins and block viral entry into the cell.
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Elevated inflammation has also been identified as an important risk factor for COVID-19 severity and mortality. Together with older age and major comorbidities, predictors of COVID-19 fatality mainly include elevated inflammatory markers. This suggests that mortality might be related to virally driven hyper-inflammation, known as the “cytokine storm.”
It is well known that vitamin D sufficiency reduces the risk of a cytokine storm and regulates thrombotic pathways. Emerging research suggests that vitamin D sufficiency may attenuate the cytokine storm during COVID-19 disease, helping to maintain lung and endothelial function, and decreasing COVID-19 severity and mortality.
Moreover, vitamin D can help maintain the physical barriers within the body. For example, vitamin D can help prevent invaders (such as viruses) from reaching tissues sensitive to infection by supporting the upkeep of tight junctions and gap junctions in the gut. Think about it like vitamin D reinforcing the gates that surround your city, making it harder for invaders to get in.
Lastly, vitamin D plays a direct role in lung permeability through the RAS. Put as simply as possible, angiotensin-converting enzyme 2 (ACE2) receptors are expressed on the surface of lung epithelial cells and serve as a major entry point into the cells for SARS-CoV-19. Once the virus attaches to ACE2, it reduces its activity.
ACE2 is important because it catalyzes the cleavage of another peptide called angiotensin II. When COVID-19 down regulates ACE2, high concentrations of angiotensin II accumulate. This leads to unopposed inflammation, potentially lethal acute respiratory distress syndrome (ARDS), and sudden and severe cardiac inflammation. Vitamin D can prevent the buildup of angiotensin II by increasing the expression of ACE2 and by inhibiting renin (another enzyme required for angiotensin II), thus reducing the risk of severe lung and cardiovascular injury.
Other Ways Vitamin D May Support COVID-19 Outcomes
Vitamin D can support other health-related characteristics associated with COVID-19 and, therefore, indirectly reduce the risk of negative health outcomes if the virus is contracted. For example, studies have found an inverse correlation between vitamin D levels and severe cases of pneumonia, risk of sepsis, ARDS, heart failure, and diabetes, all of which have been associated with COVID-19 case fatality rates. One could assume that the beneficial effects of vitamin D on each of these diseases would support more positive health outcomes.
Of particular interest in COVID-19, multiple studies demonstrate an association between vitamin D deficiency and increased risk and severity of respiratory infections. Several studies have found an inverse relationship between the risk of respiratory viral pathogens, including influenza, and vitamin D levels.
For example, in perhaps the largest epidemiological study to date, Ginde et al. found a significantly increased prevalence of upper respiratory tract infection among groups with vitamin D levels less than 30 ng/mL compared to those with 30 ng/mL or higher. Similarly, a recent meta-analysis of 25 randomized controlled trials demonstrated that vitamin D supplementation protects against acute respiratory tract infections, particularly in patients presenting with low serum vitamin D levels. However, not all studies have found this association.
The Bottom Line
As discussed here, emerging evidence demonstrates that higher serum vitamin D concentrations are associated with reduced risk and severity of COVID-19. Vitamin D is likely to support the population through various mechanisms, such as maintaining epithelial layers and tight junctions in the gut, reducing the survival and replication of the virus, lessening the production of pro-inflammatory cytokines and the “cytokine storm,” and increasing ACE2 expression.
However, it’s important to note that the evidence to date suggests that vitamin D levels before COVID-19 infection is what matters most. Moreover, the most substantial evidence to date comes from observational studies that report an inverse association between vitamin D concentration and COVID-19 incidence, severity, and mortality. Observational studies are not considered “gold standard” evidence. More research — including randomized controlled trials — needs to be conducted for scientists to gain more clarity.
Overall, it seems possible that vitamin D prophylaxis may decrease the incidence and severity of COVID-19, especially in settings where low serum vitamin D levels are common. Vitamin D deficiency could be a helpful adjunct in assessing a person’s potential of developing severe COVID-19 symptoms. Moreover, micronutrients, such as vitamin D are essential for optimal health and physiological function with or without illness. Therefore, vitamin D levels should be considered in all individuals.
Vitamin D Guidelines to Follow
COVID-19 isn’t the only worldwide pandemic we are dealing with at the moment. Vitamin D deficiency is also sweeping the globe. It is estimated that as many as 1 billion people worldwide may be classified as having insufficient levels of this important vitamin.
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In the Endocrine Society’s Practice Guidelines on vitamin D, deficiency is defined as serum 25(OH)D levels < 20 ng/mL, vitamin D insufficiency as 21–29 ng/mL, and vitamin D sufficiency as at least 30 ng/mL. These guidelines have been based on bone health outcomes, such as the prevention of osteoporosis and rickets. However, mounting evidence suggests that higher levels may be needed for reported non-skeletal benefits of vitamin D, including optimal immune function.
According to the current evidence on COVID-19, it seems that levels as high as 50 ng/mL could be beneficial. Given that COVID-19 will continue to threaten public health for some time, and that current evidence suggests vitamin D plays a vital role in immunity and COVID-19 outcomes, it may be more critical now than ever to know your vitamin D levels.
