Representative photo: Nastya Dulhiier/Unsplash.
The recent publication of a high-profile study from India showing that patients with severe COVID-19 infections were more likely to have low vitamin D levels as well, and that the death rate was significantly higher among those with low vitamin D, has caused a flutter in the medical research community as well as among non-experts.
The authors of the study have also written that their results indicate mass supplementation of vitamin D to those at risk of developing COVID-19 infections.
Although this is one of many studies linking vitamin-D deficiency to severity of disease and fatality in COVID-19 patients, it is also unique in several ways.
Importantly, it was prospective, which means it studied patients using criteria that were determined before their hospital admission. This is as opposed to retrospective studies, which look at patients who have already been treated.
Second, it was in the Indian population. Other researchers have described low vitamin-D levels and poor outcomes in severe illness in western populations, attributing the deficiency to lower sunlight exposure. This relationship may not hold out in Asian populations.
The study authors have also added to the growing body of evidence suggesting a link between low vitamin D and death in patients with COVID-19.
We can understand the nuances of this finding by weighing the available evidence, as well as piece together the role vitamin D supplements can really play vis-à-vis the pandemic.
A short history
The role of vitamin D in preventing respiratory infections dates back almost 90 years, when doctors administered cod-liver oil to determine if it reduced absenteeism among industrial workers. Vitamin D has been shown to possess several anti-inflammatory properties that reduce the severity and duration of infections.
Although vital for bone health, muscle function and the immune system, experts have also touted vitamin D as a panacea from cancer to depression to cardiac disease.
However, note that these claims have been systematically disproved. There are three factors as to why.
First, vitamin D is a negative acute phase reactant, meaning its levels fall when there is an ongoing inflammation in the body. That is, there is a possibility that vitamin D levels can fall as a result of severe infections rather low vitamin-D levels predisposing the body to severe infection.
The second reason is an abundance of confounding factors – these are conditions associated with both low vitamin-D levels and severe infections, such as advanced age, obesity, heart disease and alcohol intake. In patients meeting one or more of these conditions, low vitamin-D levels are associated with severe infections instead of causing them. In this scenario, treating patients with severe infections with vitamin-D supplementation will not be helpful.
The third reason is the heterogeneity of data. Studies have been highly variable with respect to the active form of vitamin D each one studied, the outcomes (death, duration of illness and association with other markers of inflammation), and the forms and duration of vitamin-D supplementation. As a result, even though there is no dearth of literature on vitamin D plus COVID-19, combining all of the studies to get a meaningful answer is problematic at best.
In clinical trials
In situations where confounding factors are abundant and there is a considerable amount of therapeutic uncertainty, the answer is clinical trials. There are several ongoing clinical trials to determine if vitamin D supplementation can reduce the severity or mortality of COVID-19.
Only two of them have been completed thus far. The first had only 40 patients – 16 who received vitamin D and 24 who didn’t – and showed that vitamin-D deficient asymptomatic or mildly symptomatic COVID-19 patients who received high-dose supplements were more likely to test negative on day 14.
Another study, available as a preprint paper, described a trial with 240 patients showing supplementation of vitamin D did not reduce the duration of hospitalisation or complications due to severe COVID-19.
However, experts have said these hospital-based trials are unlikely to yield practice-changing results since most patients presenting to the hospital already have moderate-to-severe disease. That is, inflammation has already occurred and routine treatment with dexamethasone may interfere with researchers’ understanding of the relationship between vitamin D and the inflammatory response.
What is likely to be a more relevant clinical question is whether supplementation to the general population reduces the risk of contracting COVID-19 or developing a severe form of the disease. But on the flip side, such a trial will require thousands of participants who will need to be followed-up for several months.
Extrapolating from the well-established literature, we can say that vitamin D supplements are probably beneficial in preventing severe respiratory tract infections in those with vitamin-D deficiency or who are likely to be deficient.
This refers to regular supplementation rather than intermittent mega-doses. It is a low-cost and low-risk intervention that may result in less severe infections. The data has consistently shown that administering high-dose vitamin D in critically-ill and deficient patients has no impact, so if vitamin D has any value, it is likelier to be preventive than curative.
In the current context, where it is not clear how soon the majority of the population will receive vaccines, routine vitamin D supplementation to those likely to be vitamin-D deficient – the elderly, children, those who are malnourished, economically disadvantaged groups and those living in overcrowded environments – is a worthwhile exercise. Even if we can’t know if such a supplementation drive will definitely stave off COVID-19, doing so will still at least improve general health, well-being and help develop better immunity.
And for those who can afford it, diets rich in vitamin D, physical exercise and exposure to sunlight are especially important in these months of lockdowns, stress and social isolation. At the least, avoiding vitamin D deficiency has never been so critical.
Dr Narayana Subramaniam is a head and neck surgical oncologist at the Mazumdar Shaw Medical Centre, Bengaluru.