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Prevention of covid-19 and other acute respiratory infections with cod liver oil supplementation, a low dose vitamin D supplement: quadruple blinded, randomised placebo controlled trial

Sep 2022  
  Source   PDF   All Studies   Meta AnalysisMeta
ICU admission -0% Improvement Relative Risk Hospitalization 11% Severe case -20% Case 0% Vitamin D  Brunvoll et al.  Prophylaxis  DB RCT Is prophylaxis with vitamin D + cod liver oil beneficial for COVID-19? Double-blind RCT 34,601 patients in Norway (November 2020 - June 2021) Higher severe cases with vitamin D + cod liver oil (not stat. sig., p=0.17) Very low dose vitamin D, relatively high D levels for both groups Brunvoll et al., BMJ, September 2022 Favorsvitamin D Favorscontrol 0 0.5 1 1.5 2+
Vitamin D for COVID-19
8th treatment shown to reduce risk in October 2020
*, now with p < 0.00000000001 from 122 studies, recognized in 9 countries.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,400+ studies for 79 treatments.
RCT 17,278 low-risk patients (zero mortality) treated with 5mL/day cod liver oil (~400IU vitamin D) and 17,323 placebo patients in Norway with, showing no significant differences with treatment. The placebo group had higher vitamin D at baseline, and both groups had comparable vitamin D during treatment (74 vs. 63 nmol/L). 23% of control patients took vitamin D supplements and 62% consumed fatty fish (typically a good source of vitamin D). Adherence was low (<70% for "strict" compliance, which only required >0.5L consumed, or treatment for > "2-3" months).
This is the 22nd of 30 COVID-19 RCTs for vitamin D, which collectively show efficacy with p=0.0000032.
This is the 95th of 122 COVID-19 controlled studies for vitamin D, which collectively show efficacy with p<0.0000000001 (1 in 587 sextillion).
risk of ICU admission, 0.3% higher, RR 1.00, p = 1.00, treatment 4 of 17,278 (0.0%), control 4 of 17,323 (0.0%).
risk of hospitalization, 10.9% lower, RR 0.89, p = 1.00, treatment 8 of 17,278 (0.0%), control 9 of 17,323 (0.1%), NNT 17692.
risk of severe case, 20.0% higher, RR 1.20, p = 0.17, treatment 121 of 17,278 (0.7%), control 101 of 17,323 (0.6%).
risk of case, no change, RR 1.00, p = 0.98, treatment 227 of 17,278 (1.3%), control 228 of 17,323 (1.3%), NNT 42377.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Brunvoll et al., 7 Sep 2022, Double Blind Randomized Controlled Trial, placebo-controlled, Norway, peer-reviewed, mean age 44.9, 15 authors, study period 10 November, 2020 - 2 June, 2021, dosage 400IU daily, this trial uses multiple treatments in the treatment arm (combined with cod liver oil) - results of individual treatments may vary, trial NCT04609423 (history). Contact:
This PaperVitamin DAll
Prevention of covid-19 and other acute respiratory infections with cod liver oil supplementation, a low dose vitamin D supplement: quadruple blinded, randomised placebo controlled trial
Sonja H Brunvoll, Anders B Nygaard, Merete Ellingjord-Dale, Petter Holland, Mette Stausland Istre, Karl Trygve Kalleberg, Camilla L Søraas, Kirsten B Holven, Stine M Ulven, Anette Hjartåker, Trond Haider, Fridtjof Lund-Johansen, John Arne Dahl, Haakon E Meyer, Arne Søraas
BMJ, doi:10.1136/bmj-2022-071245
Objective To determine if daily supplementation with cod liver oil, a low dose vitamin D supplement, in winter, prevents SARS-CoV-2 infection, serious covid-19, or other acute respiratory infections in adults in Norway.
Asher, Tintle, Myers, Lockshon, Bacareza et al., Blood omega-3 fatty acids and death from COVID-19: A pilot study, Prostaglandins Leukot Essent Fatty Acids, doi:10.1016/j.plefa.2021.102250
Bassatne, Basbous, Chakhtoura, El Zein, Rahme et al., The link between COVID-19 and VItamin D (VIVID): A systematic review and metaanalysis, Metabolism, doi:10.1016/j.metabol.2021.154753
Bolland, Avenell, Grey, Vitamin D and acute respiratory infection: secondary analysis of a previous randomised controlled trial and updated metaanalyses, medRxiv, doi:10.1101/2022.02.03.22270409
Butler-Laporte, Nakanishi, Mooser, Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study, PLoS Med, doi:10.1371/journal.pmed.1003605
Chen, Mei, Xie, Low vitamin D levels do not aggravate COVID-19 risk or death, and vitamin D supplementation does not improve outcomes in hospitalized patients with COVID-19: a metaanalysis and GRADE assessment of cohort studies and RCTs, Nutr J, doi:10.1186/s12937-021-00744-y
Deschasaux-Tanguy, Srour, Bourhis, Nutritional risk factors for SARS-CoV-2 infection: a prospective study within the NutriNet-Santé cohort, BMC Med, doi:10.1186/s12916-021-02168-1
Greiller, Martineau, Modulation of the immune response to respiratory viruses by vitamin D, Nutrients, doi:10.3390/nu7064240
Holt, Talaei, Greenig, Risk factors for developing COVID-19: a population-based longitudinal study (COVIDENCE UK), Thorax, doi:10.1136/thoraxjnl-2021-217487
Holter, Pischke, De Boer, Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients, Proc Natl Acad Sci U S A, doi:10.1073/pnas.2010540117
Jiang, Li, Wang, Effect of marine-derived n-3 polyunsaturated fatty acids on major eicosanoids: a systematic review and meta-analysis from 18 randomized controlled trials, PLoS One, doi:10.1371/journal.pone.0147351
Jolliffe, Cajr, Sluyter, Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials, Lancet Diabetes Endocrinol, doi:10.1016/S2213-8587(21)00051-6on15
Jolliffe, Holt, Greenig, Vitamin D supplements for prevention of Covid-19 or other acute respiratory infections: a phase 3 randomized controlled trial (CORONAVIT), medRxiv, doi:10.1101/2022.03.22.22271707
Kaya, Pamukçu, Yakar, The role of vitamin D deficiency on COVID-19: a systematic review and meta-analysis of observational studies, Epidemiol Health, doi:10.4178/epih.e2021074
Kiecolt-Glaser, Belury, Andridge, Malarkey, Hwang et al., Omega-3 supplementation lowers inflammation in healthy middle-aged and older adults: a randomized controlled trial, Brain Behav Immun, doi:10.1016/j.bbi.2012.05.011
Ma, Zhou, Heianza, Qi, Habitual use of vitamin D supplements and risk of coronavirus disease 2019 (COVID-19) infection: a prospective study in UK Biobank, Am J Clin Nutr, doi:10.1093/ajcn/nqaa381
Mai, Langhammer, Chen, Cajr, Cod liver oil intake and incidence of asthma in Norwegian adults--the HUNT study, Thorax, doi:10.1136/thoraxjnl-2012-202061
Manson, Brannon, Rosen, Taylor, Vitamin D deficiency -is there really a pandemic?, N Engl J Med, doi:10.1056/NEJMp1608005
Martineau, Cates, Urashima, Vitamin D for the management of asthma, Cochrane Database Syst Rev, doi:10.1002/14651858.CD011511.pub2
Oscanoa, Amado, Vidal, Laird, Ghashut et al., The relationship between the severity and mortality of SARS-CoV-2 infection and 25-hydroxyvitamin D concentration -a metaanalysis, Adv Respir Med, doi:10.5603/ARM.a2021.0037
Pham, Rahman, Majidi, Waterhouse, Neale, Acute respiratory tract infection and 25-hydroxyvitamin D concentration: a systematic review and meta-analysis, Int J Environ Res Public Health, doi:10.3390/ijerph16173020
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Story, Essential sufficiency of zinc, ω-3 polyunsaturated fatty acids, vitamin D and magnesium for prevention and treatment of COVID-19, diabetes, cardiovascular diseases, lung diseases and cancer, Biochimie, doi:10.1016/j.biochi.2021.05.013
Talaei, Faustini, Holt, Determinants of pre-vaccination antibody responses to SARS-CoV-2: a population-based longitudinal study (COVIDENCE UK), BMC Med, doi:10.1186/s12916-022-02286-4
Villasis-Keever, López-Alarcón, Miranda-Novales, Efficacy and safety of vitamin D supplementation to prevent COVID-19 in frontline healthcare workers. a randomized clinical trial, Arch Med Res, doi:10.1016/j.arcmed.2022.04.003
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Other acute respiratory infections were indicated by the third and fourth ' 'co-primary endpoints: a negative SARS-CoV-2 test result and self-reported symptoms. Side ' 'effects related to the supplementation were self-reported. The fallback method was used to ' 'handle multiple comparisons.</jats:p>\n' ' </jats:sec>\n' ' <jats:sec>\n' ' <jats:title>Results</jats:title>\n' ' <jats:p>Supplementation with cod liver oil was not associated with a reduced risk ' 'of any of the co-primary endpoints. Participants took the supplement (cod liver oil or ' 'placebo) for a median of 164 days, and 227 (1.31%) participants in the cod liver oil group ' 'and 228 (1.32%) participants in the placebo group had a positive SARS-CoV-2 test result ' '(relative risk 1.00, multiple comparison adjusted confidence interval 0.82 to 1.22). Serious ' 'covid-19 was identified in 121 (0.70%) participants in the cod liver oil group and in 101 ' '(0.58%) participants in the placebo group (1.20, 0.87 to 1.65). 8546 (49.46%) and 8565 ' '(49.44%) participants in the cod liver oil and placebo groups, respectively, had ≥1 negative ' 'SARS-CoV-2 test results (1.00, 0.97 to 1.04). 3964 (22.94%) and 3834 (22.13%) participants in ' 'the cod liver oil and placebo groups, respectively, reported ≥1 acute respiratory infections ' '(1.04, 0.97 to 1.11). Only low grade side effects were reported in the cod liver oil and ' 'placebo groups.</jats:p>\n' ' </jats:sec>\n' ' <jats:sec>\n' ' <jats:title>Conclusion</jats:title>\n' ' <jats:p>Supplementation with cod liver oil in the winter did not reduce the ' 'incidence of SARS-CoV-2 infection, serious covid-19, or other acute respiratory infections ' 'compared with placebo.</jats:p>\n' ' </jats:sec>\n' ' <jats:sec>\n' ' <jats:title>Trial registration</jats:title>\n' ' <jats:p>\n' '\n' ' <jats:ext-link xmlns:xlink="" ' 'xlink:href="NCT04609423" ext-link-type="clintrialgov">NCT04609423</jats:ext-link>\n' ' .\n' ' </jats:p>\n' ' </jats:sec>', 'DOI': '10.1136/bmj-2022-071245', 'type': 'journal-article', 'created': {'date-parts': [[2022, 9, 8]], 'date-time': '2022-09-08T00:00:18Z', 'timestamp': 1662595218000}, 'page': 'e071245', 'update-policy': '', 'source': 'Crossref', 'is-referenced-by-count': 1, 'title': 'Prevention of covid-19 and other acute respiratory infections with cod liver oil ' 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