Low plasma vitamin D level has increased risk of COVID-19 infection — Israel population study

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Vitamin D is recognised as an important co-factor in several physiological processes linked with bone and calcium metabolism, and also in diverse non-skeletal outcomes, including autoimmune diseases, cardiovascular diseases, type 2 diabetes, obesity and cognitive decline, and infections. In particular, the pronounced impact of vitamin D metabolites on the immune system response, and on the development of COVID-19 infection by the novel SARS CoV-2 virus, has been previously described in a few studies worldwide.

The collaborative group of scientists from the Leumit Health Services (LHS) and the Azrieli Faculty of Medicine of Bar-Ilan University aimed to determine associations of low plasma 25(OH)D with the risk of COVID-19 infection and hospitalisation. Using the real-world data and Israeli cohort of 782 COVID-19 positive patients and 7,025 COVID-19 negative patients, the groups identified that low plasma vitamin D level appears to be an independent risk factor for COVID-19 infection and hospitalisation.

"The main finding of our study was the significant association of low plasma vitamin D level with the likelihood of COVID-19 infection among patients who were tested for COVID-19, even after adjustment for age, gender, socio-economic status and chronic, mental and physical disorders," said Dr Eugene Merzon, head of the department of managed care and leading researcher of the LHS group. "Furthermore, low vitamin D level was associated with the risk of hospitalisation due to COVID-19 infection, although this association wasn't significant after adjustment for other confounders," he added.

"Our finding is in agreement with the results of previous studies in the field. Reduced risk of acute respiratory tract infection following vitamin D supplementation has been reported," said Dr Ilan Green, head of the LHS Research Institute.

"According to our analysis, persons that were COVID-19 positive were older than non-infected persons. Interestingly, the two-peak distributions for age groups were demonstrated to confer increased risk for COVID-19: around ages 25 and 50 years old," said Dr Milana Frenkel-Morgenstern, the leader of the Azrieli Faculty of Medicine research group. "The first peak may be explained by high social gathering habits at the young age. The peak at age 50 years may be explained by continued social habits, in conjunction with various chronic diseases," Frenkel-Morgenstern continued.

"Surprisingly, chronic medical conditions, like dementia, cardiovascular disease, and chronic lung disease that were considered to be very risky in previous studies, were not found as increasing the rate of infection in our study," noted Professoe Shlomo Vinker, LHS Chief Medical Officer. "However, this finding is highly biased by the severe social contacts restrictions that were imposed on all the population during the COVID-19 outbreak. Therefore, we assume that following the Israeli Ministry of Health instructions, patients with chronic medical conditions significantly reduced their social contacts. This might indeed minimise the risk of COVID-19 infection in that group of patients," explained Vinker.

Dr Dmitry Tworowski and Dr Alessandro Gorohovski. from the Frenkel-Morgenstern laboratory at Bar-Ilan University's Azrieli faculty of medicine, suggest that the study will have a very significant impact. "The main strength of our study is its being large, real-world, and population-based," they explained.

Now researchers are planning to evaluate factors associated with mortality due to COVID-19 in Israel. "We are willing to find associations to the COVID-19 clinical outcomes (for example, pre-infection glycaemic control of COVID-19 patients) to make the assessment of mortality risk due to COVID-19 infection in Israel," said Merzon.

Aim: To evaluate associations of plasma 25(OH)D status with the likelihood of coronavirus disease (COVID‐19) infection and hospitalization.
Methods: The study population included the 14,000 members of Leumit Health Services who were tested for COVID‐19 infection from February 1st to April 30th 2020, and who had at least one previous blood test for plasma 25(OH)D level. "Suboptimal" or "low" plasma 25(OH)D level was defined as plasma 25‐hydroxyvitamin D, or 25(OH)D, concentration below the level of 30 ng/mL.
Results: Of 7,807 individuals, 782 (10.1%) were COVID‐19‐positive, and 7,025 (89.9%) COVID‐19‐negative. The mean plasma vitamin D level was significantly lower among those who tested positive than negative for COVID‐19 [19.00 ng/mL (95% confidence interval [CI] 18.41‐19.59) vs . 20.55 (95% CI 20.32‐20.78)]. Univariate analysis demonstrated an association between low plasma 25(OH)D level and increased likelihood of COVID‐19 infection [crude odds ratio (OR) of 1.58 (95% CI 1.24‐2.01, p<0.001)], and of hospitalization due to the SARS‐CoV‐2 virus [crude OR of 2.09 (95% CI 1.01‐ 4.30, p<0.05)]. In multivariate analyses that controlled for demographic variables, and psychiatric and somatic disorders, the adjusted OR of COVID‐19 infection [1.45 (95% CI 1.08‐1.95, p<0.001)], and of hospitalization due to the SARS‐CoV‐2 virus [1.95 (95% CI 0.98‐4.845, p=0.061)] were preserved. In the multivariate analyses, age over 50 years, male gender and low‐medium socioeconomic status were also positively associated with the risk of COVID‐19 infection; age over 50 years was positively associated with the likelihood of hospitalization due to COVID‐19.
Conclusion: Low plasma 25(OH)D level appears to be an independent risk factor for COVID‐19 infection and hospitalization.

Eugene Merzon, Dmitry Tworowski, Alessandro Gorohovski, Shlomo Vinker, Avivit Golan Cohen, Ilan Green, Milana Frenkel Morgenstern

Bar-llan University material (in Hebrew) The FEBS Journal abstract

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