Many studies have been conducted to determine treatment options to combat the coronavirus disease 2019 (COVID-19) pandemic. Significant attention has been given to the role of vitamin D in preventing and treating COVID-19. Several preclinical studies have indicated that vitamin D metabolites play important roles in immune responses to respiratory viruses.
Moreover, low levels of 25-hydroxyvitamin D3 (25(OH)D3) have been observed to increase the risk of acute respiratory infections. A recent meta-analysis suggested that vitamin D supplementation could reduce the risk of respiratory infections compared to a placebo.
Serious cases of COVID-19 have been associated with uncontrolled activation of immune cells, increased inflammation, and excessive release of proinflammatory cytokines. Long-chain omega-3 fatty acids such as docosahexaenoic acid and eicosapentaenoic acid have been found to possess anti-inflammatory properties. Therefore, ensuring sufficient levels of vitamin D and these fatty acids can serve as a cost-effective way to prevent serious COVID-19 as well as SARS-CoV-2 infections.
Cod liver oil is a low-dose vitamin D supplement comprising docosahexaenoic acid and eicosapentaenoic acid. Taking cod liver oil during winter is a long tradition in Norway to prevent vitamin D deficiency.
A new study published in the British Medical Journal (BMJ) aimed to analyze whether cod liver oil could prevent serious COVID-19, SARS-CoV-2 infection, or other acute respiratory infections during the winter of 2020-2021.
About the study
The study was a parallel group treatment, randomized, two-armed, and quadruple masked trial consisting of participants who were 18 years of age and above, had a Norwegian personal identity number, as well as access to the secure national digital governmental identification service. Randomization of participants took place in a 1:1 ratio to take placebo or cod liver oil with a daily dodge of 5 ml. Both the placebo and cod liver oil underwent blind testing by an experienced taste panel who were unable to distinguish between the two.
Randomization was performed without stratification or blocking at the Department of Research Support, Oslo University Hospital. The collection, storage, and analysis of data were also carried out by The University of Oslo.
Participants were required to complete baseline questionnaires that included questions on personal data, vitamin D, and others before they received either the placebo or cod liver oil. They were followed up after six months on compliance with the intervention, SARS-CoV-2 infection, COVID-19 vaccination, acute respiratory infections, and experience of any side effects.
Compliance was described as strict if more than 5ml of placebo or cod liver oil was taken for more than 2 to 3 months. Compliance was described as loose if more than 1 ml of placebo or cod liver oil was taken for about a month or taken more than one day a week. The side effects were graded and categorized as per the Common Terminology Criteria for Adverse Events (CTCAE).
An assessment of four co-primary endpoints was carried out. The first was a positive SARS-CoV-2 oropharyngeal or nasopharyngeal swab test detected by reverse transcriptase quantitative polymerase chain reaction at a Norwegian lab and reported to the Mandatory Norwegian Surveillance System for Communicable Diseases (MSIS). The second endpoint was the occurrence of serious COVID-19 that was associated with admission to the hospital or death. The third endpoint was the occurrence of participants with one or more negative SARS-CoV-2 test results recorded in MSIS. The fourth endpoint was the occurrence of participants who reported one or more acute respiratory infections.
The number of participants admitted to the hospital or intensive care unit for COVID-19 comprised the predefined secondary endpoint. Exploratory endpoints comprised self-reported changes in blood levels of 25(OH)D3 and omega 3 index, blinding of the study supplement, and side effects. Blood samples were collected from the participants before and during supplementation for analysis of the levels of omega-3 fatty acids and 25(OH)D3. Finally, SARS-CoV-2 antibody analysis was carried out at baseline.
The results indicated that a total of 34,741 participants were included in the study, where more than half of the participants were women, had a mean age of 44.9 years, and had a body mass index of 26.1 at baseline. Seventeen thousand two hundred seventy-eight participants were given cod liver oil, while 17,323 were given the placebo.
Most of the participants reported not using any vitamin D supplementation before the study, while 39.8% reported about 30 hours of sun exposure from July to October 2020, and 61.5% reported consumption of fatty fish. Moreover, 35.6% were found to have received one or more doses of a COVID-19 vaccine.
A total of 455 participants reported a positive SARS-CoV-2 test result with equal distribution between the place and cod liver oil groups. Serious COVID-19 was reported by 101 participants in the placebo group and 121 participants in the cod liver oil group. A total of 17 participants were hospitalized, out of which eight were in the intensive care unit. Moreover, the relative risk of serious COVID-19 was observed to be 1.20 for the cod liver oil group compared to the placebo group.
Furthermore, 17,111 participants were found to show one or more negative SARS-CoV-2 test results whose distribution was similar in both the groups, while 7,798 participants reported one or more acute respiratory infections. Analysis of blood samples revealed only slightly increased concentrations of 25(OH)D3 in the cod liver oil group compared to the placebo group. The mean concentration of 25(OH)D3 was found to be increased by 15.0 nmol/L, while the omega-3 index was increased by 1.9%.
Eleven point 3 percent and 10.1% of participants in the placebo and cod liver oil group, respectively, reported one or more side effects, with mild gastrointestinal symptoms belonging to CTCAE grade 1 being the most common side effect. Grade 2 side effects were more often observed in the placebo group. Finally, 7616 participants in the placebo group and 7220 in the cod liver group did not know which supplementation they were taking or believed to take the placebo, while 1,058 in the placebo group and 1,966 in the cod liver oil group believed to take the cod liver oil supplementation.
Therefore, the current study demonstrated that a low dose supplementation of vitamin D along with docosahexaenoic acid and eicosapentaenoic acid for six months was not suitable for preventing SARS-CoV-2 infections, serious COVID-19, and other acute respiratory infections. However, the intake of this supplementation produced only low-grade side effects.
The current study has certain limitations. First, self-reported end-point data could introduce bias. Second, the intervention time was relatively short, and the longer effects of cod liver oil could not be evaluated. Third, the effects of vitamin D and omega-3 fatty acids could not be distinguished. Fourth, the effect of vitamin D on the risk of SARS-CoV-2 could not be evaluated at the start of the trial. Finally, the number of participants included in the trial was lower than the expected number.