Many studies have been conducted to determine treatment options to combat the coronavirus disease 2019 (COVID-19) pandemic. Much attention has been paid to the role of vitamin D in the prevention and treatment of COVID-19. Several preclinical studies have indicated that vitamin D metabolites play an important role in immune responses to respiratory viruses.
Study: Prevention of covid-19 and other acute respiratory infections with cod liver oil supplementation, a low-dose vitamin D supplement: placebo-controlled, randomized, quadruple-blind trial. Image credit: Iryna Pohrebna/Shutterstock
In addition, 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.
Severe 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 may serve as a cost-effective way to prevent severe infections by COVID-19 and SARS-CoV-2.
Cod liver oil is a low-dose vitamin D supplement that includes docosahexaenoic acid and eicosapentaenoic acid. Taking cod liver oil during the 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 severe infections with COVID-19, SARS-CoV-2 or other acute respiratory infections during the winter of 2020- 2021
About the study
The study was a parallel-group treatment, randomized, two-arm, quadruple-masked trial consisting of participants aged 18 years or older, who had a Norwegian personal identity number, as well as access to the ‘secure national government digital identification. Randomization of participants was performed in a 1:1 ratio to take placebo or cod liver oil with a daily dose of 5 ml. Both the placebo and cod liver oil were blind tested by an experienced taste panel that could not tell the difference between the two.
Randomization was performed without stratification or blocking at the Research Support Department of Oslo University Hospital. Data collection, storage and analysis were also performed by the University of Oslo.
Participants had to complete baseline questionnaires that included questions about personal data, vitamin D and others before receiving the placebo or cod liver oil. They were followed up after six months for intervention compliance, SARS-CoV-2 infection, COVID-19 vaccination, acute respiratory infections, and experience of any side effects.
Compliance was described as strict if more than 5 ml of placebo or cod liver oil was taken for more than 2 or 3 months. Compliance was described as loose if more than 1 ml of placebo or cod liver oil was taken for approximately one month or taken more than one day per week. Side effects were graded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE).
An assessment of four co-primary endpoints was conducted. The first was a positive test for SARS-CoV-2 oropharyngeal or nasopharyngeal swabs detected by quantitative reverse transcriptase polymerase chain reaction in a Norwegian laboratory and reported to the Norwegian Mandatory Surveillance System for Communicable Diseases (MSIS ). The second criterion was the occurrence of severe COVID-19 that was associated with hospital admission 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 criterion was the occurrence of participants who reported one or more acute respiratory infections.
The number of participants admitted to hospital or intensive care unit for COVID-19 comprised the pre-defined secondary endpoint. Exploratory endpoints included self-reported changes in blood levels of 25(OH)D3 and omega 3 index, study supplement blinding, and side effects. Blood samples were collected from participants before and during supplementation to analyze levels of omega-3 fatty acids and 25(OH)D3. Finally, a SARS-CoV-2 antibody assay was performed at baseline.
Results of the study
The results indicated that a total of 34,741 participants were included in the study, where more than half of the participants were female, had an average age of 44.9 years and a body mass index of 26.1 at baseline basic Seventeen thousand two hundred seventy-eight participants received cod liver oil, while 17,323 received the placebo.
Most participants reported not using any vitamin D supplements before the study, while 39.8% reported about 30 hours of sun exposure from July to October 2020 and 61.5% reported fatty fish consumption. In addition, 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 an equal distribution between the site and cod liver oil groups. 101 participants in the placebo group and 121 participants in the cod liver oil group reported severe COVID-19. A total of 17 participants were hospitalized, of which eight were in the intensive care unit. In addition, the relative risk of severe COVID-19 was observed to be 1.20 for the cod liver oil group compared to the placebo group.
In addition, 17,111 participants were found to show one or more negative SARS-CoV-2 test results whose distribution was similar in the two 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 25(OH)D3 concentration was found to increase by 15.0 nmol/L, while the omega-3 index increased by 1.9%.
Eleven point 3% and 10.1% of participants in the placebo and cod liver oil groups, respectively, reported one or more side effects, with the most common side effect being mild gastrointestinal symptoms belonging to CTCAE grade 1 . Grade 2 side effects were observed more frequently in the placebo group. Finally, 7616 participants in the placebo group and 7220 in the cod liver group did not know which supplement they were taking or believed they were taking the placebo, while 1058 in the placebo group and 1966 in the cod liver oil group believed they were taking the liver of cod oil supplementation.
Therefore, the current study showed that low-dose vitamin D supplementation along with docosahexaenoic acid and eicosapentaenoic acid for six months was not adequate to prevent severe SARS-CoV-2, COVID-19, and other acute respiratory infections . However, the intake of this supplementation produced only low-grade side effects.
limitations
The current study has certain limitations. First, self-reported endpoint data could introduce bias. Second, the intervention time was relatively short and the longer-term effects of cod liver oil could not be assessed. 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 assessed at the start of the trial. Finally, the number of participants included in the trial was lower than the expected number.