Vitamin D and COVID 19: The Evidence for Prevention and Treatment of Coronavirus (SARS CoV 2)

Professor Roger Seheult, MD explains the important role Vitamin D may have in the prevention and treatment of COVID-19. Dr. Seheult illustrates how Vitamin D works, summarizes the best available data and clinical trials on vitamin D, and discusses vitamin D dosage recommendations. Roger Seheult, MD is the co-founder and lead professor at medcram.com. He is an Associate Professor at the University of California, Riverside School of Medicine and Assistant Prof. at Loma Linda University School of Medicine Dr. Seheult is Quadruple Board Certified: Internal Medicine, Pulmonary Disease, Critical Care, and Sleep Medicine Interviewer: Kyle Allred, Producer and Co-Founder of MedCram

 Kyle Allred: 

Dr. Seheult, you've advocated for vitamin D as a potential way to prevent COVID-19 infections to prevent severe COVID-19 infections. You've talked about this for a few months now and over the past several months, the evidence continues to grow. There are more and more publications in peer-reviewed medical journals about the possible connection between vitamin D and COVID-19. So you've put together a presentation for us. Tell us about what your presentation's all about. 

Dr. Seheult: 

Yeah! thanks, Kyle. So we've been talking about vitamin D as a potential therapeutic agent for COVID-19 since March, and since that time a lot of other people have become involved in looking at that agent, as well a number of research studies have been done, and the purpose of this is to sort of look at the evolution and the thinking of the use of vitamin D in COVID-19. So what we do is we look back even before COVID-19 and what was the evidence for vitamin D in acute chest infections, for instance influenza, and what was the data there? And then we look at the epidemiological evidence for vitamin D as a therapeutic agent in COVID-19, and then finally moving along to actual cases, hospitalizations, and then we build up with that hierarchy of evidence with vitamin D and COVID-19 to randomized placebo-controlled trials, which of course are the gold standard for therapeutics.

 Okay, so let's talk about vitamin D. The first thing you've got to understand is that vitamin D is not just a vitamin. Vitamin D is actually a hormone and if you notice here by the structure you'll see that it is a steroid hormone, which means it can go into the nucleus. It can go through membranes and make effective changes and, specifically, the vitamin D receptor is a member of this nuclear receptor/steroid hormone super family and so, as you can see here, we have vitamin D going through the membrane and affecting a binding to the receptor and then it actually goes into the nucleus, where it can affect transcriptional change. This is really important. So this is not just some vitamin that you need to supplement with; this is actually a hormone that changes the way your cells in the body actually behave.

 Kyle: 

Is this idea unique to vitamin D or does this happen with other vitamins? And in addition to that what are some of the main differences between a vitamin and a hormone? 

Dr. Seheult: 

Good question. So, you know, a vitamin is actually a shortened version of a vital amine, vital meaning you need it to live and an amine is a type of chemical compound. You know, vitamin D is not even an amine. Of course it’s vital, but it's not as if you need a certain amount of this substance to just keep the body going and doing what it needs to do. No, I mean vitamin D is so much more complex than that. We used to think that vitamin D was just involved in calcium regulation, and that is certainly true there's no question about that, but vitamin D is so much more than that. It's a fat soluble vitamin, which means it can pass through membranes without any problem. It doesn't need to be regulated. It can bind with the receptor and go directly into the cellular portion, the nucleus in fact, and actually cause or prevent transcription of RNA, and we've seen that there are vitamin D receptors in numerous cell types, including the cell types of the immune system. So in that sense, it is a hormone but in another sense, you can only produce enough of this if you have enough sunlight or if you're taking this in a dietary supplement form. You can't make this without sunlight or getting a dietary form, so in that sense it is vital that you have it, and in the loose sense it is a vitamin. So to get to your second question about hormones and vitamins, hormones are something that the body uses to signal and to make effect changes throughout the body. For instance, insulin is a hormone. Cortisol is a hormone. These things circulate through the body and they have different effects on different target tissues. Vitamins are more along the lines of something that you need as a co-factor or something else to get something to work, and so in that sense vitamin d is certainly a vitamin because your body needs it in order to live but in other sense, it's so much more than just the vitamin. So how do you get this vitamin D? I know this looks a little complicated, but bear with me. The key that you need to understand is that it's the 1,25(OH)2 vitamin D that's the active form, and it says here that it does come from the kidneys, but in fact we now know that the rate limiting step that puts that one hydroxyl group on is not just in the kidneys; it's also in the immune cells, and it can actually put that on and have effective change in your immune cells themselves. So let's talk a little bit about how this happens. So there's basically two ways you can get vitamin D into your diet. You can either eat it through a supplementation, swallow it, you can take pills, it's also found in fish oil, certain types of mushrooms, egg yolks, and also red meat, or the majority of people get vitamin D into their system from the sun. 

Why is that? 

Because ultraviolet B radiation penetrates down deep into the dermis, where this cholesterol derivative is converted into pre-vitamin D3 and then finally into vitamin D. Now that vitamin D3, after it's produced by the sun, goes to the liver and the 25-hydroxyl gets put onto it. This species here, the 25-hydroxy vitamin D, is what we actually measure in the blood. Whether you get it from diets or whether you get it from the sun, there's two ways of getting it, but this is how we can measure it, and that's how you're going to see it measured and reported in the rest of this presentation is 25(OH)D. This is kind of like the storage product in your body. It's fat soluble, it is stored in the fat, then when it's needed, it can either go to the immune system where it's converted into 1,25(OH)2D, which is the active form, or it can go to the kidney and it can be converted there to 1,25(OH)2D. Now the one in the kidney is usually used for metabolism of calcium and phosphorus and things of that nature, but there's a whole other area. In fact, they found many vitamin D receptors in the leukocytes or the white blood cells, your immune cells, in the body. Now, the other thing you ought to know is that this 1.25()H)2D, which is the active form, can be inactivated when they put a hydroxyl group ("they" being the 24-hydroxylase enzyme) can inactivate it by hydroxylatin 24 position could also do it here with 25 hydroxy from the kidney as well. So this is the inactive form. There is some evidence and if you want more information about this, look at COVID-19 update 83 in our MedCram series, and you'll see that high fructose corn syrup actually can accelerate this inactivation of both the 125-dihydroxy vitamin D and also the 25-hydroxy vitamin D to the inactive form, so that's not to say that other sugars with fructose couldn't do that, but that’s what the studies showed that we presented in update 83. So you may be supplementing, you may be out in the sun, but if you have a diet that's high in high fructose corn syrup, and I'm not talking about fructose from fruits and vegetables, but actually high fructose corn syrup, that is something that can cause problems and you may not get enough 125 dihydroxy vitamin D. We'll put a link to that video number 83. 

Okay, so you may ask, "Well what's the problem? 

I mean, if we just need to go out in the sun and get plenty of vitamin D, why is this issue?" Well, the issue is that if you were to look at recent studies that look at how often we here in the United States and, in fact, around the world spend outdoors, it's actually pretty small -- 7.6 percent of the day we spend outdoors. The problem is in the winter time, the sun gets up late and goes down early, and also it's not as high in the sky as it should be to get that direct radiation of ultraviolet B, and so it's coming at an angle. You don't get very good exposure and, in fact, for those people who are living above the 35th parallel or living below the 35th parallel in the southern hemisphere, this can be a very significant issue. The 35th parallel, for those who don't know, sort of runs through the middle of the United States. Now some suggest that this may be the reason why we see an increase in viral infections in the winter time -- whether it's in the northern hemisphere or the southern hemisphere, winter time is when you're having less sun exposure.

 Kyle: 

But couldn't this also be explained, could the increase in viral infections also be explained, by just people spending more time indoors in close confinement? You know windows closed and potential for spread that way, among other potential confounding variables? 

Dr. Seheult: 

Yeah, it certainly is possible. One of the things that goes against that though, Kyle, is that for instance in the United States in the winter time, in California, for instance, southern California, it rarely gets cold enough that you have to be indoors, but we still see an increase in spike in influenza during that time. What is certain though in California and, this is where the 35th parallel sort of runs right through southern California, is studies have shown that if you live above the 35th parallel, you can't really get enough vitamin D just by sun exposure in the winter time. So while it is possible that there could be confounders. We're seeing the sunlight exposure correlating with the increase in infectious diseases. I would note if you look at this graphic from the CDC in terms of statistics, we see that in just the very months where we have vitamin D deficiency is where we have spikes and increases in influenza, so we've got good data that shows that a major cause of vitamin D deficiency is inadequate exposure to sunlight. Also have good data that we'll talk about that there is an association between vitamin D and the BMI, and that patients with kidney disease, just like we see in COVID-19 can lose vitamin D3 out of their system.We also have good data that for more than a century, vitamin D deficiency has been suggested to increase the susceptibility to infections, and when you look at the extreme vitamin D deficiencies, for instance in children with nutritional rickets, they also had an increased risk of respiratory tract infections or RTIs, and as we talked about the seasonality of these RTIs and low 25-hydroxy vitamin D levels during winter time has been suggested as the seasonal stimulus for these infections, and if this is so, obviously this would be a major public health factor. And as we talked about, vitamin D may play an increased role in calcium metabolism; it may actually play a role as stimulation of the innate immune system and other immune functions. As we talked about this VDR, or this vitamin D receptor, has been shown to be present in myeloid and lymphoid lineage cells, and these are the cells that are important in fighting off COVID-19,for instance, monocytes and neutrophils. We also got good evidence that shows that vitamin D may enhance the expression of human cathelicidin, which is an antimicrobial peptide which is of specific importance in host defenses against, specifically, respiratory tract pathogens. So one of the things that you've got to understand right off the bat, and it makes a little confusing, is that different parts of the world measure vitamin D or 25-hydroxy vitamin D in your blood using different units.

 So throughout this talk you're going to see 25-hydroxy vitamin D levels being reported in two types of units: 

• one is nanograms per milliliter (ng/mL)
• the other one is nanomoles per liter (nmol/L) 

and, frankly, you're going to see both of those being used, and I don't want you to get too hung up on these levels here because a lot of different organizations have their own thoughts on what should be deficient, insufficient, and optimal. This is really just to give you an idea about where those ranges exist. Sometimes historically they'll ask for your vitamin D levels to be higher if they're treating heart disease or cancer, and then generally speaking, vitamin D levels greater than 100 nanograms per milliliter are just too high, and you have to be careful when it gets into that range. Now some other places they'll measure in something called nanomoles per liter, and actually if you just want a quick way of converting you simply multiply by 2.5 and you'll get these numbers here, which are a legitimate way of measuring it, but not one that we're maybe used to. But you might see it, so just make sure when you see studies and they report 25-hydroxy vitamin D levels that you're understanding what units they're using, so you can make sense of it. Okay, so let's take a look at the evidence. We'll sort of start out with observational studies and we'll end up with randomized prospective controlled trials. So we knew very early on, this is a paper that was published back in 1985 looking at vitamin D and age, and what we found was that as you get older, the ability for your skin to produce vitamin D3 drops by more than twofold as you get up into the 70s and the 80s. The other thing that we knew from a long time ago back in 2012 is that there is a difference in terms of vitamin D and race or skin color. Here you can see the graph looking at different levels of vitamin D. Here's less than 10 here's 11 to 20, 21 to 30, and greater than 30. And these bars simply represent white is white, black is black, and the gray are Mexican- Americans. This is a study that was done in the United States, and what you can see here in this observational study, greater than 30, which would be considered to be adequate, the majority of that population is white. As we go down below 20, in this range, that the people that make up the majority of this population are disproportionately darker skinned people, so this is certainly a public health issue that needs to be addressed. Another thing that we've known about for some time, for about 20 years at least, is vitamin D and BMI. 

Of course, vitamin D is a fat soluble vitamin, and as such it's going to be stored in the fat. And so if you have a lot of adipose tissue or fat, then you're going to have a larger capacity to hold vitamin D, which means you're going to have less soluble vitamin D to be used. This is a direct quote from this study, "because humans obtain most of their vitamin D requirement from exposure to sunlight, the greater than 50 decreased bio availability of cutaneously synthesized vitamin D in the obese subjects could account for the consistent observation by us and others that obesity is associated with vitamin D deficiency. 

Oral vitamin D should be able to correct the vitamin D deficiency associated with obesity, but larger than usual doses may be required for very obese patients." Okay, so where are we right now with vitamin D supplementation? Currently there's no international consensus. We know that supplementation of vitamin D can help in terms of fractures. Now there are some studies that show that vitamin D may be associated with increased risk of myocardial infarction, but in actuality those studies were related more to calcium supplementation with or without vitamin D, so not a direct association. 

The target for prevention of fractures is around 30 to 40 nanograms per milliliter and that, if you have levels greater than 150 nanograms per milliliter, that is associated with hypercalcemia. So what do people say? There's some people that say you should take 4,000 international units or less; some others say up to 10,000 international units. There's not really a consensus. There are some recommendations from the endocrinology society, and we will discuss those. 

Okay so let's look at the evidence of vitamin D insufficiency and deficiency and mortality from studies that were done not on COVID, but prior to COVID, but still looking at respiratory diseases. So here's an interesting study that was done looking at about 10,000 patients in Germany with 50- to 70-year-olds. It was prospective, so that's definitely a positive for this study, but it was an observational study, so they weren't intervening here, and look at the years for follow-up: 15-year follow-up in these patients. So let's take a look and see what they did. They measured these patients in Germany and looked at their vitamin D levels, and you can see that here on the x-axis. So again this is in nanomoles per liter, so you have to divide by 2.5 to get nanograms per milliliter, and generally they made some cutoffs here. This was at 30 and this here was at 50. And so they said if you're greater than 50, then that's good. If you're in the middle portion that's 30 to 50 nanomoles per liter, then that's sort of in the middle, and then here you've got less than 30. That's what they figured as deficient, and then they just followed them. They just watch them and they see what they did, and they looked at the death certificates after 15 years in these patients that started to die, and they wanted to see what was it that they died from, and this is what they found: those people that had vitamin D levels of greater than 50 had a better survival in terms of respiratory mortality than those that had less than 30, and of course the 30 to 50 were somewhere in the middle, but definitely statistically significant in terms of vitamin D levels predicting respiratory mortality. In fact, from the study, they said statistically after adjustment for sex age and season of blood draw, school education, smoking, BMI, physical activity and fish consumption, 41 percent of the variability in respiratory mortality during this 15-year follow-up period was independently associated with 25-hydroxy vitamin D levels less than 50. 

Well it's one thing to say that somebody with a specific value has a likelihood of dying. It's quite another thing to say that number caused the patient to end up that way. So in other words there's a difference between association and causation. That's the first thing that you learn in medical school when you take epidemiology. So here is a great meta-analysis that's often cited, and you should keep an eye on. It was published in the British medical journal and they did a meta-analysis. 

They did a meta-analysis of many many different studies; they pulled them together to see whether or not vitamin D supplementation in non-COVID patients. These are patients that don't have COVID-19. These had regular respiratory diseases like the flu and they wanted to see whether or not vitamin D supplementation improved mortality, and so they looked at vitamin D supplementation. They looked at about 25 randomized controlled trials. These are very good quality subjects and what they found was that vitamin D supplementation did reduce the risk of acute respiratory illnesses. Let's take a look at that data, so here you can see all of the different studies that were done in the randomized controlled trials. Did the studies say yes vitamin D had a benefit or no vitamin D did not have a benefit? You can see those here on the right side showed that there was no benefit or is actually worsening and those here on the left side show that there was a benefit when they averaged all of the patients together in these studies they came up with this final answer, here, which was less than one, which showed that there was a benefit. Let me just quote to you from this study. 

It was very large study -- landmark study -- it says, "our study reports a major new indication for vitamin D supplementation: the prevention of acute respiratory tract infection. We also show that people who are very deficient in vitamin D and those receiving daily or weekly supplementation without additional doses experienced a particular benefit. Our results add to the body of evidence supporting the introduction of public health measures such as food fortification to improve vitamin D status particularly in the setting where profound vitamin D deficiency is common." So you can't really underestimate this study. I mean,it looked at 25 randomized controlled trials, put them in a meta-analysis, and it came up with this as a final analysis. 

Here's another study. This one was done in Japan, and it looked at a randomized trial of vitamin D supplementation to prevent seasonal influenza A in school children, and this was done about 10 years ago. There was 334 school children, each of them were given either 1200 international units per day of vitamin D3, or they were given placebo and the end point was looking for influenza A by doing nasal swab antigen testing, and what they found over a winter season was that those subjects that got the supplemental vitamin D only had a 10.8 percent prevalence of influenza A, whereas those that got placebo had an 18.6 incidence of influenza A, and the absolute risk reduction, simply the difference between those two, is 7.8, which translates into a number needed to treat of 13. That's a pretty darn low number, which means that this intervention is pretty powerful, and you can see here the other related indices here showing that it was statistically significant. So clearly here vitamin D supplementation in school children -- these are children that would not normally necessarily be at risk for having vitamin D deficiency -- but even in this population it was able to reduce the incidence of influenza A. Okay, so let's talk about COVID itself and what we started to find out early on in COVID-19 when we started to research this is some uncanny similarities between what COVID-19 look like from a biochemical standpoint and what vitamin D deficiency looks like from a biochemical standpoint. Now this doesn't prove anything, but it certainly raises your eyebrows and you start to look a little bit closer, because what we saw was that in both conditions IL-6 was elevated, tumor necrosis factor alpha was elevated, gamma interferon was elevated in vitamin D deficiency and also in COVID-19 late in the course. The Th1 adaptive response was also elevated late in the course of COVID-19. We see both ACE2 expression reduced in both conditions and a hypercoagulability in both, and so that gave us pause and started to see well maybe vitamin D may play a role in COVID-19. 

Kyle: 

Would you expect vitamin D deficiency to also mirror other viral infections, or is this something unique to COVID-19?

 Dr. Seheult: 

No, I think it could also mirror other types of infections we see this during this time of year; we see increases in coronaviruses in general, rhinoviruses, we also see it in in influenza. The one thing that we don't see in those other viruses, however, Kyle, that we do see in COVID-19 is this hypercoagulable state. It's not as pronounced as we're seeing it in COVID-19. There was a recent article that was published in the New England Journal of Medicine, actually not recent it's been a couple of months now, that showed that in autopsies in patients with COVID-19 compared to those who did not have COVID-19, there was a nine-fold increase in blood clots in the lung tissue. So that is something that is very unique and then when we started to look at the epidemiology of patients with COVID-19 again, more eyebrows being raised, here's a pretty powerful study looking at 17 million, patients specifically looking at about 10,000 COVID-19 deaths, and what do we see we see something really interesting. If you look here at the age group this is nothing new. We know this that those who are higher in age are more likely to die from COVID-19, and you can see here the higher in age we go, the more risk there is in that category. We can see that male gender has some risk as well. Here we see with obesity that as the obesity level goes up, the risk starts to go up as well, and here we see again with ethnicity, as we start to compare to caucasian or white, that all of these darker skinned races have increased risk for death in COVID-19. And if you will remember, these are exactly the same three things that we saw put people at risk for vitamin D deficiency: both elderly age, increased obesity, and darker skin color, and so one has to wonder, now is this coincidental or is this something else that we need to investigate? Is it possible that vitamin D may have a role in the mortality and morbidity of COVID-19? 

Kyle: 

So that was a great chart that you just showed about different patient characteristics and hazard ratios associated with those patient characteristics, and I was impressed by it and then I looked closer and I saw that smoking status, specifically current smokers was actually a negative risk factor. Presumably, these patients would have better outcomes than non-smokers. That made me question the validity of this data, but what's your thought on this? How can you explain that? 

Dr. Seheult:

 Oh! no i don't think it should make you question at all. You know, early on we felt that it was the patients with lung disease that were going to be the ones that were ending up in the hospital, but clearly that's not the case. The type of people that we're seeing that are having severe reactions from COVID are the ones with cardiovascular disease. This is a vascular inflammatory condition, not one that necessarily hurts the lung from a respiratory standpoint. There's several explanations for this; nicotine is is a known anti-inflammatory and of course it's through inflammation that COVID does its dirty business. There's also well-known in COVID-19 -- uh sorry -- in smoking increases in nitric oxide. ,Nitric oxide is a vasodilator so it may actually be beneficial in this sort of a situation. Certainly not saying that we should go out and start smoking here, certainly because there's other problems, but, Kyle, this isn't the first time that we've had a disease where active smoking actually improves the outcome of the disease. I mean look at ulcerative colitis; that's well known to have a more milder course in patients who smoke, but it's not a reason to smoke, but it's not a reason to say that the study is incorrect. Well then it starts to get even more interesting, because when you start to look at countries and you start to look at populations, we start to see something quite interesting. If we look at the equator, which is right here at zero degrees latitude, as we start to move away from the equator we start to have less direct sunlight, and we start to see here that populations as a whole start to increase in terms of the mortality rates, and let me just read you a quote from the study that was published here in just April. It says, "when mortality per million is plotted against latitude, it can be seen that all countries that lie below 35 degrees North have relatively low mortality. Thirty-five degrees North also happens to be the latitude above which people do not receive sufficient sunlight to retain adequate vitamin D levels during the winter. This suggests a possible role for vitamin D in determining outcomes for COVID19. 

There are outliers of course -- mortality is relatively low in nordic countries -- but there vitamin D deficiency is relatively uncommon, probably due to widespread use of supplements. Italy and Spain, perhaps surprisingly, have relatively high prevalences of vitamin D deficiency. Vitamin D deficiency has also been shown to correlate with hypertension, diabetes, obesity, and ethnicity -- all features associated with the increased risk of severe COVID19." And here is another paper along the same lines. This one published in May of 2020, titled "The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality." So this study looked at 20 European countries looked at specifically the average vitamin D levels, looked at COVID cases and also COVID mortality, and this of course was as of April of 2020. So they looked at these 20 different countries and what they found was an inverse relationship with this r and p value that showed that the higher the vitamin D levels of that country, the lower the COVID-19 cases per million population. You can see there a fairly straight line going through this plot. So once again, these are nanomoles per liter, so you need to divide by 2.5 to get nanograms per deciliter. 

Now this is for cases, what about mortality? 

Well they did the same thing for mortality and it was very very similar, so again mean vitamin D levels that were very high had almost zero percent mortality, whereas those that were very low, like around 40 to 50 in this situation, had a higher mean COVID-19 mortality per 1 million population. Okay, well, what about these patients specifically? Here's a paper that was published in nutrients, and it looked at 107 patients that were hospitalized in Switzerland, and what they did was they looked at the vitamin D levels in those patients that were positive for SARS-CoV-2 and those that were negative for SARS-CoV-2, and what they found was that those that were negative for SARS-CoV-2 had higher vitamin D levels than those that were positive for SARS-CoV-2, and this was statistically significant, but of course again, this is an association and not necessarily a causation. We see that it's associated with a low vitamin D level. It's possible that the SARS-CoV-2 infection may be causing the vitamin D levels to go down, and that was the subject of a letter to the editor titled -

"Vitamin D deficiency in COVID-19: Mixing up cause and consequence," 

and what they were able to show here in about nine subjects when they gave lipopolysaccharide to healthy volunteers, which is another way of inducing the immune system, is that they found that plasma vitamin D levels did in fact drop slightly, and if you look here at the scale it was on the order of maybe about five points. They were able to show that when somebody has an infection or is undergoing an immune response their vitamin D levels can drop and so it is possible but this is a modest drop here. Something that we ought to keep in mind as we go forward now of course the SARS-CoV-2 infection may cause a vitamin D level to go down, but only after you've been infected. What about those people that have had vitamin D levels checked well prior to them getting an infection? Well here's a study that looked at low plasma 25-hydroxy vitamin D levels as an associated risk of increased COVID-19 infection, and what they showed here they took 14,000 subjects with at least one test for COVID-19 and a previous vitamin D, and what they found was that they had to exclude about 6,000 of them because they did not have a former vitamin D level and so 7,800 of them had a test for COVID-19 and had a vitamin D level on record, and they were able to show that about 10 percent of these patients had positive COVID-19 tests and about 90 did not, so what did they show here? They divided levels of vitamin D at around 30, and so these are the people that were low here on the left and these are the people here that were normal. Notice that there was a big gap here, not a lot of people who were elderly and had normal vitamin D levels. I found that very interesting, and when you look at this scattergram, you'll see that the majority of the patients were actually in the lower amount, so they were less than 30. So this is not like an insignificant or rare problem. So this flow chart may look confusing at first, but if you look at this the point, is it's just a tiny amount of the normal vitamin D levels that make up a portion of the positive SARS-CoV-2 population. Here is another article as well from Israel that showed that low plasma 25-hydroxy vitamin D levels were associated with an increased risk of COVID-19 infection. This was a population-based study, again looking at baseline vitamin D levels not ones that they were obtaining after they developed COVID-19 or had a COVID-19 test, and what they showed when adjusted for age and demographics and comorbidities that vitamin D levels of 75+ compared to less than 75 had a significant difference in terms of whether or not these patients would have either a SARS-CoV-2 infection or a COVID-19 hospitalization. In other words, if it was less than 75, they were 1.45 times as likely to get an infection and almost two times more likely to get hospitalization. So again this is in nanomoles per liter, so you have to divide by 2.5 to get nanograms per milliliter, and here is yet another link between vitamin D deficiency and COVID-19 in a very large population, this time looking at 52,000 matched to 524,000 controls that was matched for sex, age, and geographical location, and what they showed here, this bell-shaped distribution in red are the SARS-CoV-2 positives and of course, everybody else in gray, and there's definitely a shift to the lower values of vitamin D and here in females, it even made a bigger impact, the lower levels were definitely associated with SARS-CoV-2 positivity. How do you explain that? Yes it's hard to say. Obviously, the differences between men and women are very, very large in terms of hormones and things of that nature, although it wouldn't be surprising if they found out that it had to do with hormone levels. Recently they've been releasing information about pregnant women in COVID and that pregnant women have a increased risk of severity and of course pregnant women have elevated estrogen levels, progesterone levels, and so the question is, why is that the case? We don't know, but it could be that it's accentuated in pregnancy. Obviously when they're not pregnant, there is a baseline elevation in estrogen. We're not seeing that in a baseline situation, but it could affect vitamin D because vitamin D once again, just like estrogen, just like progesterone, is a steroid hormone, so don't have a good answer for that at this point, and not to be outdone, the United States also published theirs. This was a whopping study of almost 200,000 de-identified test results from clinical laboratories looking at vitamin D levels and SARS-CoV-2 positivity, and so when you look at this, overall you can see very clearly that vitamin D levels are inversely related to SARS-CoV-2 positivity rate with the lower levels being associated with being positive for SARS-CoV-2, and you can see that it's around 50 where it starts to take off and go up, and when they looked at this to see whether or not something was generating this -- any particular part of the country or age or anything like that --they found that it really did not matter in terms of geography, that there was still the same relationship as you went down in vitamin D levels, there was an increase in SARS-CoV-2 positivity rate, but interestingly, there were higher rates of SARS-CoV-2 in the northern region of the United States, above the 35th parallel, whereas in the central and southern states, it was relatively low, but the relationship still existed. This also existed in terms of race, so it didn't matter what race you were: if you had lower vitamin D levels you had an increased risk of SARS-CoV-2 positivity, but again, the darker skinned races had a higher risk of SARS-CoV-2 positivity with respect to the white baseline. Here in this case in terms of age, again it really didn't matter whether age was greater than 60 or less than 60, and here ironically it was higher in the younger age, because we know that SARS-CoV-2 positivity is more prevalent in the younger populations, but hospitalizations are more prevalent in the older populations, and then of course again, it didn't matter whether you're male or female, as your vitamin D levels go down your SARS-CoV-2 positivity goes up again this is showing an association, not necessarily a causation. 

Kyle: 

That data looks impressive when it's charted out, and it looks like there's a clear correlation between vitamin D levels and COVID-19 infections, but this is observational data, and you've talked a lot about in your COVID-19 updates about how observational data is really limited in a lot of ways, and it really needs to be backed up by randomized placebo-controlled prospective trials. Could it be that people that have higher vitamin D levels are also the people that are more likely to take better care of themselves in general? They're more likely to get outside, maybe they're healthy enough to actually get outside and get some natural sunlight. Maybe they are people that are engaged enough in their own health to actually take vitamin D supplements, eat a healthy diet in the first place. 

Dr. Seheult: 

Well on the surface it’s certainly possible. Yeah those people in the middle class who have the ability to get outside are probably the ones also that are going to take time and take care of themselves, but you know you also have to take into consideration that this study is looking at everybody, not just those who go outside because they choose to go outside, but those people who go outside because they have to go outside, because they're laborers, because that's part of their job. They have no choice but to go outside and I would say that those probably outnumber those that go outside by choice, because it's a health issue and even those patients who probably aren't taking care of themselves as well as middle class people might be doing, they also, it seems as they fit into the same data, have an improvement as well, and here is another study that was published this time with 105 patients that were hospitalized with COVID-19, and what they wanted to look at here was progression. So of 105 patients that were admitted with COVID-19 type symptoms, they found that those that were negative represented about 33 percent and those that were positive represented 66.7 percent, and as you can see here the average vitamin D level was lower in those positive SARS-CoV2 patients and higher in the negative patients. So here, ostensibly, they're having the same immune reaction, because they're coming with the same symptoms, but in this situation it is this group that is SARS-CoV-2 positive, and they have lower vitamin D levels. Now when you look at that and break it out and you see if their levels were less than 30 or greater than 30, those that had greater than 30 had lower peak d-dimer levels. Why is that important? D-dimer is considered to be a risk factor for getting blood clots in COVID-19. Also if you'll notice here that is the higher vitamin D levels here that had a lower incidence of ventilator requirements. Okay so what does this study show? It shows that potentially vitamin D levels are associated with a worse outcome or worse course of SARS-CoV-2 in the hospital. Here's another study looking at the very same thing in terms of vitamin D levels in the hospital and outcomes, and you can see that when they divided the patients between vitamin D, less than 12, which is pretty low versus greater than 12, you can see here that the survival probability in these patients when they set it to 12 was a huge difference in terms of survival probability. When they changed it to 20, you can see also there was still a difference in survival probability, but not to the same degree, and of course they followed them out for about a hundred days in this trial. So once again, vitamin D levels seem to be associated with a worse progression of the course of COVID-19 in the hospital. Okay, so up to this point we've been talking about how vitamin D is associated with bad outcomes, but that doesn't say necessarily that it's the cause of the bad outcomes. You have to be very, very careful when you say that something is associated with something, because it could be due to any number of co-founders, right? It could actually be that SARS-CoV-2 reduces the vitamin D level and we've shown that that's the case acutely at least, but not necessarily chronically. It could be that there's another factor that's causing both a susceptibility to SARS-CoV-2 infection and also a vitamin D level, and so if you just change the vitamin D level, that won't necessarily make the SARS-CoV-2 any better, so we have to establish then by doing a randomized controlled trial or interventional trials to show that if you give vitamin D to somebody who is either pre-COVID or in COVD, that you can get better outcomes, and that's exactly what they tried to do here in this Spanish study that was published just in October of 2020. It is titled the "Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: 

A pilot randomized clinical study." So what is calcifidiol? 

This is important for you to understand what that is. Calcifediol is the 25- hydroxy vitamin D3. This is not what you normally take as a vitamin D supplement, because when you take a vitamin D supplement, it has to be metabolized in the liver as we mentioned and have the 25-hydroxyl group put on it. Here, calcifidiol already has the 25-hydroxy group on it, so it doesn't need to be metabolized, it's ready for the one hydroxylase enzyme to activate it and for it to be used. So it kind of speeds up the process, and in this situation what they did was they took patients with COVID-19 and randomized them to not receive calcifediol. So this is the placebo group, or receive calcifediol, this is the intervention group, and what they found was that in the calcifediol group, and so just so you're aware that they gave them a pretty high dose on day one, then they gave it to them a few days later, and then again on day seven. What they found was that in the intervention group, only two percent of those patients went to the intensive care unit, whereas in the placebo group 50 of those went to the intensive care unit. Now something you should understand is that this had a total of 76 patients in it. 76 patients is not that much but I know that they are planning on doing a much bigger clinical trial with about a thousand patients, and here is another study that is really interesting because at least here I guess in France what they do is every two to three months, they give about 80,000 international units of vitamin D in these nursing home patients, so when these nursing home patients started to be admitted to the hospital with COVID-19, they asked the question: did this patient get this 80,000 units within the last month or has it been longer than a month since they got it? And for those patients that had gotten it within the last month, they had a much better survival than those that had gone further than a month out, and this was 66 patients in this cohort, so sort of a quasi-experimental study, because of the situation that these patients were in. Some have been given recent vitamin D supplementation and some hadn't, and when they looked at that, there was a statistically significant difference, as you can see here, p of 0.002. Well here was another study. This was a multi-center, double-blinded, randomized control trial and interestingly here, they looked at 240 patients, which is not small, but what they did give them was on admission a whopping dose of 200,000 international units of vitamin D3 or placebo, and what they wanted to see if there was any difference in clinical outcomes. Well if you look here over on the right you'll see that the blue group was the intervention group. That was the one that received the vitamin D, and you can see that there was a statistically significant increase in their circulating 25-hydroxy vitamin D levels in the placebo group. There was no difference, and so despite the fact that their circulating levels of vitamin D went up, there were no differences in clinical outcomes including mortality or ventilator days. A couple of criticisms of the study is they only gave one dose, and why is that a criticism? Well if you look at that original British Medical Journal meta-analysis that we talked about at the beginning of the video, they made a point of saying that it was basically repeated doses on a daily basis or on a weekly basis, not bolus dosing, which seemed to help. The second criticism is that even in medications that we give that we know work like antibiotics and bacterial infections; we don't just give one whopping dose of antibiotics and hope that they improve. The other thing was that this was given rather late. Remember that the vitamin D3 has to be metabolized in the liver to the 25-hydroxy vitamin D, and that can take some time as well. The most recent study that's come out though was this one from India titled "Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomized, placebo-controlled trial." This is also known as the shade study and here they looked at 40 COVID-19 positive patients and here they gave 60,000 units daily for seven days and they gave 24 patients placebo, so the total here was 16 got the intervention, 24 controls got the placebo, and in terms of their outcomes, they were looking at how many of them were SARS-CoV-2 negative by day 21 and were there any biomarker reductions, and so the results were that 62.5 percent versus 20.8 percent were SARS-CoV-2 negative by day 21 in the intervention group, and those that got vitamin D and fibrinogen, which is a surrogate for inflammation was significantly decreased in the intervention group as well, and while we're on the topic of critically ill COVID-19 patients and inflammatory markers here's a study that was just published in November looking at just that with vitamin D levels you see here that there was a group A that was admitted to a hospital. These were basically people who were asymptomatic for the 12 days. These patients were admitted to the hospital, but to an isolation ward not because they needed hospitalization and group A are those asymptomatics that were there for 12 days with no symptoms, and there was a total of 91 of those patients. The B were those that were admitted to the intensive care unit; there's about 63 patients of those a total of 154 in the study; you can see here those patients with greater than 20 nanograms per milliliter of vitamin D were much more prevalent in the asymptomatic group, and those that had serum 25-hydroxy vitamin D levels less than 20 were predominant here in group B, and we can see that those patients that had low vitamin D levels had significantly higher il-6 had almost statistically significantly higher tumor necrosis factor alpha, and had higher serum ferritin levels, which is also a surrogate for inflammatory markers in COVID-19. Secondary endpoint was low vitamin D levels in fatality rates, and there was a really big difference between those that had low vitamin D levels and those that had normal vitamin D levels, and this led the authors to state this: this all translates into increased mortality in vitamin D deficient COVD-19 patients. As per the flexible approach in the current COVID-19 pandemic authors recommend mass administration of vitamin D supplements to populations at risk for COVID-19." So what about it? What about supplementation of vitamin D? Are you taking it seriously? Well even before COVID-19, certain countries were taking this seriously and here's a review that was done out of Helsinki, Finland, titled "Vitamin D fortification of Fluid Milk Products and Their Contribution to Vitamin D Intake and Vitamin D Status in Observational Studies." There are a number of different countries and they have different approaches. For instance, in Finland, the type of fortification in their food is voluntary, but as it turns out, everybody's doing it, and so it's as if it were mandatory in Norway. It is voluntary in Sweden. It is mandatory in Canada. It is mandatory, however, in the United States. It's voluntary, so some manufacturers of fluid milk, acidified milk, and cultural milk, and even yogurt, do put vitamin D in those foodstuffs. However, in Ireland, they do not and this is what one of the commentators on the Irish longitudinal study on aging had to say about vitamin D in their study. They say Ireland does not have any formal vitamin D food policy. We practice a voluntary, but not mandatory food fortification policy where food manufacturers can decide to fortify or not their food products with vitamin D. The vitamin D status of those in Ireland is lower than either the United States or Canada, who have systemic mass vitamin D food fortification. 

However, vitamin D deficiency is not inevitable in older adults in Ireland and the ability to have sufficient vitamin D status year-round is an achievable goal that many countries meet. For example, another European country, Finland, which is at a much higher latitude and therefore receives less sunshine than Ireland, has virtually eliminated vitamin D deficiency in its population with rates of less than one percent. This is due in part to a successful food fortification and vitamin D supplementation policy and educating the public and medical practitioners on the importance of vitamin D. This vitamin D success story demonstrates what could be achieved in Ireland. It can happen in other places as well. 

Okay, so when it comes to supplementation, let's see what the guidelines are. This is the endocrine society clinical practice guidelines that were published back in 2011. And if you look under the heading, recommended dietary intakes for vitamin D for patients at risk for vitamin D deficiency, and you go on down to the bottom, you'll see here, under 2.6, their recommendations. And let's go over what those recommendations are as you can see, unless you're a child then basically what they're saying is that 4,000 international units a day for anyone greater than 8 years of age is the upper limit for supplementation with vitamin D without medical supervision. 

So another question is exactly what are they worried about? What is the frequency? What is the relevance of vitamin D toxicity? 

Well to get a better understanding of that, we go to a publication in Frontiers in Endocrinology out of Poland, and in this article, it states that the Endocrine Society and the Institute of Medicine have both stated that vitamin D toxicity is extremely rare, and that concentrations usually of 25-hydroxy vitamin D have to exceed 150 nanograms per milliliter, which is 375 nanomoles per liter, and not only that, there has to be increased calcium intake, and so because it's very rare. It's led them to state that they believe that vitamin D is probably one of the least toxic fat soluble vitamins, much less toxic than vitamin A, and a researcher, Didenkov, looked at 20,000 serum 25-hydroxy vitamin D samples at the Mayo Clinic from 2002 to 2011 to look and see whether or not there was actually any evidence of vitamin D toxicity, and out of those 20,000 only one patient with a 25-hydroxy vitamin D concentration of 364 nanograms per milliliter, which is a whopping 910 nanomoles per liter, was diagnosed with hypercalcemia. Similarly, another researcher looked at healthy adults in a clinical setting that were receiving 50,000 units of vitamin D2 every two weeks, which is approximately equal to 3,300 international units a day for up to six years, and their concentrations were only 40 to 60 nanograms per milliliter and they had no evidence of vitamin D toxicity. This also goes along with a study in Canada where they researched Canadians taking up to 20,000 international units of vitamin D3 per day, and they had significant increases of 25-hydroxy vitamin D concentrations up to 60 nanograms per milliliter, but again without any evidence of toxicity. 

So it looks as though based on that data that supplementation is relatively safe, but how much should you supplement, and does it make a difference about your BMI? Well, this was an interesting article that was published titled, "The Importance of Body Weight for the Dose Response Relationship of Oral Vitamin D Supplementation and Serum 25-Hydroxyvitamin D in Healthy Volunteers." In relation to this study, they took 17,000 patients and looked at vitamin D levels, and there was a wide range of vitamin D levels in this population anywhere from four nanograms per milliliter to 158 nanograms per milliliter, and people were supplementing anywhere from nothing to 55,000 international units a day, and what they found was pretty interesting. They found that early on supplementation per thousand international units brought up people's levels pretty quickly, but then as the amount of supplementation started to go up, the levels started to go up more slowly, such that in the first thousand units that you take as a supplement, each thousand units would increase the level in your blood by 4.8 nanograms per milliliter, but if you got up to the 10,000 range or the 50,000 range, even 15,000 to 20,000 range, 1,000 units would only raise it up by about a tenth of that, or 0.4 nanograms per milliliter, so in other words down here, a thousand international units when taking a low amount would raise your level by 4.8 nanograms per milliliter, but if you're already taking a large amount, each additional increase by a thousand international units would only raise it by about a tenth of that, so you can see that there is definitely a non-linear relationship there. 

Furthermore, BMI also had a lot to play in this as well. So for those that are normal BMI, and that by definition is less than 25, and then you have overweight, and that is 26 to 30, and then you have obesity, which is 30 plus. What they found in comparison to a normal BMI was, first of all, generally overweight people were on average three nanograms per milliliter less in terms of their serum vitamin d, and that obese patients were eight milligrams per deciliter. Now it gets even more complicated there, because what they found was that it took more vitamin D to get them up to a regular level than would be expected if they were overweight or obese. In fact, their recommendations is that for people who are overweight they should take 1.5 times what is normally recommended to get their vitamin D levels up, and for those that are obese, have a BMI of greater than 30, it actually is 3.0 times as much, and that might be related to the fact that vitamin D, of course, is fat soluble. So there are a lot of things to take into consideration and this is a moving target. Also take under consideration the fact that currently we are moving into winter months, but again these all need to be parsed with the season and weight and age and all of those sorts of things that we talked about. Now while this is a distribution of vitamin D in Germany. I'm sure it's not very different from what it is here in the United States, and as you can see 50 millimoles per liter is really on the low side, and that would correlate with about 20 nanograms per milliliter. So you can see here how significant that severe deficiency in 25-hydroxy vitamin D can be. There are a number of people that are at deficiency based on this. I feel not only is there a role for all of us to be taking vitamin D supplementation at least during the winter months, but I also feel strongly that practitioners in the hospital may want to look at this in terms of their treatment of patients in the hospital. Now I do not have randomized controlled trial data yet, conclusively, that shows that this works, but if we look at the risks of vitamin D supplementation and the potential benefits, I think the benefit-to-risk ratio is high. 

Dr. Fauci himself is supplementing with vitamin D, and while there are certain groups of people that should be very careful with supplementing with vitamin D, such as patients with sarcoid or other granulomatous diseases, or patients with renal issues, without discussing at first with their doctors, I do see a role for supplementation, especially in this winter season when COVID is running rampant. I can't tell you as an individual how much vitamin D to take, because I'm not your doctor, and I'm not here to give you medical advice, but I am still taking 5,000 international units daily, and when I had my levels checked, when I was taking 2,000 international units daily, my level was only 48 nanograms per milliliter, and I am living in sunny southern California. I plan on making more videos about what I am doing, and what I think we should all be doing in terms of protecting ourselves from COVID-19. 

Please share this with as many of your loved ones as possible, because I think this could potentially be beneficial in our fight against COVID-19, and for more information, visit us at MedCram.com

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