Researchers investigating possible link between vitamin D deficiency and COVID-19
For months, many of us have stayed home on the advice of health experts, quarantining indoors to help slow the spread of the coronavirus. Now some researchers are investigating the possibility that spending a little more time in the sun could actually help prevent COVID-19.
That's because sunshine is a key ingredient for our bodies to make vitamin D.
After seeing a correlation between severe COVID-19 patients and vitamin D deficiency, the researchers hypothesized that the vitamin, absorbed through sunlight by the skin, could play a role in helping the body's immune system fight the novel coronavirus.
An earlier observational study of 499 patients by the University of Chicago found that patients with untreated vitamin D deficiencies were almost twice as likely to test positive for COVID-19 compared to those with enough vitamin D.
More research is needed still, and it's also unclear whether low vitamin D levels are simply an effect of severe disease, rather than a cause.
"The correlation is not causation. So we need to actually do a clinical trial," said Arizona State University researcher James Adams.
The question at the heart of these trials is, does vitamin D deficiency cause severe COVID-19 symptoms, or is vitamin D deficiency just another symptom of COVID-19?
Adams's theory is that rather than treating COVID-19 symptoms after the fact, vitamin D could play a role in preventing serious infections —resulting in milder infections or perhaps no infection at all. To test this, he is running a preliminary study of vitamin D in COVID-19 patients in conjunction with the Southwest College of Naturopathic Medicine.
In the phase one clinical trial, researchers will administer supplemental vitamin D for two weeks to participants who have tested positive for COVID-19 but have not yet developed severe symptoms. All participants in the study must also show a vitamin D deficiency in initial screenings.
After two weeks, researchers will measure participants' vitamin D levels and measure any changes in the severity of COVID-19 symptoms. The study will continue to track symptoms at four weeks and six weeks after initial treatment.
In addition to measuring vitamin D, the study will also measure other cells that are important for overall health, such as vitamin C.
Low levels can go unnoticed
Vitamin D deficiencies are more common than one might think, according to naturopathic doctor Sarah Trahan, who works at the college and is collaborating with Adams on the study.
"Generally anyone we test, if they're not supplementing, they're deficient," she said.
Many of these deficiencies tend to go unnoticed, according to Lise Alschuler, a naturopathic doctor at the University of Arizona's Andrew Weil Center for Integrative Medicine.
While deficiencies become more obvious when patients have less than 20 nanograms of vitamin D per milliliter of blood, she said many of her patients have between 20 and 30 nanograms per mL, which is less than the 40-50 nanograms per mL that she considers ideal.
"So they're not going to get rickets, but they're going to have insufficient vitamin D for optimal health," Alschuler said. "And that's where a lot of people fall, even in Arizona, surprisingly, because we have so much sun."
Screening for vitamin D deficiency is not done as frequently by physicians as Alschuler would hope, but it's something she is working to raise more awareness about.
Deficiencies in vitamin D tend to be more prevalent among those who are older, obese or who have darker colored skin. So far, people in these categories have also been linked with disproportionate rates of severe COVID-19 and COVID-19 related deaths.
"These are all three major risk factors with COVID-19, and they all relate to vitamin D," Adams said.
Older people tend to make less vitamin D, whereas the melanin in darker skin blocks more UV rays from the sun, which are needed to make vitamin D, according to Trahan.
According to a CDC study published in 2006, 21% of non-Hispanic white people are at risk of having inadequate levels of vitamin D, versus 73% of Black people and 42% of Hispanic people.
The higher rate of deficiency among overweight people is thought to be because vitamin D dissolves in fat, so more vitamin D is being absorbed by fat cells and not going into the bloodstream.
Vitamin D deficiencies may not be to blame for the disproportionate impact of COVID-19 on these populations. There could be other factors at play such as socioeconomic status, genetics or increased presence of other diseases.
Vitamin supplements are one option
Still, Adams thinks it's worth investigating, especially since administering normal doses of vitamin D is extremely safe and relatively cheap.
"Let's try to make the immune system as healthy as possible," he said. "If someone has a weakened immune system because of vitamin D deficiency, then other treatments like vaccines may not work as well."
Rather than being the main treatment to prevent or cure COVID-19, Adams sees vitamin D as a potential supplemental treatment in addition to drugs or vaccines, especially since it is thought to play a role in immune system health.
While vitamin D has no serious risks when taken at the right levels, Trahan cautioned against taking too much supplemental vitamin D. Taking too much could increase the risk for kidney damage, kidney stones or other complications from too much calcium buildup in the blood.
To get a normal level naturally, Trahan said people with lighter skin can go outside in the middle of the day for about 15 minutes without sunscreen on, since sunscreen blocks vitamin D absorption. For those with darker skin, she said it may take about twice as long to get normal levels from the sun.
Because unprotected sun exposure could increase the risk for skin cancer, taking supplements as an alternative is typically fine if a person takes less than 4,000 international units of vitamin D daily, according to Martin Hewison, a professor at the University of Birmingham in the U.K. who has studied the vitamin for years.
"There has never been a single example of any toxic side effects in anybody taking less than 4,000 international units per day," he said.
Understanding the role of vitamin D
While vitamin D is often thought of as important for calcium absorption and bone health, its exact function in the immune system is not fully understood and needs to be further researched.
Many cells in the body have vitamin D receptors, which are areas on the cell that vitamin D can bind with.
"Those receptors, they're like a basket, and when it catches a vitamin D ball, basically the receptor activates and it creates actions within the cell," Alschuler said.
One effect is that vitamin D seems to help initiate an inflammatory response in cells, but also regulate inflammation to keep it in check, according to Alschuler. In particular, vitamin D may be able to suppress inflammatory signals called cytokines. Targeting inflammatory cytokines is important because an over-release of these signals causes an immune system overreaction, known as cytokine storms, which have been blamed for many COVID-19 deaths and damaging side effects.
But vitamin D also interacts with other key cells in the immune system, according to Hewison.
"It's a good jack of all trades," Hewison said. "It helps in all the places where you'd want it to...it's not just a one-trick pony."
People with lower levels of vitamin D seem less able to make a protein called cathelicidin, which helps destroy the outside membrane or envelope of bacterias and viruses.
"It just punches holes in the membranes of the bacteria and kills them," Hewison explained.
Vitamin D also helps promote what is essentially an immune system housekeeping process called autophagy, where the body removes damaged or failing cells and recycles them to create newer, healthier cells, Hewison said. This process can help eliminate invading organisms from the body, he said.
One study Hewison worked on suggested that vitamin D could control iron levels inside a cell, which help give the cell energy but can be taken advantage of by viruses that enter the cell. In the case of a viral infection, he said the vitamin appears to help iron leave the cell so that it does not get hijacked for use by the virus.
'We know its potential'
While these findings are intriguing, Hewison said there has not been much success with using vitamin D for infection treatment.
"This is more important for long term preventative measures," he said. "Once you've got the disease...does it work really as well as we think? I think the simple answer is no."
He says this is because once an infection gets into a body's system, the bacteria or virus will try to evade immune system responses promoted by vitamin D.
He added that there is no clear-cut evidence that vitamin D supplements would prevent COVID-19, but that further studies were needed.
"We know its potential. The real issue is going to be getting some good studies that answer a key question," he said. "Is vitamin D deficiency a causative factor in these sorts of diseases or are the diseases actually contributing to vitamin D deficiency?"
As someone who has been taking 2,000 international units of vitamin D daily for years and hasn't had a cold or cough since, Hewison is certainly a believer in the potential preventative power of vitamin D, but some in the scientific community are more skeptical, making obtaining funding for further studies a challenge.
However, he thinks that in the case of this pandemic, it's worth investigating any potential benefits, especially one this cheap and plentiful.
"What have you got to lose?" he said.
Further study is needed
Rather than wait for grant funding, which can take months, researchers at ASU are fundraising money for their study, which has enrolled 40 participants. Adams said they hope to get funding to enroll an additional 60 participants so that they can get better statistical results.
Since the study is not giving placebos to any participants, it's possible that any recorded benefits could just be the result of a bias called the placebo effect. In other words, improvements could result from a belief in the treatment, rather than as a result of the treatment itself. Without a placebo, there is no control baseline to measure the treatment against.
To better analyze the data, Adams said researchers will compare it to historical data of COVID-19 symptom development.
Another potential issue with this study is that participants must be able to speak English. This could lead to an overrepresentation of white participants.
However, Adams said the study is open to all races and ethnicities and that approximately 40% of the participants enrolled so far are minorities, and many of them are Hispanic. The reason for the English requirement, he said, is that including more languages in the study would require hiring additional staff and translators.
"We would have to have all aspects of the process done by someone who is fluent in that language," he said. "It would be so much more expensive."
The research team hopes to complete the study in another month or two, and if it goes well, Adams hopes to do a placebo-controlled study of 10,000 participants. He plans to submit a proposal to the National Institutes of Health to secure more funding for the next stage of study.
Instead of enrolling people who have tested positive for COVID-19, he said the phase 2 study would enroll those who haven't yet tested positive for COVID-19. The study would compare participants who received a placebo with those who received vitamin D to see if the latter group has lower rates of COVID-19 after a six month period.
While he hopes these studies will show a positive impact in lowering the rate of COVID-19, Adams is not marketing vitamin D as a cure to stop the pandemic and believes that if it proves effective, it will be just one piece of the puzzle.
"We hope that we can reduce their severity of symptoms," Adams said. "We're not recommending this as a treatment now, we're saying this is a treatment we think is worth investigating."
https://www.azcentral.com/story/news/local/arizona-science/2020/07/22/coronavirus-research-study-link-between-vitamin-d-deficiency-covid-19/5445070002/
That's because sunshine is a key ingredient for our bodies to make vitamin D.
After seeing a correlation between severe COVID-19 patients and vitamin D deficiency, the researchers hypothesized that the vitamin, absorbed through sunlight by the skin, could play a role in helping the body's immune system fight the novel coronavirus.
An earlier observational study of 499 patients by the University of Chicago found that patients with untreated vitamin D deficiencies were almost twice as likely to test positive for COVID-19 compared to those with enough vitamin D.
More research is needed still, and it's also unclear whether low vitamin D levels are simply an effect of severe disease, rather than a cause.
"The correlation is not causation. So we need to actually do a clinical trial," said Arizona State University researcher James Adams.
The question at the heart of these trials is, does vitamin D deficiency cause severe COVID-19 symptoms, or is vitamin D deficiency just another symptom of COVID-19?
Adams's theory is that rather than treating COVID-19 symptoms after the fact, vitamin D could play a role in preventing serious infections —resulting in milder infections or perhaps no infection at all. To test this, he is running a preliminary study of vitamin D in COVID-19 patients in conjunction with the Southwest College of Naturopathic Medicine.
In the phase one clinical trial, researchers will administer supplemental vitamin D for two weeks to participants who have tested positive for COVID-19 but have not yet developed severe symptoms. All participants in the study must also show a vitamin D deficiency in initial screenings.
After two weeks, researchers will measure participants' vitamin D levels and measure any changes in the severity of COVID-19 symptoms. The study will continue to track symptoms at four weeks and six weeks after initial treatment.
In addition to measuring vitamin D, the study will also measure other cells that are important for overall health, such as vitamin C.
Low levels can go unnoticed
Vitamin D deficiencies are more common than one might think, according to naturopathic doctor Sarah Trahan, who works at the college and is collaborating with Adams on the study.
"Generally anyone we test, if they're not supplementing, they're deficient," she said.
Many of these deficiencies tend to go unnoticed, according to Lise Alschuler, a naturopathic doctor at the University of Arizona's Andrew Weil Center for Integrative Medicine.
While deficiencies become more obvious when patients have less than 20 nanograms of vitamin D per milliliter of blood, she said many of her patients have between 20 and 30 nanograms per mL, which is less than the 40-50 nanograms per mL that she considers ideal.
"So they're not going to get rickets, but they're going to have insufficient vitamin D for optimal health," Alschuler said. "And that's where a lot of people fall, even in Arizona, surprisingly, because we have so much sun."
Screening for vitamin D deficiency is not done as frequently by physicians as Alschuler would hope, but it's something she is working to raise more awareness about.
Deficiencies in vitamin D tend to be more prevalent among those who are older, obese or who have darker colored skin. So far, people in these categories have also been linked with disproportionate rates of severe COVID-19 and COVID-19 related deaths.
"These are all three major risk factors with COVID-19, and they all relate to vitamin D," Adams said.
Older people tend to make less vitamin D, whereas the melanin in darker skin blocks more UV rays from the sun, which are needed to make vitamin D, according to Trahan.
According to a CDC study published in 2006, 21% of non-Hispanic white people are at risk of having inadequate levels of vitamin D, versus 73% of Black people and 42% of Hispanic people.
The higher rate of deficiency among overweight people is thought to be because vitamin D dissolves in fat, so more vitamin D is being absorbed by fat cells and not going into the bloodstream.
Vitamin D deficiencies may not be to blame for the disproportionate impact of COVID-19 on these populations. There could be other factors at play such as socioeconomic status, genetics or increased presence of other diseases.
Vitamin supplements are one option
Still, Adams thinks it's worth investigating, especially since administering normal doses of vitamin D is extremely safe and relatively cheap.
"Let's try to make the immune system as healthy as possible," he said. "If someone has a weakened immune system because of vitamin D deficiency, then other treatments like vaccines may not work as well."
Rather than being the main treatment to prevent or cure COVID-19, Adams sees vitamin D as a potential supplemental treatment in addition to drugs or vaccines, especially since it is thought to play a role in immune system health.
While vitamin D has no serious risks when taken at the right levels, Trahan cautioned against taking too much supplemental vitamin D. Taking too much could increase the risk for kidney damage, kidney stones or other complications from too much calcium buildup in the blood.
To get a normal level naturally, Trahan said people with lighter skin can go outside in the middle of the day for about 15 minutes without sunscreen on, since sunscreen blocks vitamin D absorption. For those with darker skin, she said it may take about twice as long to get normal levels from the sun.
Because unprotected sun exposure could increase the risk for skin cancer, taking supplements as an alternative is typically fine if a person takes less than 4,000 international units of vitamin D daily, according to Martin Hewison, a professor at the University of Birmingham in the U.K. who has studied the vitamin for years.
"There has never been a single example of any toxic side effects in anybody taking less than 4,000 international units per day," he said.
Understanding the role of vitamin D
While vitamin D is often thought of as important for calcium absorption and bone health, its exact function in the immune system is not fully understood and needs to be further researched.
Many cells in the body have vitamin D receptors, which are areas on the cell that vitamin D can bind with.
"Those receptors, they're like a basket, and when it catches a vitamin D ball, basically the receptor activates and it creates actions within the cell," Alschuler said.
One effect is that vitamin D seems to help initiate an inflammatory response in cells, but also regulate inflammation to keep it in check, according to Alschuler. In particular, vitamin D may be able to suppress inflammatory signals called cytokines. Targeting inflammatory cytokines is important because an over-release of these signals causes an immune system overreaction, known as cytokine storms, which have been blamed for many COVID-19 deaths and damaging side effects.
But vitamin D also interacts with other key cells in the immune system, according to Hewison.
"It's a good jack of all trades," Hewison said. "It helps in all the places where you'd want it to...it's not just a one-trick pony."
People with lower levels of vitamin D seem less able to make a protein called cathelicidin, which helps destroy the outside membrane or envelope of bacterias and viruses.
"It just punches holes in the membranes of the bacteria and kills them," Hewison explained.
Vitamin D also helps promote what is essentially an immune system housekeeping process called autophagy, where the body removes damaged or failing cells and recycles them to create newer, healthier cells, Hewison said. This process can help eliminate invading organisms from the body, he said.
One study Hewison worked on suggested that vitamin D could control iron levels inside a cell, which help give the cell energy but can be taken advantage of by viruses that enter the cell. In the case of a viral infection, he said the vitamin appears to help iron leave the cell so that it does not get hijacked for use by the virus.
'We know its potential'
While these findings are intriguing, Hewison said there has not been much success with using vitamin D for infection treatment.
"This is more important for long term preventative measures," he said. "Once you've got the disease...does it work really as well as we think? I think the simple answer is no."
He says this is because once an infection gets into a body's system, the bacteria or virus will try to evade immune system responses promoted by vitamin D.
He added that there is no clear-cut evidence that vitamin D supplements would prevent COVID-19, but that further studies were needed.
"We know its potential. The real issue is going to be getting some good studies that answer a key question," he said. "Is vitamin D deficiency a causative factor in these sorts of diseases or are the diseases actually contributing to vitamin D deficiency?"
As someone who has been taking 2,000 international units of vitamin D daily for years and hasn't had a cold or cough since, Hewison is certainly a believer in the potential preventative power of vitamin D, but some in the scientific community are more skeptical, making obtaining funding for further studies a challenge.
However, he thinks that in the case of this pandemic, it's worth investigating any potential benefits, especially one this cheap and plentiful.
"What have you got to lose?" he said.
Further study is needed
Rather than wait for grant funding, which can take months, researchers at ASU are fundraising money for their study, which has enrolled 40 participants. Adams said they hope to get funding to enroll an additional 60 participants so that they can get better statistical results.
Since the study is not giving placebos to any participants, it's possible that any recorded benefits could just be the result of a bias called the placebo effect. In other words, improvements could result from a belief in the treatment, rather than as a result of the treatment itself. Without a placebo, there is no control baseline to measure the treatment against.
To better analyze the data, Adams said researchers will compare it to historical data of COVID-19 symptom development.
Another potential issue with this study is that participants must be able to speak English. This could lead to an overrepresentation of white participants.
However, Adams said the study is open to all races and ethnicities and that approximately 40% of the participants enrolled so far are minorities, and many of them are Hispanic. The reason for the English requirement, he said, is that including more languages in the study would require hiring additional staff and translators.
"We would have to have all aspects of the process done by someone who is fluent in that language," he said. "It would be so much more expensive."
The research team hopes to complete the study in another month or two, and if it goes well, Adams hopes to do a placebo-controlled study of 10,000 participants. He plans to submit a proposal to the National Institutes of Health to secure more funding for the next stage of study.
Instead of enrolling people who have tested positive for COVID-19, he said the phase 2 study would enroll those who haven't yet tested positive for COVID-19. The study would compare participants who received a placebo with those who received vitamin D to see if the latter group has lower rates of COVID-19 after a six month period.
While he hopes these studies will show a positive impact in lowering the rate of COVID-19, Adams is not marketing vitamin D as a cure to stop the pandemic and believes that if it proves effective, it will be just one piece of the puzzle.
"We hope that we can reduce their severity of symptoms," Adams said. "We're not recommending this as a treatment now, we're saying this is a treatment we think is worth investigating."
https://www.azcentral.com/story/news/local/arizona-science/2020/07/22/coronavirus-research-study-link-between-vitamin-d-deficiency-covid-19/5445070002/
