Vitamin D Failed to Stop COVID, Other Respiratory Infections

Vitamin D supplements did not ward off COVID-19 or other respiratory infections, two randomized controlled trials showed.

Among 6,200 participants in a phase III study from the U.K., 2.6% of those in the control group developed COVID-19 compared with 3.6% of those who received 800 IU vitamin D daily (OR 1.39, 95% CI 0.98-1.97) and 3.0% who received 3,200 IU daily (OR 1.13, 95% CI 0.78-1.63) over 6 months of follow-up, reported Adrian Martineau, PhD, of Queen Mary University of London, and colleagues.

As for other acute respiratory tract infections, 4.6% of participants in the control group developed at least one infection of any cause compared with 5.7% in the lower-dose group (OR 1.26, 95% CI 0.96-1.66) and 5.0% in the higher-dose group (OR 1.09, 95% CI 0.82-1.46).

In a second trial out of Norway that looked at daily supplementation with cod liver oil (which carries low doses of vitamin D, vitamin A, and omega-3 fatty acids) during the winter months, a similar proportion of participants who took the supplement or placebo for a median of 164 days tested positive for SARS-CoV-2 (1.31% vs 1.32%; relative risk [RR] 1.00, 97% CI 0.82-1.22), reported Arne Søraas, MD, PhD, of Oslo University Hospital, and colleagues.

Both studies were published in The BMJ.

“There is no hard evidence that nutritional supplements will impact susceptibility to COVID-19,” Martineau told MedPage Today in an email. “If people want protection, by far the most effective thing they can do is get vaccinated.”

The U.K. investigators had previously found immunomodulatory effects “with 2 weekly large bolus doses” of vitamin D in patients with pulmonary tuberculosis. “These effects were largely anti-inflammatory — although that could in theory be good for COVID-19 as well … we were reasonably optimistic that it would also show protection against COVID-19,” Martineau said.

In an accompanying editorial, Peter Bergman, PhD, of the Karolinska Institutet in Stockholm, noted that while observational studies have shown that patients with low levels of vitamin D may be at risk for more severe COVID-19, “this association could be due to reverse causality or confounding.”

“Both COVID-19 and vitamin D deficiency are independently associated with obesity, old age (>65 years), and male sex,” he added.

These two new randomized studies add “much needed evidence to this important question,” he continued. While “both research teams should be commended for having completed large and well-designed clinical trials during the COVID-19 pandemic with its unforeseen logistical challenges,” most of the participants in the trials were healthy and a “highly effective vaccine” was rolled out during the trial.

Bergman also expressed concern over the effects that vitamin A in cod liver oil may have had as an immunomodulator on vitamin D-mediated effects on the immune system.

As for the Norwegian researchers, they were “extremely disappointed,” Søraas told MedPage Today in an email.

“The trial was an enormous effort, first and foremost from the 35,000 participants that have taken 5 mL of cod liver oil or placebo (corn) oil every morning for 6 months,” he noted. “This is a costly result in many ways. We, and our sponsor, who produces cod liver oil, would of course have liked a different result, but when it turned out as it did, we were satisfied that it was so definitive.”

With nearly 8,000 respiratory infections in each of the cod liver oil and placebo groups, “we would have been able to detect even minute effects of vitamin D on such infections, but we did not,” he added. “This is contrary to many observational studies.”

“Our study is a very good example of how results from observational studies need to be confirmed in randomized trials before you can recommend something to everybody,” he said. “It is not enough to have a good theory and some observations before you say that the whole population should take something.”

Study Details

For their study, Martineau and colleagues included 6,200 participants (median age 60.2, 67% women) who were not taking vitamin D supplements at baseline. Of the 2,674 participants with blood 25-hydroxyvitamin D concentration <75 nmol/L, 1,328 were randomized to 800 IU vitamin D daily and 1,346 were randomized to 3,200 IU vitamin D daily; 2,949 participants received placebo.

In addition to the similar results for the primary outcome, beneficial secondary effects were also not observed. “We looked at related outcomes including severity of COVID-19 (i.e., whether or not illness precipitated hospital admission) and risk of long COVID, but we didn’t see an effect for either of these outcomes,” Martineau said.

The Norwegian study, which took place from November 2020 to June 2021, randomized 34,601 participants (mean age 44.9, 64.5% women) who were not taking vitamin D supplements at baseline to either 5 mL of cod liver oil or 5 mL of corn oil (placebo) every day for 6 months.

Four co-primary endpoints were predefined: a positive SARS-CoV-2 test determined by RT-PCR; serious COVID-19 defined as self-reported dyspnea, hospital admission, or death; a negative SARS-CoV-2 test result; and self-reported symptoms.

Serious COVID-19 was identified in 0.70% of participants in the cod liver oil group and in 0.58% of those in the placebo group (RR 1.20, 98.2% CI 0.87-1.65), while 49.46% and 49.44%, respectively, had one or more negative SARS-CoV-2 test results (RR 1.00, 99.9% CI 0.97-1.04), and 22.94% and 22.13% reported one or more acute respiratory infections (RR 1.04, 99.9% CI 0.97-1.11).

Bergman pointed out that COVID vaccination may have masked any effect of vitamin D in these studies, which was a limitation.

Please enable JavaScript to view the comments powered by Disqus.