May 15, 2020
Jacob Schor, ND, FABNO
We’ve finally got our hands on a published paper on vitamin D and Covid-19 to reference and so open up a discussion on the topic. Until now the articles being quoted on vitamin D are either old and not about the current Covid pandemic or are pre-prints, that is, still unpublished and so not peer reviewed.
The timing is funny in a way as just the other day hand written signs appeared around the corner on someone’s front lawn encouraging sunbathing to fight the virus and explicitly suggesting vitamin D to kill Covid. It’s funny as the home is best known as the one with the nude statue. I always thought it was about art; now I see it’s about sunbathing.
The new study written by Ilie, Stefanescu and Smith was published a few days ago. In it they investigate the hypothesis that there is an association between mean levels of vitamin D in various countries with cases and mortality caused by COVID-19. It was a relatively simple study. Mean levels of vitamin D were obtained from existing published literature. The number of cases of COVID-19/million population in each of the European countries and mortality caused by this disease/million population was obtained up until April 8, 2020. Statistical analyses were carried out using the Pearson Correlation Coefficient Calculator.
They report that mean vitamin D (17.89 ng.ml) was negatively correlated with the number of cases of COVID-19 in each country and so was the mean vitamin D levels with the number of deaths caused by COVID-19.[i]
[i] Ilie, P.C., Stefanescu, S. & Smith, L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin Exp Res (2020).
The idea that Vitamin D supplementation could protect action against pulmonary infections dates all the way back to French publications in the 1940s that suggested application for treating tuberculosis. [1] [2] [3] In 2016, John Cannell proposed that vitamin D was the “… ‘seasonal stimulus’ intimately associated with solar radiation [that] explained the remarkable seasonality of epidemic influenza…”, an idea that Hope-Simpson had pioneered in his 1981 article and subsequent 1992 book.[4] [5] Hope-Simpson was a highly respected epidemiologist, famous for correlating shingles with herpes zoster infections during childhood. [6] Influenza outbreaks displayed such a distinct seasonal variability that Hope-Simpson theorized that something in ultraviolet light (UV) exposure lowered incidence. Cannell connected UV exposure with vitamin D production and suggested that vitamin D was protective. This conclusion seemed so obvious that we were surprised that no one had thought of it sooner. Since then vitamin D and its potential to prevent or ameliorate influenza and upper respiratory infections has been studied extensively.
The data has not proven as conclusive as we had assumed it would be.
Studies initially reported consistent associations between low vitamin D and susceptibility to acute respiratory tract infections. This led to multiple randomized clinical trials to see whether vitamin D supplementation changed the course of acute respiratory infection. By 2017, five separate meta-analyses had been published aggregating data from up to 15 primary trials. Two of these studies reported significant protective effects, [7] [8] but the other three found no statistically significant effect. [9] [10] [11] A sixth meta-analysis that was published in 2017, by Adrian Martineau et al, reported a statistically significant benefit, though much smaller than Cannell and other proponents had predicted.
Martineau’s group combined data from 25 RCTs (n=11,321) and their analysis found that vitamin D supplementation reduced the risk of acute respiratory tract infection by about 12%. The protective effects were seen only in those taking daily or weekly vitamin D doses. Those who took either large bolus doses alone or with the daily doses saw no benefit.[12]
In recent weeks there have been several other interesting articles released that suggest vitamin D is associated with the severity of Covid-19 disease. They haven’t been officially published yet so in themselves, shouldn’t be used as reliable information. There’s this thing about preprint articles; until information has gone through peer review, we are supposed to pretend they don’t exist. That’s a whole different discussion that let’s leave alone for now.
A short pre-print report by Mark Alipio, released April 9, 2020, describes his retrospective multicenter study of 212 Covid-19 cases in the Philippines. Data on clinical features and vitamin D levels were obtained from patient medical records. The majority of cases had ordinary clinical outcomes. Mean 25(OH)D was 23.8 ng/ml. Vitamin D levels were lowest in the critical cases and highest in the mild cases. These associations were statistically significant. For each standard deviation increase in serum 25(OH)D, “… the odds of having a mild clinical outcome rather than a severe outcome were increased approximately 7.94 times (OR=0.126, p<0.001) …” The odds of a critical outcome were reduced nearly twenty-fold (OR=0.051, p<0.001). “The results suggest that an increase in serum 25(OH)D level in the body could either improve clinical outcomes or mitigate worst (severe to critical) outcomes, while a decrease in serum 25(OH)D level in the body could worsen clinical outcomes of COVID-2019 patients.” [13]
A second preprint article on vitamin D and Covid-19 was posted to SSRN by a group of Indonesian researchers, Raharusun et al, on April 30, 2020. Their study was also retrospective and included 780 Covid-19 cases. Data here too was extracted from medical records. The study goal was to determine mortality patterns and associated risk factors. The data analysis revealed the majority of the fatalities were male, older, and with pre-existing conditions. Below normal vitamin D levels were associated with increasing chances of death. The outcome differences the authors report were striking: “98.9% of Vitamin D deficient cases died …. 87.8% of Vitamin D insufficient cases died … Only 4.1% of cases with normal Vitamin D levels died….” [14]
Taken together these three articles seem to provide a convincing argument for vitamin D supplementation. The problem is that finding an association does not prove causation. There has been a growing concern in recent years that there is something missing in our understanding of vitamin D. Studies that have supplemented vitamin D have not seen the dramatic decrease in morbidity and mortality that earlier studies that report associations had predicted.
Low vitamin D status is associated with greater morbidity and mortality from a wide range of conditions. Patients assume that this proves taking vitamin D will help these conditions. Unfortunately, the studies that have attempted to prove the benefits of taking vitamin D have reported mostly weak results.
Low vitamin D status is strongly associated with increased cancer risk and heart disease, but supplementation has not been a reliable treatment. Manson et al reported in a 2019 issue of NEJM results from their large (n= 25,871) nationwide clinical trial supplementing with vitamin D (2,000 IU/day). “Supplementation with vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events than placebo.” [15]
In 2019 the British Medical Journal published results from Zhang et al who reported results from a meta-analysis that combined data from 52 clinical trials (n= 75,454) and looked at risk of all cause, cardiovascular, and cancer mortality. Vitamin D supplementation was not associated with all cause mortality, cardiovascular mortality, or non-cardiovascular mortality, though it was significantly associated with a 16% reduction in risk of cancer death (with D3 having a significantly better impact than D2).[16] While a 16% reduction is welcome, earlier predictions had suggested a greater benefit.[17] Feskanich et al suggested vitamin D might cut colon cancer risk in older women by half? [18] Cedric Garland predicted that 1,000 IU/day of vitamin D would decrease colorectal cancer risk by half.[19]
These weak results have led many researchers to wonder if there might be something more to ultraviolet exposure that leads to health benefit; vitamin D levels might only be a way to assess long term UV exposure. [20] Vitamin D in the blood may drop when someone is unwell, what is called a reactive nutrient. Iron levels do this; they drop when infection, cancer or arthritis is present. We see this pseudo-iron deficiency cause ‘anemia of chronic disease’ and ‘anemia of malignancy.’ These syndromes result from the original infection or chronic disease. Yet it is easy to think that iron deficiency is connected to these chronic conditions in a causal manner.
In this current paper of focus, Petre Ilie et al provides a good rational with which to argue that vitamin D supplements may work against Covid-19. He points out that vitamin D levels do not vary by latitude in Europe as we might expect. Mean vitamin D in Spain is 10.42 ng/ml, in Italy 11.22 and in the Nordic countries 18.03 ng/ml. In Italy by the way, 76% of women over 70 years of age have been found to have circulating levels below 12.02 ng/ml.[21]
There are several explanations for this latitude reversal. Culturally Southern Europeans prefer shade to strong sun compared to Northern Europeans. Their darker skin pigmentation decreases vitamin D synthesis. But most important, people in Northern European countries consume vitamin D supplements, cod liver oil and D-fortified foods and this improves their status. [22]
This gives us reason to believe that D supplementation might be effective.
In recent weeks most of us have become familiar with the list of risk factors that increase severity of Covid-19 symptoms along with risk of death from the illness. Most of these same comorbidities are associated with low vitamin D status. African Americans, who are reported to have disproportionately high mortality rates from Covid-19, have lower than average vitamin D levels. [23] In a 2018 study, average vitamin D (n=328) among black Americans living in St. Louis was less than 15 ng/ml.[24] Obesity [25], hypertension [26] and diabetes [27] are all also associated with low vitamin D status.
Together these various studies begin to provide a compelling argument to supplement with vitamin D during this pandemic. Granted that some of the information we are relying on to push this forward is still unpublished. This is balanced by a long history of vitamin D’s use for respiratory infections.
Returning to Adrian Martineau’s meta-analysis on vitamin D and respiratory infections, their findings provide information on dosing that we might want to generalize and apply to many of our patients, especially if considering Covid-19 prophylaxis. Their report suggests that large boluses of vitamin D decrease efficacy. In regard to prevention of respiratory infection, more protection was seen in study participants who took daily or weekly doses of vitamin D, a 19% reduction in risk of infection. In those who received one or more large bolus doses, even along with daily doses, no significant protection was observed. Although it was popular some years back to give very large vitamin D doses, extrapolating from these findings suggests we avoid bolus dosing if we seek to protect from respiratory infections.
[1] Gounelle H, Vallette A, Bachet M. Fortes surcharges en vitamine D2 chez les tuberculeux pulmonaires; hypercalcémie sérque. C R Seances Soc Biol Fil. 1945 Oct;139:930.
[2] Binet L, Bour H. Essais de traitement de la tuberculose pulmonaire par des nebulisations de vitamine D2. Prog Med (Paris). 1946 Dec 24;74(24):579-81.
[3] Phelan JJ. Calciferol in pulmonary tuberculosis. Lancet. 1947 May 31;1(6457):764.
[4] Hope-Simpson RE. The role of season in the epidemiology of influenza. J Hyg (Lond). 1981 Feb;86(1):35-47.
[5] Hope-Simpson RE. The Transmission of Epidemic Influenza. Springer. 1992.
[6] Cannell JJ1, Vieth R, Umhau JC, et al. Epidemic influenza and vitamin D.
Epidemiol Infect. 2006 Dec;134(6):1129-40. Epub 2006 Sep 7.
[7] Bergman P, Lindh AU, Björkhem-Bergman L, Lindh JD. Vitamin D and Respiratory Tract Infections: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. PLoS One2013;356:e65835.
[8] Charan J, Goyal JP, Saxena D, Yadav P. Vitamin D for prevention of respiratory tract infections: A systematic review and meta-analysis. J Pharmacol Pharmacother2012;356:300-3.
[9] Mao S, Huang S. Vitamin D supplementation and risk of respiratory tract infections: a meta-analysis of randomized controlled trials. Scand J Infect Dis2013;356:696-702.
[10] Xiao L, Xing C, Yang Z, et al. Vitamin D supplementation for the prevention of childhood acute respiratory infections: a systematic review of randomised controlled trials. Br J Nutr 2015;356:1026-34.
[11] Vuichard Gysin D, Dao D, Gysin CM, Lytvyn L, Loeb M. Effect of Vitamin D3 Supplementation on Respiratory Tract Infections in Healthy Individuals: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. PLoS One2016;356:e0162996.
[12] Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017 Feb 15;356:i6583.
[13] https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3571484
Mark Alipio. Vitamin D Supplementation Could Possibly Improve Clinical Outcomes of Patients Infected with Coronavirus-2019 (COVID-19). SSRN. 9 Apr 2020 Last revised: 7 May 2020
[14] Raharusun, Prabowo and Priambada, Sadiah and Budiarti, Cahni and Agung, Erdie and Budi, Cipta, Patterns of COVID-19 Mortality and Vitamin D: An Indonesian Study (April 26, 2020). SSRN: https://ssrn.com/abstract=3585561 or http://dx.doi.org/10.2139/ssrn.3585561
[15] Manson JE, Cook NR, Lee IM, et al. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med. 2019 Jan 3;380(1):33-44.
[16] Zhang Y, Fang F, Tang J, et al. Association between vitamin D supplementation and mortality: systematic review and meta-analysis. BMJ. 2019 Aug 12;366:l4673.
[17] Grant WB. An estimate of the global reduction in mortality rates through doubling vitamin D levels. Eur J Clin Nutr. 2011 Sep;65(9):1016-26. doi: 10.1038/ejcn.2011.68. Epub 2011 Jul 6.
[18] Feskanich D, Ma J, Fuchs CS, Kirkner GJ, Hankinson SE, Hollis BW, Giovannucci EL. Plasma vitamin D metabolites and risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev. 2004 Sep;13(9):1502-8.
[19] Gorham ED, Garland CF, Garland FC, et al. Vitamin D and prevention of colorectal cancer. J Steroid Biochem Mol Biol, Oct 2005;97(1-2):179-94.
[20] van der Rhee HJ, de Vries E, Coebergh JW. Regular sun exposure benefits health.
Med Hypotheses. 2016 Dec;97:34-37.
[21] Lips P, Cashman K, Lamberg-Allardt C et al (2019) Current vitamin D status in European and Middle East countries and strate- gies to prevent vitamin D deficiency: a position statement of the European Calcified Tissue Society. Eur J Endocrinol 180:23–54
[22] Ilie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin Exp Res (2020).
[23] Ginde AA, Liu MC, Camargo CA., Jr Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Arch Intern Med. 2009;169(6):626–632.
[24] McKee A, Lima Ribeiro SM, Malmstrom TK, et al. Screening for Vitamin D Deficiency in Black Americans: Comparison of Total, Free, Bioavailable 25 Hydroxy Vitamin D Levels with Parathyroid Hormone Levels and Bone Mineral Density. J Nutr Health Aging. 2018;22(9):1045-1050.
[25] Vimaleswaran KS, Berry DJ, Lu C, Tikkanen E, et al. Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med. 2013;10(2):e1001383.
[26] Joukar F, Naghipour M, Hassanipour S, et al Association of Serum Levels of Vitamin D with Blood Pressure Status in Northern Iranian Population: The PERSIAN Guilan Cohort Study (PGCS). Int J Gen Med. 2020 Mar 11;13:99-104.
[27] Grammatiki M, Rapti E, Karras S, Ajjan RA, Kotsa K. Vitamin D and diabetes mellitus: Causal or casual association? Rev Endocr Metab Disord. 2017 Jun;18(2):227-241.
Dr. Jacob Schor 
May 16, 2020 at 12:51 pm
Dear Dr. Schor, Thank you for this review. To me, testing for 25-OHD seems like the joke about the man looking for his keys under the streetlight because the light is better there. 25-OHD isn’t even vitamin D, as you know. There has always been something stinky about the idea that even teenagers living in Florida have low vitamin D levels, or that 90% of African Americans have low vitamin D levels.
So, it was with a kind of relief to read Alan Gaby’s viewpoints on all of the meta-analyses on vitamin D and to hear his viewpoint: Although low 25-OHD levels are present in many conditions, perhaps they are just reflective of inflammation. Your take is confirming that. Here’s one interview with him that discusses this: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469459/
”
One of the common examples I see concerns people with lower levels of vitamin D, which is measured as 25-hydroxyvitamin D. People with lower 25-hydroxyvitamin D levels have a higher incidence of many diseases. Researchers and practitioners often conclude that if you give a vitamin D supplement to people with low 25-hydroxyvitamin D levels, you will prevent various diseases. However, that conclusion does not follow at all from an observational study. Observational studies prove associations, but they do not prove that intervening to change the variable in questionâin this case, increasing the 25-hydrxyvitamin D levelâwould be useful.
One of the confounding factors is that 25-hydroxyvitamin D levels decline in response to inflammation. If you have a chronic inflammatory diseaseâand many diseases have an inflammatory componentâyour vitamin D level is going to be lower than if you donât have such a disease. Therefore, the association between 25-hydroxyvitamin D and various diseases may simply mean that people with inflammation have more health problems than people without inflammation, and it may have nothing to do with vitamin D itself.
We’ve gone whole-hog on getting 25-OHD levels up to 50-70 ng/ml or even higher. But we don’t really have a lot of research demonstrating the benefits. We do have a couple of papers on women and breast cancer indicating that higher levels are preventive. It would be good to see more to validate what we are actually recommending.
As a professor when I talk about vitamin D, I do talk about the wide bridge between the way we test, what the research demonstrates, and the way we practice.
I so enjoy your writing!
Thank you. Liz
Prof. Liz Lipski, PhD, CNS, FACN, BCHN, IFMCP, LDN Director of Academic Development / Nutrition Programs Information on our nutrition programs: https://wrap.co/wraps/910e4ab0-afbe-415e-ab76-784ad0522b26
Maryland University of lntegrative Health 7750 Montpelier Road | Laurel, MD 20723 828-775-4123 llipski@muih.edu | http://www.muih.edu
Liz Lipski Professor / Director of Academic Development – Nutrition and Integrative Health Maryland University of lntegrative Health 7750 Montpelier Road, Laurel, MD 20723 Phone: 410-888-9048ext. – llipski@muih.edu | http://www.muih.edu ________________________________
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May 16, 2020 at 3:34 pm
Thanks for this in depth note Liz. Most of which I agree with most of the time by the way.
I’ve written about the discrepancies several times in recent years:
https://www.naturalmedicinejournal.com/blog/vitamin-d-wrong-direction
https://www.naturalmedicinejournal.com/journal/2018-03/vitamin-d-and-calcium-fail-reduce-fractures
and basically argued against the seemingly unanimous belief by alternative practitioners that vitamin D would be a panacea for most ills. This is not a popular position.
I have also suggested strongly that vitamin D’s benefit may be hormetic, in particular against certain cancers and the point of maximum benefit was much lower that the levels most practitioners have had their patients try to reach.
This is particularly true in prostate cancer.
https://www.naturalmedicinejournal.com/journal/2019-05/diet-and-risk-prostate-cancer-recurrence
My belief is that in many conditions we see an association of low D and high disease morbidity but that fixing the vitamin D by supplementation will not produce significant relief.
I don’t know what the final answer will be with covid-19. Low vitamin D may simply serve as a predictor of who will most likely suffer the most. Still this new European study made me negate this belief for several reasons. The first is the unexpected distribution of vitamin D levels in Europeans with Northerners having higher levels and lower covid-mortality. The argument that their elevated levels were secondary to supplementation made me wonder, could supplementation work here in this condition even though benefits have been weak in cancer, CVD and bone loss.
My second thought is what’s there to lose? Would taking a bit of vitamin D pose major risk? No. If the benefit only mimicked the best of the outcomes reported in the metas of respiratory infection studies and decreased infections by 12%, well that’s still better than any therapy has been proven to do so far so why not.
This virus has caught us unprepared and we are being forced to make decisions based on less than adequate information. doing things that might help even though not proven to, well it’s become part of our modern world.
Nice to hear from you.
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May 19, 2020 at 11:27 am
Hi, Jacob,
Another great article — thanks.
What do you make of the hypothesis, presented in this podcast by Australian doctor Paul Mason MD, that vitamin D is merely a surrogate marker for sunlight, and that the immune & metabolic benefits we attribute to D actually derive from the nitric oxide triggered by sun exposure? I find it an intriguing hypothesis.
Separately, as a lover of Mediterranean food, I’m chagrined by his assertion that olive oil — along with *all* oils — should be shunned and replaced with saturated fat in cooking. Your thoughts?
I hope you and Rena are well! Warmly, Conner
On Sat, May 16, 2020 at 10:47 AM Dr. Jacob Schor wrote:
> Dr. Jacob Schor posted: ” May 15, 2020 Jacob Schor, ND, FABNO We’ve > finally got our hands on a published paper on vitamin D and Covid-19 to > reference and so open up a discussion on the topic. Until now the articles > being quoted on vitamin D are either old and” >
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May 27, 2020 at 1:54 pm
I’ve written about this idea before, that our faith in vitamin D might be misplaced. Initially most research did use D levels as a surrogate for sun exposure and at some point we started to think that D was the ticket. In this covid study though because the latitude differences were thought to be due to supplementation, I am willing to think that supplements might help. If you bug me I’ll find that review I wrote where I considered all the other things sun exposure does aside from make more D. It was a few years ago.
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