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being quoted on vitamin D are either old and not about the current Covid pandemic or are pre-prints, that is, still unpublished and so not peer reviewed.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.    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.  Hope-Simpson was a highly respected epidemiologist, famous for correlating shingles with herpes zoster infections during childhood.  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,   but the other three found no statistically significant effect.    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.
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.” 
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….” 
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.” 
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). While a 16% reduction is welcome, earlier predictions had suggested a greater benefit. Feskanich et al suggested vitamin D might cut colon cancer risk in older women by half?  Cedric Garland predicted that 1,000 IU/day of vitamin D would decrease colorectal cancer risk by half.
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.  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.
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. 
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.  In a 2018 study, average vitamin D (n=328) among black Americans living in St. Louis was less than 15 ng/ml. Obesity , hypertension  and diabetes  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.
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