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

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’s 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 
superfamily 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 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 cofactor or something else to  get something to work, and so in that sense 
vitamin d is 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 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 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 2D, which is the active form,  or it can go to the kidney and it can be 
converted there to 1,25 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 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 an 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   the other one is nanomoles per 
liter 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 bioavailability 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-2infection 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?  yeah it’s hard to say. Obviously, the 
differences between men and women are very,  very large in terms of 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 was 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, that 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’s 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 of course we’ll give 
you a link to this in the description below.   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 55,000international 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 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 is 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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