As the number of confirmed COVID-19 cases passes four million, scientists are scrambling to find out everything they can about the virus to develop ways of preventing and treating it.
One new avenue of research is the role that vitamin D might play in both the severity of COVID-19 and the risk of developing the disease. A handful of recent studies claim to have found a link between low vitamin D levels and COVID-19 fatality. But can a deficiency of this vitamin really increase your risk of death from the virus?
Vitamin D helps to regulate the amount of calcium and phosphate in the body, both of which are needed to keep bones, teeth and muscles healthy. Very few foods naturally contain the vitamin, but the body is able to produce it when the skin is directly exposed to the sun.
Significantly, vitamin D is also thought to play an important role in the body's immune response, according to Bruce Troen, Professor and Chief, Division of Geriatrics and Palliative Medicine, from the University at Buffalo, New York. He told Newsweek there is strong body of evidence from before the pandemic demonstrating that vitamin D deficiency is correlated with an increased susceptibility to respiratory tract infections.
There are two parts of the immune system that are relevant when it comes to COVID-19: one is called innate immunity and the other is adaptive immunity.
Recent research has shown that one of the most dangerous aspects of COVID-19—as well as a host of other diseases—is its apparent ability to induce what is known as a cytokine storm in patients. This is when the immune system produces an excess of immune cells that secrete messenger proteins known as cytokines. This overabundance of cytokines can lead to inflammation in the lungs, which can be fatal in severe cases.
Vitamin D regulates the response of white blood cells in the body, preventing them from releasing an excess of inflammatory cytokines.
"Innate immunity is often related to the ability to produce these inflammatory cytokines. And we know that vitamin D has an impact on innate immunity, Troen said. "It also has an impact on what's called adaptive immunity, which is the part of our immune system that gets us to respond to specific stresses.
"So when we have any infection by viruses or bacteria, we have the ability, at least for those folks where the immune system is working well, to respond with the production of antibodies that can help to fight infection and hopefully protect against the infection in the future."
Unfortunately, many populations around the world suffer from high levels of vitamin D deficiency or insufficiency, according to Troen. While there are different classifications, scientists often consider Vitamin D deficiency as below 20 nanograms per millimeter, while an insufficiency is anything between 20 and 30.
"It turns out that regardless of geographic location, there is a significant amount of vitamin D insufficiency and deficiency across the planet, with some estimates as high as 70 percent," Troen said. "And this is even in sunny locations. I used to be down at the University of Miami and we did one study which showed that even in that sunny location, you could have significant incidence of deficiency and insufficiency."
That being the case, the population as a whole is vulnerable to any disease where vitamin D status may be important.
So what does some of the recent research looking at the link between vitamin D and COVID-19 demonstrate? Troen points to two separate observational studies from the Philippines and Indonesia respectively, which showed the prevalence of low vitamin D levels was much higher in those with severe COVID-19 illness, compared to those who had sufficient levels.
The Philippine study found that vitamin D deficiency was associated with a nearly 20-fold increase in critically ill outcomes with COVID-19. The Indonesian research came to the conclusion that vitamin D deficiency was associated with a tenfold increase in mortality; and vitamin D insufficiency with a roughly sevenfold increase in mortality.
It is important to note correlation does not equal causation—this is not proof vitamin D status plays a role in risk of death. Furthermore, both of these studies are pre-print studies, meaning they have not been peer-reviewed by other experts. Several research groups have been releasing preliminary results in this manner during the pandemic in order to disseminate information regarding the virus quickly. However, it is important to look at these studies with greater scrutiny than those accepted for publication in scientific journals.
Nevertheless, Troen says he has confidence in the findings of both papers because they took into account actual measurements of vitamin D levels in patients. "What's really good about [the Philippine study] is that they were actually able to look at the specific outcomes of 212 patients who had COVID infection and their measured vitamin D status," he said. "They found that the odds of having a critical outcome, meaning the patient got the acute respiratory distress syndrome and actually ended up in an ICU and on ventilator, was almost 20 times higher than having a clinical outcome if you are vitamin D deficient. I think this is very powerful information.
"In Indonesia they were able to look at 780 cases and they also had information that gave them explicitly the vitamin D status, as well as the outcomes, including mortality, for the COVID-19 infection."
Importantly, Troen notes that the latter study did well to take into account other variables that may have had an impact on the risk of dying from COVID-19. "We know that many frail older adults who have multiple medical conditions are the ones who are most risk for the for not only contracting the disease, but being in hospital, and unfortunately, ultimately, dying. So it may be difficult to say 'is it just the vitamin D status of those individuals, which is often worse than others who were younger in the community? Or is it some of these other confounding factors?'
"These investigators were able not only to identify vitamin D status, but then they were able to control for age, gender, and comorbidities, meaning other medical conditions."
However, other researchers urge caution in interpreting the results of these studies, especially as they have not yet been peer-reviewed.
"These are both provocative but not even close to definitive," Daniel Culver, Director of the Interstitial Lung Disease Program in the Department of Pulmonary, Medicine at the Cleveland Clinic told Newsweek. "Both of these studies are 'causal inference' studies—in other words association studies that attempt to look at whether a certain exposure (in this case Vitamin D) is correlated with a certain outcome."
"Causal inference studies are difficult to perform because there are a large number of potential missteps that can lead to erroneous conclusions. For example, if vitamin D levels are really a marker for better diet, or more access to healthcare, or any of a variety of other variables that are not statistically assessed, then it is not the vitamin D that is the cause of the better or worse outcomes but rather the other factors."
He also said there is an absence of data in those studies regarding how the vitamin D was measured, when it was measured, and baseline health of the individuals. This means it is difficult to extrapolate the data to the general population. Both of the studies are hypothesis-forming but are not conclusive. Moreover, extrapolating these results to other populations is risky." he said.
Another study recently published in the journal Aging Clinical and Experimental Research (ACER) found an association between low average levels of vitamin D and high numbers of COVID-19 cases and mortality rates across 20 European countries.
The study suggested that countries like Italy and Spain with the highest reported vitamin D deficiency are also those with higher COVID-19 infections and mortality. Even though Italy and Spain receive a lot of sunshine, the researchers suggest that they may have lower average vitamin D levels than some less sunny northern European countries, in part, because in southern Europe, people, particularly the elderly, tend to avoid strong sun. Southern Europeans also tend to have darker pigmentation, which can also reduce the natural synthesis of vitamin D.
Unlike the two studies from southeast Asia, this research only estimated levels of vitamin D in the patients it examined rather than looking at actual measurements, meaning that future studies will be needed to confirm its findings, Sue Shapses, a professor in the Department of Nutritional Sciences at Rutgers University, with an adjunct position at the Rutgers Robert Wood Johnson Medical School, who was not involved in the ACER paper, told Newsweek.
The authors also note that their study contains several other limitations, such as differences between cases, testing and measures taken to curb the spread across the countries sampled. "Finally, and importantly, one must remember correlation does not necessarily mean causation," Petre Cristian Ilie, a urologist from Queen Elizabeth Hospital King's Lynn NHS Foundation Trust in the U.K. and lead author of the ACER paper, said in a statement.
According to Shapses, while current evidence does not provide definitive answers, it would not be surprising if vitamin D deficiency or insufficiency played a role in COVID-19 mortality. "There is ample evidence that vitamin D deficiency is associated with an increased susceptibility to infection so it makes sense that when persons are infected with COVID-19 and have [very low levels of vitamin D,] they would be at higher risk of fatality due to an inability to fight the infection," she said.
Joan Lappe, a professor of medicine at Creighton University, agrees that vitamin D insufficiency likely increases risk for COVID-19. She told Newsweek that vitamin D can reduce risk of infections through several mechanisms. This includes stimulating production of chains of amino acids known as cathelicidins and defensins that can lower viral replication rates, and by reducing pro-inflammatory cytokines that produce the inflammation and injure the lining of the lungs, leading to pneumonia. She also said there are other factors that suggest low levels of vitamin D may increase the risks from COVID-19.
"One, the outbreak occurred in winter, when vitamin D levels are lowest; two, there were fewer cases in the Southern Hemisphere near the end of summer; and three, COVID-19-fatality rates increase with age and with chronic disease, both of which are associated with lower vitamin D levels," she said.
Given the spread of the virus and prevalence of vitamin D deficiency around the world, the potential for increased COVID-19 risk from low vitamin D levels raises a significant questions about whether we should be providing supplements to people in order to protect them from the disease, Troen said.
"But while I'm a significant proponent of maintaining very good vitamin D status, there's no evidence unfortunately that getting vitamin D acutely, either before or during the infection might make a difference. It's very, very hard to tell," he said.
"I think it's important to remember that vitamin D status is something that often persists for years and decades. So we know that people who are vitamin D deficient or insufficient often are in that situation for [a long time] before they get significant illnesses."
Culver also notes that, to date, studies of vitamin D supplementation in viral infections have not consistently demonstrated a benefit.
"Vitamin D levels have certainly been associated with a wide number of infectious and inflammatory disorders, and may potentially play an important role in the risk for COVID outcomes, but I would caution individuals not to supplement Vitamin D—beyond a multivitamin— without advice from their healthcare provider," he said.
Nevertheless, the experts Newsweek spoke to agreed maintaining sufficient vitamin D levels was important because it could help to protect against a host of other conditions, even it turns out t provide little benefit against COVID-19.
"We have potentially much to gain by having better vitamin D status, and relatively little to lose," Troen said. He said that while there are some people with certain conditions need to be careful about vitamin D intake, "in most folks, vitamin D supplementation can be done both effectively and very inexpensively."
"I believe that the benefits that would accrue from that would be a better innate and adaptive immune system that might help to, if not protect from infection directly, at least allow the individuals to fight that infection and hopefully not suffer the dire consequences as so many have."
Correction 5/16/20, 08:43 a.m.: This article has been corrected to make it clear that pre-prints are studies that have not been peer-reviewed. We regret the error.
The article has been updated to include an additional affiliation for Sue Shapses.
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Aristos is a Newsweek science reporter with the London, U.K., bureau. He reports on science and health topics, including; animal, ... Read more
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