Vitamin D levels may play significant role in COVID-19 incidence and mortality

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Separate studies have found a significant correlation between vitamin D levels and COVID-19 incidence and mortality rates. The first is a statistical analysis by Northwestern University of data from hospitals and clinics across China, France, Germany, Italy, Iran, South Korea, Spain, Switzerland, the UK and the US. The second, British, study was across 20 European countries, with ageing populations in Spain, Italy and Switzerland especially affected.

The first study, 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 UK and the US.

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.”

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 hypothesised that differences in healthcare quality, age distributions in population, testing rates or different strains of the coronavirus might be responsible. But Backman remained sceptical. “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 analysing 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 defence 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.”

Abstract
Background: Large-scale data show that the mortality of COVID-19 varies dramatically across populations, although the cause of these disparities is not well understood. In this study we investigated whether severe COVID-19 is linked to Vitamin D (Vit D) deficiency.
Method: Daily admission, recovery and deceased rate data for patients with COVID-19 from countries with a large number of confirmed patients (Germany, South Korea (S. Korea), China (Hubei), Switzerland, Iran, UK, US, France, Spain, Italy) as of April 20, 2020 were used. The time-adjusted case mortality ratio (T-CMR) was estimated as the number of deceased patients on day N divided by the number of confirmed cases on day N-8. The adaptive average of T-CMR (A-CMR) was further calculated as a metric of COVID-19 associated mortality in different countries. Although data on Vit D level is not currently available for COVID-19 patients, we leveraged the previously established links between Vit D and C-Reactive Protein (CRP) and between CRP and severe COVID-19, respectively, to estimate the potential impact of Vit D on the reduction of severe COVID-19.

Findings: A link between Vit D status and COVID-19 A-CMR in the US, France, and the UK (countries with similar screening status) may exist. Combining COVID-19 patient data and prior work on Vit D and CRP levels, we show that the risk of severe COVID-19 cases among patients with severe Vit D deficiency is 17.3% while the equivalent figure for patients with normal Vit D levels is 14.6% (a reduction of 15.6%).
Interpretation: Given that CRP is a surrogate marker for severe COVID-19 and is associated with Vit D deficiency, our finding suggests that Vit D may reduce COVID-19 severity by suppressing cytokine storm in COVID-19 patients. Further research is needed to account for other factors through direct measurement of Vit D levels.

Authors
Ali Daneshkhah, Vasundhara Agrawal, Adam Eshein, Hariharan Subramanian, Hemant Kumar Roy, Vadim Backman

Research led by Dr Lee Smith of Anglia Ruskin University (ARU) and Mr Petre Cristian Ilie, lead urologist of Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust in the UK has found an association between low average levels of vitamin D and high numbers of COVID-19 cases and mortality rates across 20 European countries.

Previous observational studies have reported an association between low levels of vitamin D and susceptibility to acute respiratory tract infections. Vitamin D modulates the response of white blood cells, preventing them from releasing too many inflammatory cytokines. The COVID-19 virus is known to cause an excess of pro-inflammatory cytokines.

Italy and Spain have both experienced high COVID-19 mortality rates, and the new study shows that both countries have lower average vitamin D levels than most northern European countries. This is partly because people in southern Europe, particularly the elderly, avoid strong sun, while skin pigmentation also reduces natural vitamin D synthesis.

The highest average levels of vitamin D are found in northern Europe, due to the consumption of cod liver oil and vitamin D supplements, and possibly less sun avoidance. Scandinavian nations are among the countries with the lowest number of COVID-19 cases and mortality rates per head of population in Europe.

Dr Lee Smith, reader in physical activity and public health at Anglia Ruskin University, said: “We found a significant crude relationship between average vitamin D levels and the number COVID-19 cases, and particularly COVID-19 mortality rates, per head of population across the 20 European countries.

“Vitamin D has been shown to protect against acute respiratory infections, and older adults, the group most deficient in vitamin D, are also the ones most seriously affected by COVID-19.

“A previous study found that 75% of people in institutions, such as hospitals and care homes, were severely deficient in vitamin D. We suggest it would be advisable to perform dedicated studies looking at vitamin D levels in COVID-19 patients with different degrees of disease severity.”

Petre Cristian Ilie, lead urologist of Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust, said: “Our study does have limitations however, not least because the number of cases in each country is affected by the number of tests performed, as well as the different measures taken by each country to prevent the spread of infection. Finally, and importantly, one must remember correlation does not necessarily mean causation.”

Abstract
WHO declared SARS-CoV-2 a global pandemic. The present aim was to propose an hypothesis that there is a potential association between mean levels of vitamin D in various countries with cases and mortality caused by COVID-19. The mean levels of vitamin D for 20 European countries and morbidity and mortality caused by COVID-19 were acquired. Negative correlations between mean levels of vitamin D (average 56 mmol/L, STDEV 10.61) in each country and the number of COVID-19 cases/1 M (mean 295.95, STDEV 298.7, and mortality/1 M (mean 5.96, STDEV 15.13) were observed. Vitamin D levels are severely low in the aging population especially in Spain, Italy and Switzerland. This is also the most vulnerable group of the population in relation to COVID-19. It should be advisable to perform dedicated studies about vitamin D levels in COVID-19 patients with different degrees of disease severity.

Authors
Petre Cristian Ilie, Simina Stefanescu, Lee Smith

Northwestern University material

medRxiv abstract (not peer reviewed)

Anglia Ruskin University material

Aging Clinical and Experimental Research abstract

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