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Two large studies out of the UK and Norway show vitamin D supplementation has no benefit — as low dose, high dose, or in the form of cod liver oil supplementation — in preventing COVID-19 or acute respiratory tract infections, regardless of whether individuals are deficient or not.
The studies, published this week in The BMJ, underscore that "vaccination is still the most effective way to protect people from COVID-19, and vitamin D and cod liver oil supplementation should not be offered to healthy people with normal vitamin D levels," writes Peter Bergman, MD, of the Karolinska Institute, Stockholm, Sweden, in an editorial published alongside the studies.
Suboptimal levels of vitamin D are known to be associated with an increased risk of acute respiratory infections, and some observational studies have linked low 25-hydroxyvitamin D (25(OH)D) with more severe COVID-19; however, data on a possible protective effect of vitamin D supplementation in preventing infection have been inconsistent.
UK Study Compares Doses
To further investigate the relationship with infections, including COVID-19, in a large cohort, the authors of the first of the two BMJ studies, a phase 3 open-label trial, enrolled 6200 people in the UK aged 16 and older between December 2020 and June 2021 who were not taking vitamin D supplements at baseline.
Half of participants were offered a finger-prick blood test, and of the 2674 who accepted, 86.3% were found to have low concentrations of 25(OH)D (< 75 nmol/L). These participants were provided with vitamin D supplementation at a lower (800 IU/day; n = 1328) or higher dose (3200 IU/day; n = 1346) for 6 months. The other half of the group received no tests or supplements.
The results showed minimal differences between groups in terms of rates of developing at least one acute respiratory infection, which occurred in 5% of those in the lower-dose group, 5.7% in the higher-dose group, and 4.6% of participants not offered supplementation.
Similarly, there were no significant differences in the development of real-time PCR-confirmed COVID-19, with rates of 3.6% in the lower-dose group, 3.0% in the higher-dose group, and 2.6% in the group not offered supplementation.
The study is "the first phase 3 randomized controlled trial to evaluate the effectiveness of a test-and-treat approach for correction of suboptimal vitamin D status to prevent acute respiratory tract infections," report the authors, led by Adrian R. Martineau, MD, PhD, of Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.
While uptake and supplementation in the study were favorable, "no statistically significant effect of either dose was seen on the primary outcome of swab test or doctor-confirmed acute respiratory tract infection, or on the major secondary outcome of swab test-confirmed COVID-19," they conclude.
Traditional Use of Cod Liver Oil of Benefit?
In the second study, researchers in Norway, led by Arne Soraas, MD, PhD, of the Department of Microbiology, Oslo University Hospital, evaluated whether that country's long-held tradition of consuming cod liver oil during the winter to prevent vitamin D deficiency could affect the development of COVID-19 or outcomes.
For the Cod Liver Oil for COVID-19 Prevention Study (CLOC), a large cohort of 34,601 adults with a mean age of 44.9 years who were not taking daily vitamin D supplements were randomized to receive 5 mL/day of cod liver oil, representing a surrogate dose of 400 IU/day of vitamin D (n = 17,278), or placebo (n = 17,323) for up to 6 months.
In contrast with the first study, the vast majority of patients in the CLOC study (86%) had adequate vitamin D levels, defined as > 50 nmol/L, at baseline.
Again, however, the results showed no association between increased vitamin D supplementation with cod liver oil and PCR-confirmed COVID-19 or acute respiratory infections, with approximately 1.3% in each group testing positive for COVID-19 over a median of 164 days.
Supplementation with cod liver oil was also not associated with a reduced risk of any of the coprimary endpoints, including other acute respiratory infections.
"Daily supplementation with cod liver oil, a low-dose vitamin D, eicosapentaenoic acid, and docosahexaenoic acid supplement, for 6 months during the SARS-CoV-2
pandemic among Norwegian adults did not reduce the incidence of SARS-CoV-2 infection, serious COVID-19, or other acute respiratory infections," the authors report.
Key Study Limitations
In his editorial, Bergman underscores the limitations of two studies — also acknowledged by the authors — including the key confounding role of vaccines that emerged during the studies.
"The null findings of the studies should be interpreted in the context of a highly effective vaccine rolled out during both studies," Bergman writes.
In the UK study, for instance, whereas only 1.2% of participants were vaccinated at baseline, the rate soared to 89.1% having received at least one dose by study end, potentially masking any effect of vitamin D, he says.
Additionally, for the Norway study, Bergman notes that cod liver oil also contains a substantial amount of vitamin A, which can be a potent immunomodulator.
"Excessive intake of vitamin A can cause adverse effects and may also interfere with vitamin D-mediated effects on the immune system," he writes.
With two recent large meta-analyses showing benefits of vitamin D supplementation to be specifically among people who are vitamin D deficient, "a pragmatic approach for the clinician could be to focus on risk groups" for supplementation, Bergman writes.
"[These include] those who could be tested before supplementation, including people with dark skin, or skin that is rarely exposed to the sun, pregnant women, and elderly people with chronic diseases."
The UK trial was supported by Barts Charity, Pharma Nord, the Fischer Family Foundation, DSM Nutritional Products, the Exilarch's Foundation, the Karl R. Pfleger Foundation, the AIM Foundation, Synergy Biologics, Cytoplan, the Clinical Research Network of the UK National Institute for Health and Care Research, the HDR UK BREATHE Hub, the UK Research and Innovation Industrial Strategy Challenge Fund, Thornton & Ross, Warburtons, Hyphens Pharma, and philanthropist Matthew Isaacs.
The CLOC trial was funded by Orkla Health, the manufacturer of the cod liver oil used in the trial. Bergman has reported no relevant financial relationships.
BMJ. Published online September 7, 2022.