What is the relationship between the severity of COVID-19 and vitamin D?

Vitamin D deficiency is associated with an increase in thrombotic episodes, which are frequently observed in COVID-19 patients.  But is there enough evidence to support the effectiveness of this theory? 

Writer: Sara Maria Majernikova
Artist: Mei-Ann Sim
Editor: Natalia Sanchez

The COVID-19 pandemic has led to existential crises, with many people comparing it to a modern apocalypse. COVID-19 is an infectious disease caused by a newly discovered coronavirus, namely SARS-CoV-2. The WHO suggests that COVID-19 can be transmitted in all areas, including climates with hot and humid weather. According to the WHO, there have been 186,889,608 confirmed cases of COVID-19, including 4,036,353 deaths. On the bright side, 170,904,646 infected people are reported to have recovered. The highest number of COVID-19 positive patients has been reported by the United States of America (a total of 73,450,049 cases), whilst the least number of infected people is in Micronesia (a total of 1 case). The UK is currently ranked at the seventh place with 5,058,093 cases (out of which 128,365 resulted in death). As of October 2021, a total of 6.64 billion vaccine doses have been administered globally. However, vaccine distribution seems not to be fast enough, hence many scientists continue to search for alternative cures that might help to fight the virus. One of those potential cures could be vitamin D.  

As the National Institute of Health (NIH) informs, vitamin D (also referred to as ergocalciferol) is a fat-soluble vitamin which is naturally present in a few foods, added to others, and available as a dietary supplement. It is also produced when ultraviolet (UV) rays from sunlight strike the skin and triggers vitamin D synthesis. Vitamin D obtained from sun exposure, foods, and supplements is biologically inert and must undergo two hydroxylations in the body for activation. Vitamin D promotes calcium absorption in the gut and maintains adequate serum calcium and phosphate concentrations, to enable normal bone mineralization and prevent hypocalcemic tetany (involuntary muscle contractions leading to cramps and spasms). It is also needed for bone growth and bone remodelling by osteoblasts and osteoclasts. Without sufficient vitamin D, bones can become thin, brittle or misshapen. NIH also informs vitamin D sufficiency prevents rickets in children and osteomalacia in adults. Furthermore, together with calcium, vitamin D also helps protect older adults from osteoporosis.

“Vitamin D is cheap, easily available and relatively safe,” says genetic epidemiologist Fotios Drenos of Brunel University London. Investigating whether the vitamin could make a difference in COVID patients “was an important question to ask,”. Hamada A. Aboubakr and his team found coronaviruses die very quickly when exposed to the UV light from the sun. Like other enveloped viruses, SARS-CoV-2 survives at room temperature or lower, and when the relative humidity is low (<50%), Basaran et al discovered vitamin D, which has immunomodulatory effect, can reduce risk of infections and concentrations of pro-inflammatory cytokines (a part of a large group of proteins, peptides or glycoproteins that are secreted by specific cells of immune system and a category of signalling molecules mediating and regulate immunity, inflammation and hematopoiesis). A total of 204 patients with COVID-19 disease were enrolled in the study. All patients had viral pneumonia, which was confirmed with chest computed tomography. All cases were divided into two groups, namely the mild (outpatients); and serious (inpatients) based on their clinical and laboratory data. Serum vitamin D levels were measured by chemiluminescence method. Researchers concluded that adequate levels of vitamin D could suppress inflammation and reduce the severity of COVID-19. Vitamin D supplementation may have an important role in decreasing the impact of the pandemic. 

Weir and et al, in a study, published in the Royal College of Physicians, suggests the severity of  COVID-19 is determined by the presence of pneumonia, severe acute respiratory distress syndrome, myocarditis, microvascular thrombosis and/or cytokine storms, all of which involve underlying inflammation. A principal defence against uncontrolled inflammation, and against viral infection in general, is provided by T regulatory lymphocytes (Tregs). Treg levels have been reported to be low in many COVID-19 patients and can be increased by vitamin D supplementation. Vitamin D deficiency is associated with an increase in thrombotic episodes, which are frequently observed in COVID-19, which has been found to occur more frequently in patients with obesity and diabetes. These conditions are reported to carry a higher mortality in COVID-19. If vitamin D does in fact reduce the severity of COVID-19 in regard to pneumonia/ARDS, inflammation, inflammatory cytokines and thrombosis, supplements would offer a relatively easy option to decrease the impact of the pandemic. 

Paul B. Whittemore reports the vitamin might be useful. People older than age 65 and people of colour are more likely to have lower levels of vitamin D. Both groups face a higher risk of poor outcomes from COVID-19, although the reasons for their vulnerability are multifaceted. In addition, Whittemore’s study has shown that countries farther away from the equator, where levels of the vitamin tend to be lower because of less sunlight, have higher COVID death rates than those closer to the equator. 

Researcher Adrian R. Martineau and his team already knew that vitamin D can be helpful in staving off respiratory infections. The 2017 meta-analysis of 25 randomized controlled trials involving about 11,000 people concluded that giving daily or weekly vitamin D supplements reduced the risk of acute respiratory infections with the strongest impact predictably falling on those who started off with a serious deficiency of the vitamin. Suzanne Elvidge informs about meta-analysis, updated this year, containing data from a total of 46 trials and 75,500 participants. Martineau’s team confirmed their earlier findings but determined the impact of the supplements appears to be quite small. 

In Brisbane, Hai Pham and her team have been leading the massive D-Health Trial, a randomized controlled trial of five years of vitamin D supplementation in 21,315 older adults. It has compared monthly high doses of the vitamin (60,000 international units) with a placebo and has looked at a wide range of outcomes, including heart disease, cancer, bone fractures and overall mortality. Acute respiratory tract infection has also been among the outcomes measured in the study, and with the COVID pandemic raging the team decided to examine their data early. Their analysis, published in the Lancet Diabetes & Endocrinology journal, showed vitamin D did not reduce the risk of acute respiratory tract infection but may have slightly reduced the duration of symptoms. 

Meltzer is leading three studies of vitamin D supplementation in populations with mixed ethnicities: one investigation in medically complex patients, a second in health care workers and a third is community-based. They will assess the impact of various dosages of the vitamin on COVID-19 symptoms and antibodies, as well as on symptoms of other respiratory diseases. Meltzer and his colleagues found in a diverse population of 4,638 people that the risk of a positive COVID test was 2.64 times greater for black individuals with low levels of vitamin D than for those with higher levels. There was no significant correlation in white participants. “Chicago has long winters, and people with darker skin produce less vitamin D. Our northern location and the predominance of black people attending the hospital allowed us to spot the link,” Meltzer observes. 

Similarly, the U.K.’s CORONAVIT trial, posted on NIH, with 6,200 participants, is looking at whether correcting vitamin D deficiency during the winter with a standard or high dose of the vitamin will reduce the risk and/or severity of COVID-19 and other acute respiratory infections. In France, the smaller CoVitTrial is assessing the impact of a single high dose or routine dose of vitamin D on high-risk older adults with COVID-19. Results of both trials should be available later this year. Another team also took a look at D levels and the risk of COVID infection but used a different methodology. They studied a group of people of European ancestry in the UK Biobank who were genetically predisposed to high or low levels of vitamin D and looked for correlations between their levels of the vitamin and their SARS-CoV-2 infection risk and severity.Their analysis showed no evidence of a preventive effect of higher vitamin levels. Still, they are  keeping an open mind and believe that large, well-controlled trials will be the gold standard, but this takes time.

Taken all together, these data points are far from being conclusive, but they served as a spur to investigate further. Fortunately, several large, potentially relevant studies of vitamin D were already underway when the pandemic struck, and others swiftly began. As Suzanne Elvidge reports the lack of a clear answer from existing studies could reflect limitations in trial design, including populations which are already replete with vitamin D, sample sizes that are too small or inconsistencies in doses or methods of measurement. Some forthcoming trials may help fill in the gaps. 

Overall, it is still uncertain whether vitamin D will prove to be a critical ingredient in fending off COVID-19 or modulating its severity. But trials may find it is useful in certain doses for certain populations. As Neale points out, “there is data that is suggestive” and enough smoke to indicate that you do not want to be vitamin-D-deficient in a pandemic. Some studies suggest there is an impact, especially for individuals who are vitamin D deficient. However, nothing can be concluded surely, the jury is still out. 

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