Vitamin D levels appear to play role in COVID-19 mortality rates

Vitamin D levels appear to play role in COVID-19 mortality rates

After studying global data from the novel coronavirus (COVID-19) pandemic, researchers have discovered a strong correlation between severe vitamin D deficiency and mortality rates.

Led by Northwestern University, the research team conducted a statistical analysis of data from hospitals and clinics across China, France, Germany, Italy, Iran, South Korea, Spain, Switzerland, the United Kingdom (UK) and the United States.

The researchers noted that patients from countries with high COVID-19 mortality rates, such as Italy, Spain and the UK, had lower levels of vitamin D compared to patients in countries that were not as severely affected.

This does not mean that everyone -- especially those without a known deficiency -- needs to start hoarding supplements, the researchers caution.

"While I think it is important for people to know that vitamin D deficiency might play a role in mortality, we don't need to push vitamin D on everybody," said Northwestern's Vadim Backman, who led the research. "This needs further study, and I hope our work will stimulate interest in this area. The data also may illuminate the mechanism of mortality, which, if proven, could lead to new therapeutic targets."

The research is available on medRxiv, a preprint server for health sciences.

Backman is the Walter Dill Scott Professor of Biomedical Engineering at Northwestern's McCormick School of Engineering. Ali Daneshkhah, a postdoctoral research associate in Backman's laboratory, is the paper's first author.

Backman and his team were inspired to examine vitamin D levels after noticing unexplained differences in COVID-19 mortality rates from country to country. Some people hypothesized that differences in healthcare quality, age distributions in population, testing rates or different strains of the coronavirus might be responsible. But Backman remained skeptical.

"None of these factors appears to play a significant role," Backman said. "The healthcare system in northern Italy is one of the best in the world. Differences in mortality exist even if one looks across the same age group. And, while the restrictions on testing do indeed vary, the disparities in mortality still exist even when we looked at countries or populations for which similar testing rates apply.

"Instead, we saw a significant correlation with vitamin D deficiency," he said.

By analyzing publicly available patient data from around the globe, Backman and his team discovered a strong correlation between vitamin D levels and cytokine storm -- a hyperinflammatory condition caused by an overactive immune system -- as well as a correlation between vitamin D deficiency and mortality.

"Cytokine storm can severely damage lungs and lead to acute respiratory distress syndrome and death in patients," Daneshkhah said. "This is what seems to kill a majority of COVID-19 patients, not the destruction of the lungs by the virus itself. It is the complications from the misdirected fire from the immune system."

This is exactly where Backman believes vitamin D plays a major role. Not only does vitamin D enhance our innate immune systems, it also prevents our immune systems from becoming dangerously overactive. This means that having healthy levels of vitamin D could protect patients against severe complications, including death, from COVID-19.

"Our analysis shows that it might be as high as cutting the mortality rate in half," Backman said. "It will not prevent a patient from contracting the virus, but it may reduce complications and prevent death in those who are infected."

Backman said this correlation might help explain the many mysteries surrounding COVID-19, such as why children are less likely to die. Children do not yet have a fully developed acquired immune system, which is the immune system's second line of defense and more likely to overreact.

"Children primarily rely on their innate immune system," Backman said. "This may explain why their mortality rate is lower."

Backman is careful to note that people should not take excessive doses of vitamin D, which might come with negative side effects. He said the subject needs much more research to know how vitamin D could be used most effectively to protect against COVID-19 complications.

"It is hard to say which dose is most beneficial for COVID-19," Backman said. "However, it is clear that vitamin D deficiency is harmful, and it can be easily addressed with appropriate supplementation. This might be another key to helping protect vulnerable populations, such as African-American and elderly patients, who have a prevalence of vitamin D deficiency."

Backman is the director of Northwestern's Center for Physical Genomics and Engineering and the associate director for Research Technology and Infrastructure at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.

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Story Source:

Materials provided by Northwestern University. Original written by Amanda Morris. Note: Content may be edited for style and length.

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Journal Reference:

1. Ali Daneshkhah, Vasundhara Agrawal, Adam Eshein, Hariharan Subramanian, Hemant Kumar Roy, Vadim Backman. The Possible Role of Vitamin D in Suppressing Cytokine Storm and Associated Mortality in COVID-19 Patients. medRxiv, Posted April 30, 2020; [link]

Vitamin D levels appear to play role in COVID-19 mortality rates

Doctor, vitamin D concept (stock image).

After studying global data from the novel coronavirus (COVID-19) pandemic, researchers have discovered a strong correlation between severe vitamin D deficiency and mortality rates.

Led by Northwestern University, the research team conducted a statistical analysis of data from hospitals and clinics across China, France, Germany, Italy, Iran, South Korea, Spain, Switzerland, the United Kingdom (UK) and the United States.

The researchers noted that patients from countries with high COVID-19 mortality rates, such as Italy, Spain and the UK, had lower levels of vitamin D compared to patients in countries that were not as severely affected.

This does not mean that everyone -- especially those without a known deficiency -- needs to start hoarding supplements, the researchers caution.

"While I think it is important for people to know that vitamin D deficiency might play a role in mortality, we don't need to push vitamin D on everybody," said Northwestern's Vadim Backman, who led the research. "This needs further study, and I hope our work will stimulate interest in this area. The data also may illuminate the mechanism of mortality, which, if proven, could lead to new therapeutic targets."

The research is available on medRxiv, a preprint server for health sciences.

Backman is the Walter Dill Scott Professor of Biomedical Engineering at Northwestern's McCormick School of Engineering. Ali Daneshkhah, a postdoctoral research associate in Backman's laboratory, is the paper's first author.

Backman and his team were inspired to examine vitamin D levels after noticing unexplained differences in COVID-19 mortality rates from country to country. Some people hypothesized that differences in healthcare quality, age distributions in population, testing rates or different strains of the coronavirus might be responsible. But Backman remained skeptical.

"None of these factors appears to play a significant role," Backman said. "The healthcare system in northern Italy is one of the best in the world. Differences in mortality exist even if one looks across the same age group. And, while the restrictions on testing do indeed vary, the disparities in mortality still exist even when we looked at countries or populations for which similar testing rates apply.

"Instead, we saw a significant correlation with vitamin D deficiency," he said.

By analyzing publicly available patient data from around the globe, Backman and his team discovered a strong correlation between vitamin D levels and cytokine storm -- a hyperinflammatory condition caused by an overactive immune system -- as well as a correlation between vitamin D deficiency and mortality.

"Cytokine storm can severely damage lungs and lead to acute respiratory distress syndrome and death in patients," Daneshkhah said. "This is what seems to kill a majority of COVID-19 patients, not the destruction of the lungs by the virus itself. It is the complications from the misdirected fire from the immune system."

This is exactly where Backman believes vitamin D plays a major role. Not only does vitamin D enhance our innate immune systems, it also prevents our immune systems from becoming dangerously overactive. This means that having healthy levels of vitamin D could protect patients against severe complications, including death, from COVID-19.

"Our analysis shows that it might be as high as cutting the mortality rate in half," Backman said. "It will not prevent a patient from contracting the virus, but it may reduce complications and prevent death in those who are infected."

Backman said this correlation might help explain the many mysteries surrounding COVID-19, such as why children are less likely to die. Children do not yet have a fully developed acquired immune system, which is the immune system's second line of defense and more likely to overreact.

"Children primarily rely on their innate immune system," Backman said. "This may explain why their mortality rate is lower."

Backman is careful to note that people should not take excessive doses of vitamin D, which might come with negative side effects. He said the subject needs much more research to know how vitamin D could be used most effectively to protect against COVID-19 complications.

"It is hard to say which dose is most beneficial for COVID-19," Backman said. "However, it is clear that vitamin D deficiency is harmful, and it can be easily addressed with appropriate supplementation. This might be another key to helping protect vulnerable populations, such as African-American and elderly patients, who have a prevalence of vitamin D deficiency."

Backman is the director of Northwestern's Center for Physical Genomics and Engineering and the associate director for Research Technology and Infrastructure at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.

---

Story Source:

Materials provided by Northwestern University. Original written by Amanda Morris. Note: Content may be edited for style and length.

---

Journal Reference:

1. Ali Daneshkhah, Vasundhara Agrawal, Adam Eshein, Hariharan Subramanian, Hemant Kumar Roy, Vadim Backman. The Possible Role of Vitamin D in Suppressing Cytokine Storm and Associated Mortality in COVID-19 Patients. medRxiv, Posted April 30, 2020; [link]

Vitamin D at High Dose Can Worsen MS, Early Study Says

High-dose vitamin D supplements appear to aggravate inflammation and myelin loss in the brain and spinal cord, and worsen the disability associated with multiple sclerosis (MS), a study in a mouse disease model reported.

Excessive use of vitamin D causes calcium levels to spike, which directly increase the inflammatory state of immune cells and their capacity to infiltrate the central nervous system (CNS; the brain and spinal cord), the researchers observed.

Supplements given in moderation, however, may help to ease disease symptoms.

The findings were presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2020, held Feb. 27–29 in Florida, in the poster “High Dose Vitamin D Worsens Experimental CNS Autoimmune Disease By Raising T Cell-excitatory Calcium.” The presenter was Sebastian Torke, PhD, with the Institute of Neuropathology, University Medical Center in Göttingen, Germany.

A large body of data suggests that low vitamin D levels raise a person’s risk of developing MS. But whether or not vitamin supplements should be given to people who already have the disease is under debate.

In general, MS patients have relatively low levels of vitamin D. Based on studies showing an association between low levels of this vitamin and a higher risk of relapses and earlier disability, doctors often recommend oral vitamin D3 (cholecalciferol) supplements to their patients.

Yet, it is unclear whether such supplements offer therapeutic benefits to MS patients, and if they do, what doses should be advised. While relatively low doses of vitamin D appear to be safe, high doses are likely toxic and potentially harmful.

Researchers set out to model the consequences of this common practice by investigating the effects of long-term vitamin D supplements given to mice.

They fed mice a diet containing either a low concentration (less than 5 IU of vitamin D3/kg of food), a standard amount (1,500 IU/kg), or a high dose (75,000 IU/kg) of vitamin D3 for 15 weeks (about three and a half months).

These three doses were chosen to generate serum levels of 25-hydroxyvitamin D [25(OH)D] — the molecule measured in a vitamin D blood test — reflective of what is typically seen in patients with vitamin D deficiency (less than 30 nmol/l), in those taking modest supplements and achieving normal vitamin D levels (100 nmol/l), and in those with disproportionally high supplements (250 nmol/l).

All three diets contained identical calcium (1%) and phosphate (0.7%) concentrations.

Researchers then induced MS-like disease in the mice and followed their clinical symptoms, CNS inflammation and damage, and immune cell behavior.

Results showed that, compared to MS mice not given supplements, a moderate dose of vitamin D eased disease severity, which was linked to an expansion of regulatory T-cells — immune cells that help to keep immune responses in check.

The opposite, however, happened in mice fed a high-dose vitamin D diet.

“High-dose, long-term vitamin D supplementation lead to much worse disease in these mice,” Torke said.

The animals had excessively high levels of the vitamin in the blood (above 200 nmol/l), and developed “fulminant” disease with severe and persistent disability. This was associated with massive CNS inflammation and the infiltration of activated  T helper 1 (Th1) and Th17 cells — immune cells that can cause inflammation and autoimmune disease — as well as demyelination (loss of myelin), a hallmark of MS.

Researchers decided that calcium is likely at fault for what they considered an “unexpected outcome.”

High-dose vitamin D caused calcium levels to rise to excessive amounts (hypercalcemia) throughout the body, triggering the activation, proliferation, and inflammatory behavior of  T-cells.

Supporting these findings, the researchers also found that exposing mice or human T-cells in vitro (in the lab) to various concentrations of calcium (equivalent to those found in vitamin D-fed mice) increased the entry of calcium into cells, and triggered the activation of pro-inflammatory pathways.

“It is not vitamin D that is bad, but too much vitamin D leads to increased calcium [levels] that promote T-cell proliferation and activation,” Torke said.

Calcium also enhances the ability of T-cells to cross the blood-brain barrier — a highly selective membrane that regulates which substances or cells carried in blood can enter the brain or spinal cord — reflecting a greater ability to infiltrate the CNS.

Inducing hypercalcemia in mice was enough to activate T-cells, confirming that this effect can also occur in a living organism (in vivo).

“These findings highlight excessive vitamin D supplementation and resulting hypercalcemia as novel risk factors promoting worsening of CNS demyelinating disease,” Torke said.

“Our data caution that in light of the currently limited information on a direct beneficial effect of vitamin D in MS, MS patients may be at danger of experiencing untoward immunological and/or clinical effects when vitamin D is supplemented excessively,” Torke concluded.