The Association Between Vitamin D Levels and COVID-19 Positivity—and More

Good afternoon. Good morning. Good evening and welcome to today’s live educational webinar where we will be discussing the association between vitamin D levels and COVID-19, and more. I will be moderating today’s webinar. Please note that due to the large number of participants, you are going to be joined in listen-only mode, but you will be able to ask questions using the chat feature. I’m Dr. Damian Alagia, the Chief Clinical Officer for Health Systems, as well as the Senior Medical Director for Advanced Diagnostics and Women’s Health at Quest Diagnostics. This program will be presented by my good friend and colleague, Dr. Harvey Kaufman. Dr. Harvey Kaufman is a Senior Medical Director of Quest Diagnostics, where he served in a variety of roles for nearly 29 years, including the first Chief Laboratory Officer. Dr. Kaufman has coauthored several publications on circulating 25 hydroxy Vitamin D, including the recent publication on the relationship between SARS-CoV-2 Net Positivity. He is a graduate of M.I.T. Boston University School of Medicine, the NYU School of Business, where he received his MBA and, of course, a diplomate of the American Board of Pathology, AP, CP and Chemical Path. Before we begin, I’d like to cover a few housekeeping items. We’re recording today’s seminar, and we’ll be posting it on our Education Center as a future on-demand educational offering, so you’ll be able to review this valuable information in the future and share it with your colleagues who couldn’t be here with us today. One PACE credit will be available for this presentation. The link to the evaluation should appear after the presentation, as well as in the follow-up email. Please again ask your questions via the chat feature and we will answer them at the end of the webinar. During the presentation, Dr. Kaufman will be covering a lot of ground, I guarantee you, so please note that I might stop him along the way and ask him to elaborate on a few points or provide a short summary of the path that we’ve traveled so far. And of course, at the end I will be asking him to provide us three take home points that will inform the care we provide for our patients. Lastly, the views and opinions presented in today’s program or those of the speaker, based upon his professional experience and expertise. Now, I would like to turn the presentation over to Dr. Kaufman. Thank you, Dr. Kaufman. Thank you, Dr. Alagia. It’s a pleasure. Today, we’re going to address one of the hottest issues in health care, which is the COVID-19 pandemic. Beyond mask and social distancing, hand-washing, testing, quarantines, and now vaccination, the question is, if vitamin D can be used to suppress the SARS-CoV-2 virus. So here’s the outline for today. It’s important to give some context about vitamin D and vitamin D in our health. So let’s start with a description of vitamin D and its role in bone health. We’ll also mention other health conditions later. So as we move along, what is vitamin D? Simply put, vitamin D is a hormone that maintains the level of calcium and phosphorus in our circulation. By promoting the absorption of calcium, it regulates bone growth. And as we’ll see, it also plays a very vital role in our immune function. So, Dr. Alagia, you and I both love history. So let me start with why vitamin D is mis called a vitamin. It starts with two of the early nutritional biochemists, Dr. Elmer Verner McCollum and his colleague Marguerite Davis. Dr. McCollum was called Dr. Vitamin by Time magazine in 1951. His rule was - it’s a great rule - eat what you want after you’ve eaten what you should. Still applies. He and Marguerite Davis discovered the first vitamin - vitamin A - and Dr. McCollum worked on vitamin B and D and worked out the effect of trace elements in our diet. When he said that milk was the greatest of all protective foods, milk consumption in the United States doubled between 1918 and 1928. Just imagine if you are an advocate for wearing a mask in a pandemic. McCollum also promoted leafy greens. His work was monumental in terms of fluorine and the prevention of tooth decay on vitamin D and vitamin E and the effect of a slew of trace minerals and nutrition. He and his colleague Kenneth Carpenter became convinced that sunshine and cod liver oil both protected against rickets, bone disease ... but that’s due to severe vitamin D deficiency. And they tested this out by carrying rats outside into the sunshine. And soon after, there was a whole generation of children who grew up on cod liver oil, and rickets was virtually wiped out. But let’s not worry about the rats. We’re going to focus on humans here. McCollum wanted milk to be fortified with vitamin D, and today, the National Dairy Council’s website welcomes researchers saying that it was McCollum who, quote, who first made the scientific connection between dairy foods and good health. I just want to point out that Dr. McCollum failed the general certification exam for high school, but it was allowed to enter high school provisionally. That concession, whoever made it, has served us all well for the subsequent century. Finally, I saw an interesting quote from Dr. McCollum when he was a full professor. He said, A professor succeeds with the students by his ability to make his conversation in lectures more interesting than song, dance, drink, and fast driving. So that’s that’s the bar for today. Let’s return to our slides. We see that the precursor to vitamin D requires sunshine and two enzymatic hydroxylations - in the liver and in our kidneys. This is why when we have liver or kidney functions are impaired, vitamin D levels decline. On this slide provides a simple schematic of the vitamin D pathway. Of note, the second hydroxylation leads to 125 dihydroxyvitamin D. That’s the active form that binds to the vitamin D receptor. 125 dihydroxyvitamin D is a very low concentration. Thus, we measure the more easily measured precursor, 25 dihydroxyvitamin D. As we move on, we can see that vitamin D is made when UV light - precisely UV rays - react with a compound 7-dehydrocholesterol in the skin. Now the best rays for UV synthesis have wavelengths of between 290 and 320 nanometers. It’s these wavelengths when present, when they are present, when the UV index is greater than three. This morning where I live, the UV index is two. Not going to get any of that UV rays of 290 to 320. Now, the angle of the sun above the horizon at sea level also affects the production of vitamin D because the atmosphere is thicker at low angles and absorbs more UV energy. So at angles greater than 45 degrees above the horizon - this is at sea level - vitamin D production will be occurring. So if our shadow is longer than we are tall - that’s an indicator of the oblique angle of the sun - we’re not making enough, or not making any vitamin D. So just like the groundhog today on Groundhog Day, check your shadow, but don’t do it right now. At higher altitudes, there’s less thinner atmosphere to absorb the UV light from the sun, so when we move higher into the mountains, we get higher, more UV exposure. Now, latitudes above 40 degrees North, which is fundamentally New York through Denver - if you draw a line through there - we’ll experience a vitamin D winter. So from around November through early March, there’ll be a sense in essence, no vitamin D synthesis in our skin. We just aren’t absorbing the right UV rays. Now, if we move closer to the equator, particularly 35 degrees North or South of the equator, we’re fundamentally getting year round production of vitamin D. So, Dr. Kaufman, I think that’s an important point. It’s not just sunlight that’s important, but it’s also the right kind of sunlight. For instance, you know, folks out in the West, where it gets maybe a little bit warmer and they want to go out skiing and they’re not covering up as much. They’re saying, well, I’m getting exposed to great sunlight and I’m getting my vitamin D, correct? And the answer is ... Probably not. I mean, you’re up in Wyoming and up in Wyoming. You’re in that Vitamin D winter. So it really depends upon both latitude, height, above sea level, the number of minutes exposed. They all come into play. Okay, so the summary point here is not just sunlight, but it’s the right kind of sunlight. Absolutely. Okay. Thank you. Please continue. And even wearing sunblock often when we’re out in the sun with sunblock, there’s enough sun exposure, UV rays to still absorb some of that, to be involved with the synthesis of vitamin D. Okay, So, Dr. Alagia, so we have to be mindful of some terms that are on the next slide. The difference between D2 and D3 are essential. D3 is so plants produce vitamin D2, animals produce D3. D3 is approximately twice as effective as D2 in raising our circulating levels of 25-hydroxy vitamin D. So in terms of over the counter supplements, they’re all D3 at this point. Years ago there was a mixture of D2s and D3s ... I don’t think you can buy a supplement with D2 anymore. So where do we get vitamin D? Well, the primary sources are supplements and some foods. Fish, cod, liver oil, fortified foods. Now, my dad and his siblings, when they were growing up, they used to line up every morning to get their their spoonful of cod liver oil. Now, each tablespoon of cod liver oil has 1360 IU’s. So try to keep that number in mind. The U.S. Institute of Medicine recommends daily allowance of 400 to 800 IU’s per day, and common supplements are 1000 or 2000 IU’s per day. Like getting vitamin D and a healthy diet gets us to generally avoid vitamin D deficiency. Unfortunately, as we’ll soon see, a large proportion of Americans are still vitamin D deficient and a large proportion are also vitamin D suboptimal. Now, the last point on this slide is that one cup of milk that’s fortified has 120 IU’s. So one would need to drink a fair number of dairy products or milk to sort of get to that minimum - and most of us don’t. All right. So, Dr. Kaufman, before we go to the next slide, I think, which is where we talk about bone health, we’re talking about the right kind of vitamin D, the right kind of sunlight with the right dose. So I’m looking at D3 2000 international units daily with the right kind of sunlight. Is that correct? That’s what I can do to get my vitamin D up. Generally, yes. But we also have to be aware that there are reasons that people remain deficient. So I for one, I have celiac disease. So for a while before I was diagnosed, I was malabsorbing so I could take a lot of supplements, but if I’m still malabsorbing, I’m not going to get any more vitamin D. So one needs to understand the medical context, at times, as to where one starts is critical, but also, if there’s any underlying medical conditions. Ok, terrific. Thank you, let’s go to our next slide then. So the role of vitamin D in bone health is extraordinarily well established. That’s sort of like the anchor that we all agree upon. Simply, vitamin D plays a central role in maintaining our levels of calcium and phosphorus and is essential for bone health. Now, I think it was last month that there was a case study in New England Journal of Medicine of a young child with rickets, who was severely vitamin D deficient. And due to the work of Dr. McCollum, we’re fortunate that these reports are exceptional; they’re really rare and when they do occur, are worthy of a case study in New England Journal of Medicine. Further, there is compelling evidence of support of the role of vitamin D in muscle strength and its role in reducing risk of falls. So those are the sort of like that the core established role for vitamin D. And, Doctor Alagia, now let’s turn to the sort of the key topic, which is vitamin D and SARS-CoV-2 and COVID-19, and a little bit more history and we’re going to start with focus on respiratory viral pathogens. So the history lesson here starts with Dr. Edgar Hope-Simpson. He stands out as another key figure in the history of medicine. He was a general practitioner who carefully recorded notes about his patients and their health conditions. In 1941, his wife gave him a book. It was written by general practitioner William Pickles called the Epidemiology in Country Practice, detailing the epidemiological research of common diseases, which could be carried out by general practitioner. Hope-Simpson modeled his life approach to medicine on this. He exchanged visits with Dr. Pickles, and few general practitioners have contributed more to medicine than Dr. Edgar Hope-Simpson. He made several contributions related to seasonal influenza, to shingles, to varicella. Others built on his work and were recognized with Nobel Prizes. Now, one of his earliest contributions was based on visiting the World Health Organization to obtain data on influenza. He showed, as we’ll see next, remarkable relationship between seasons and influenza and the relationship with distance from the equator. So the the further away from the equator - or the top and the bottom - and closer to the equator at the bottom is the middle to there. So the tropical areas had year round incidence of influenza that’s more level. Whereas as we move further away, there is much more of the seasonal pattern. He didn’t understand the basis of the solar radiation on the observed pattern of influenza, but knew that there had to be this relationship. So let’s advance four decades and summarize what we know. We need sunshine to synthesize vitamin D, and therefore there’s this strong seasonal pattern, especially as one moves further from the equator. This seasonality has been muted by fortified foods, particularly in the United States. Interesting, the peak values have not changed much over time. So on the right hand side, we see some data from northern town in Germany, in the late 1990s, and you see that the trough is about 12 and the peak is around 30. So we’ll see how that peak sort of stays the same, but the trough is going to move up over time. Despite all this fortified foods and the supplements, we still have about one third to one half of the population that are vitamin D deficient, especially in the winter. We also learned that we’re still learning a lot about the interplay between vitamin D in our immune system. It’s a critical role that it plays and we’re going to dive more to that in the next slide. Before we forget there, let’s talk about some of the vitamin D, its role in protecting us against respiratory pathogens. And this sort of gets into the more nuts and bolts of how vitamin D really works. So first there’s it works to preserve the tight junctions. So it helps avoid the immune cell infiltration into the lungs and other respiratory organs. 1,25-dihydroxyvitamin D binds to the vitamin D receptor macrophages, resulting in an increase in the production of anti-microbial peptides that have antiviral effects. And third, it decreases the pro-inflammatory cytokines synthesis by the immune system. So it modulates the immune system. 1,25-dihydroxyvitamin D inhibits the activation of B cells and immunoglobulin synthesis. So that’s on the B cell side. It also promotes T cell regulatory cells which are responsible for the anti infectious actions that are induced by interleukin 10 production, and this leads to suppression of the T helper cells and particularly of the interferon gamma. And then we get into the various interleukins so decreases interleukin 17 and 6 and 23 and 2 and also helps make the T helper cells more predominant and then the T helper cells limit the inflammatory response by inhibiting the T helper cell mediated cytokine. So you could see that there’s there’s this sort of this cycle where they all fit together and it inhibits the cell mediated cytokines as well as tumor necrosis alpha. So of note, the active form of vitamin D regulates the invariant nuclear natural killer T cells that are the regulatory cells that sort of link the innate system of the immune system that are born with the adaptive immune system. So, Dr. Alagia, what you can take from this is that vitamin D is integral role in our immune response. And thus it’s not surprising that levels of circulating 25-hydroxy vitamin D influence our response to respiratory viral pathogens. Okay, but I’d like to go back and make things simple. You know, I’m a simple, straightforward OBGYN and I do find it refreshing that the foundations and really the great knowledge about vitamin D came from two individuals, one who had a tough time getting into high school and stayed there on a provisional basis before he became a professor. This Dr. McCollum and the other one who was a country doctor, you know, who observed or closely observed patients. So what we’re seeing here is a great explanation on a biochemical or molecular level. You know, with helper cells and, you know, and your interleukin 17s and 6s, whatever. I think most importantly, you know, the people have probably moved us the farthest and the fastest are the people who just took time to observe their patients and and to, you know, make those common connections so, while this is you know, I don’t want to diminish this, but I also want to make sure that people understand that it’s the patient in front of us that makes that makes the difference, and we pay attention to them and we can really move the world, as both Dr. McCollum and Hope-Simpson did, so this is terrific, but I don’t want to get bogged down here. Yeah, no, I mean, those are great observations, and whether we’re talking about the, you know, understanding the first patients who had COVID-19 or HIV, it was doctors on the front line who are making these observations and making these connections that drives to new discoveries of medical conditions and treatments. Terrific. Thank you. Not to diminish this, by the way, but also to highlight the importance of, you know, and gratitude we have for the frontline docs. Absolutely. So the next slide describes more fully the vital role Vitamin D plays in our response to SARS-CoV-2. So using the spike glycoprotein on its surface, the SARS-CoV-2 virus binds to the angiotensin converting enzyme II. So there’s a concave surface to the virus which facilitates its binding to the receptor like a key being inserted into a lock. And then the receptor sort of like sucks in the virus. So the ACE2 acts as a cellular doorway, a receptor for the virus to get into the cell. That then leads to ultimately in some people, the disease COVID-19. The ACE2 is present in the epithelium of many cells in our body, but in particular in our nose, mouth and lungs. So this is where the virus first attacks and causes the greatest damage to our bodies. ACE2 helps modulate many activities of a protein called angiotensin II, and that increases blood pressure and inflammation, and that then increases damage to the blood vessel linings and various types of tissue injury. So it’s just that cascade from being the receptor all the way through that’s leading to this to the injury and to the respiratory fibrosis and in some cases, death. Of greatest relevance to COVID-19 is due to angiotensin II can increase the inflammation and the death of cells in the alveoli, the lining of the lungs, which are critical to bring oxygen into our bodies. These harmful effects of angiotensin II are reduced by ACE2, so when the SARS-CoV-2 virus binds to that receptor, it prevents ACE2 from performing its normal function and regulating the angiotensin II signaling. Thus, ACE2 is inhibited, removing the brakes from the angiotensin II signaling and making more angiotensin II available to injure tissues. This decrease breaking likely contributes to the injury, especially in the lungs and in the heart and the G.I. tract. So some evidence suggests that ACE2 may be higher in patients with hypertension and diabetes and coronary heart disease. It all sort of makes sense as to why those are predisposed to more severe disease. And finally, through these pathways, vitamin D deficiency may contribute to the fibrosis of fibrotic lung damage. So here we go, Dr. Alagia, with another observational study between vitamin D and respiratory infections, the observational construct is described here. Dr. Hope-Simpson reported the inverse relationship between circulating levels of vitamin D and respiratory infections, particularly influenza, is very strong. This British study looks at just a larger group of respiratory infections. Now, there’s a key number on the left hand side to remember, which is a 7% reduction in risk of infection for each one nanograms per mL increase in 25-hydroxy vitamin D, so I’ going to to quiz you later on that number. Now, on the right hand side is a previous publication that we worked on with Dr. Michael Holick by University School of Medicine and some others. The blue curve is the seasonal pattern of vitamin D, consistent with all the other data that we’ve seen from the British study and the German study. But here we see that the trough is around 22, whereas the earlier data had troughs of 12 for the German study and about 16 to 18 for that British study. Now there’s a unit conversion factor there and then that green curve is the inverse of the vitamin D curve, and it reflects our intact parathyroid hormone because intact parathyroid hormone and vitamin D play opposite roles where they self-regulate. So, Dr. Kaufman, I want to pick up on this, so what you’re saying is, again, emphasize the trough has been elevated, but the peak has really gone as high as you can go. It’s kind of like your diastolic and your systolic blood pressure. The diastolic has gone up, yeah, but the systolic has stayed the same. In this case, it’s good that the diastolic has gone up because our baseline levels of vitamin D have improved. But can you just elaborate on that a little bit more? Explain why that’s happened? It’s unclear. So I asked Dr. Michael Holick about that and he suggested that, yeah, the supplements have been very beneficial in terms of lifting the trough, but without supplements we just can’t lift the peak much. So it’s moved up a little bit, but not a lot, which is why we still have so many people in this country who are deficient and suboptimal. Okay, and just a follow up point. I’m looking at some of the chat questions and you’re going to be bombarded with lots of questions about what kind of vitamin D, when we should take it, you know, should we measure the levels beforehand. So I’m just setting you up and just letting the audience know that, yes, I am looking at these, the chat questions and appreciate them and can’t wait to ask Dr. Kaufman these questions. So this is important. Thank you. Great. So the next thing we’ll see are some observational studies. Again, there’s an inverse on that next slide, we’ll see the inverse relationship between circulating levels of vitamin D in upper and lower respiratory infections. What is controversial and we’ll get into more later is if 25-hydroxy vitamin D levels are associated with allergies and asthma and it’s been associated with some studies have shown associations, others have been somewhat equivocal. One fascinating study found that 25-hydroxy vitamin D levels in mothers affected early childhood symptoms in their offspring. So there are some times where we really can blame our parents. So that dropping out, I mentioned earlier, this is one of my favorite slides because it talks, looks at a family and a child as an obstetrician, that’s what we do, and I want to make sure that, you know, my colleagues are aware of the potential impact that the vitamin D deficiency could have on the child in terms of asthma and allergies. Now, again, these studies are equivocal, but I think it’s important for us to keep an eye on this because, again, it’s the health and well-being of the baby that’s critically important to us, the obstetricians, as well as the health and well-being of the mother and the family, but we’re also focused on the baby. All right. Terrific. Yeah so, Dr. Alagia, you pointed out the obvious here that the image there is of a black family and there is some controversy as to what is the ideal level of vitamin D in black non-Hispanics versus white non-Hispanics. So blacks, non-Hispanics have lower levels of vitamin D, But interestingly enough, you would think they’d have lower bone mass as the opposite. Paradoxically, they have increased bone mass mass compared to white non-Hispanics. So Dr. Thadhani at Mass General a number of years back studied this, and what he discovered was that the vitamin D binding protein is lower in blacks. Most blacks carry a gene variant that’s linked to lower levels of this protein. So imbalance, he postulates that there’s a balance in the bioavailable levels of vitamin D that are similar between blacks and white non-Hispanics. There is no commercial assay for vitamin D receptor binding receptor. So that’s a research activity at this time, but there’s a lot that we’re going to still learn in the years ahead about these dynamics and about the influence of certain genes. Well, I know that Dr. McCollum would be, you know, singing and dancing, drinking and driving fast right now because we’re moving along very nicely. I, I appreciate that because I think it expands the dimensions of vitamin D that a lot of us don’t fully understand. So I appreciate this immensely. Please continue. Great. So I’m not a fan of the National Health and Nutrition Examination surveys nhanes because of the scant data that goes into the modeling. Nevertheless, when nhanes studies come out with something that I like, I’ll quote them, so in this case, I will. They found an inverse relationship between vitamin D and lung function, and an inverse relationship between vitamin D and infections, consistent with other studies. So that’s nice that we started getting more and more evidence in support of these relationships. So the missing link is randomized clinical trials, and as they pertain to influenza and seasonal respiratory infections, vitamin D really is a wonder drug that greatly reduces these infections among school age children. Supplementation, such as cod liver oil that my father took as a child, is also effective. You know, notwithstanding the valuable impact that had on you, you might want to do for other alternatives for children getting children to take cod liver oil may be a challenge. Yeah, over the counter supplements are much easier now so let yeah let’s turn Dr. Alagia, to the pandemic because that is the crux of this story. It’s one of the most interesting stories in this pandemic. So several studies have showed the strong relationship, and now remember, this is not causal. We’re showing statistical relationships, looking at data with, you know, we’re not quite at the randomized clinical trial. And these studies have looked at the relationship between vitamin D and SARS-CoV-2 and COVID-19. There’s been more than 50 published studies. The meta analysis supports the associations. The most well-covered story involved 489 patients, not a lot. It was published in JAMA, but it got a lot of coverage. The relative risk of testing positive for COVID-19 was 1.77 times higher, about 1.8 times higher, greater for patients with likely deficient vitamin D status compared to patients with likely sufficient values of vitamin D. And the authors concluded more study is needed. So indeed, others continued the study. And there’s several things here, but I’m going to just jump to the one on the right. It’s a really study of 7807 subjects, so the scale is moving up, and it confirms the initial findings. Now recognized in all of these studies, there are confounding variables. There’s influences of patients with diabetes and hypertension and heart disease and obesity, issues of race and ethnicity and other issues that may influence these observations. Next slide. Now a meta analysis of 16 studies strengthens the individual findings and suggests in eight of these studies of a linear inverse relationship between Vitamin D and SARS-CoV-2 or COVID-19. So again, just putting the studies together and these a meta analysis reinforces each of the individual studies and then we get to our study. It’s likely the largest study came from the Quest Diagnostics’ data that’s published in PLOS One with our coauthor, Dr. Michael Holick, and of Boston University School of Medicine, and unlike other studies that bucketed 25-hydroxy vitamin D into deficient and suboptimal and optimal, or even two buckets because of the scale of nearly 192,000 patients, we were able to look at that as less than 20, all the way up to greater than 60 and each value in between. Now what’s amazing is the phenomenal relationship, the correlation coefficient for those who are into those things was 0.96 - extraordinarily high. You can see that the linear curve with that relationship, so now to put this yeah. I’m sorry is so for people who have who are graphically impaired as I might sometimes be or for people who are driving their car and don’t have the chance to look at this graph, can you just explain what this you know, the x and y axis looks like, and what we’re supposed to take from this? And I realize these are causal or not causal connections, but they’re pretty impressive. So can you elaborate on this a little bit? Yeah. So on the y axis, we have the positivity rate for those tested for SARS-CoV-2 molecular test, nucleic acid amplification test. On the x axis are values of 25-hydroxy vitamin D. Generally speaking, values below 20 are considered deficient, values 20 to 29 are considered suboptimal, values 30 and higher are considered optimal. The Endocrine Society, and many experts suggest that 30 might be okay for bone health, but values are a bit higher in the forties, may be better as we think about other medical conditions. The other aspect to look at in all of those seasonal curves, there’s troughs in the winter and that one doesn’t want to stay in that trough too long, or at all. So you sort of got to compensate for that so that we want to really want to be ideally 30 and above in the winter and even higher in the summer. Okay, although all of your graphs are terrific, this is my favorite, you know, because I think it explains in one shot what we’re talking about. Terrific. Please continue. Yeah. So with the help of Justin Niles and others, we went ahead and looked at this data in lots of different ways. Patients in northern latitudes had higher risk for the same level of 25-hydroxy vitamin D, suggesting that there’s something different about being in northern latitude because, you know, for a value of 30, an integrated panel of vitamin D, one might think that the risk of SARS-CoV-2 would be identical to those in the central and southern latitudes, but it’s not, so there’s something different. And recall early on that was New York, New Jersey, New England that got hit heavy and those were northern latitudes, so that may be one factor. On the right hand side, we looked at black non-Hispanics and Hispanics and white non-Hispanics. If you can see the three curves the relationship holds for each of these. And what we did is for each result, match the zip code with the US census data. It’s all de-identified, massively aggregated, but there’s clearly three separate curves suggesting that there’s other factors beyond 25-hydroxy vitamin D that accounts for why these three curves are different and not on top of each other. And then finally, we looked at age and sex. We looked at patients who were under 60 and 60 and above, they’re a bit closer, but there’s clearly a separation there. We looked at male versus female. Again, the curves are very close and the relationship holds for all of them. And then finally we looked at the data and we adjusted the model and it created an adjusted odds ratio. So in the adjusted model, we compensate for all the other factors except for the ones that we want to focus on. So if we look at male versus female, using female as a reference, males were 1.24 times likelihood to have SARS-CoV-2 for the same level of vitamin D. Now, the key number here on this slide though, is the one above that, which is the 0.984. So one minus .984 is 016, otherwise known as 1.6%. So for every 1.6% reduction in vitamin D, sorry, let me do it the other way around. For every nanogram per mL decrease in vitamin D, there’s a 6.4%. Sorry, let me get the numbers straight again. There’s a 1.6% increase in SARS-CoV-2 positivity, so let’s multiply the numerator and denominator by four, which gets us to 6.4%. Inverse relationship for each, for each for nanogram per mL of vitamin D, and that old study that I asked you to remember earlier, it was 7% - very close suggesting that these relationships are consistent. And then finally, let me share some more recent studies. One study showed the relationship between 25-hydroxy vitamin D and mortality. Dr. Michael Holick, again, was an author in this study. Only 9.7% of patients older than 40 who were vitamin D sufficient succumb to the infection, compared to 20% who had circulating levels of 25-hydroxy vitamin D that were less than 30. So of note, the editors raised concern about this study, but there’s a basically a twofold difference based on the vitamin D levels. There was a piece in JAMA recently that summarized other recent studies. One of them was a French study reported the 14 day mortality of 77 elderly patients. The mean age was 88, not a large number of patients, but the data is compelling. They compared patients who were regularly supplementing with vitamin D in the preceding 12 months compared to those who started supplementation after their COVID-19 diagnosis. And then there’s patients who didn’t take vitamin D at all. The long term supplementers had a 93% survival rate. So remember that, 93%, compared to 82% survival rate in those who only more recently started supplementing. And that was compared to 69% survival rate for the group that didn’t take any vitamin D. So the study reported 93% reduction associated, a 93% reduced risk for those who were regularly supplementing with vitamin D. So in other words, the no supplementation group was associated with a 14 times risk of death compared to those who are regularly supplementing with vitamin D. Very small study, but extraordinarily impactful. Randomized clinical trials continue to be the gold standard, and there’s one pilot randomized clinical trial that looked at the rate of ICU admissions and death of 76 patients. Now, again, a very small number. These were 76 patients with and without in-hospital vitamin D supplementation. In a reported 98% of the treatment group did not get admitted to the ICU versus 50% admission in the untreated group of which 15% - two patients - later died. So compelling, but we need larger studies. And until then, we just pile up these stories, the evidence of the role of vitamin D in SARS-CoV-2 in COVID-19. So Dr. Kaufman, I’ll just just summarize - it looks like more vitamin D is better. Or, having a sufficiently high vitamin D levels above 40, have at least a temporal relationship to improved health care. The other thing I want to point out is that, you know, we’re moving along very nicely, but I want to make sure we have time for the questions because we’ve got a lot of questions from our audience. So not I don’t want to skip through anything but just maybe kind of attenuate some of these decks. Absolutely. So let me let’s roll around a little faster. So there are associations with vitamin D in other health conditions, the relationship between vitamin D levels and numerous medical conditions could fill shelves and many webinars. Many of them are compelling, some of them less so. In each study, they vary. There’s limitations in each of these studies, and while there’s no compelling evidence of causation or that rectification of deficiency affects disease development or progression, there’s a lot of studies ongoing. And then there’s studies on cancer are extremely interesting, and if we find that we can prevent many cancers with a simple with the sunshine vitamin, that would be amazing. One study in 2006, using data on over 4 million cancer patients from 13 different countries showed a marked difference in cancer risk for a number of different cancers between countries classified based on whether they were sunny, or not sunny. Now, many studies are underway, but the most important one is the vital studies, the vitamin D and Omega-3 trial. It’s a randomized clinical trial that’s organized through the Brigham and Women’s Hospital in Boston. It’s an ongoing research study of about 26,000 men and women across the United States. And whether or not taking vitamin D supplements, it’s 2000 IUs per day or Omega-3 and OmegaQuants one gram per day reduces the risk for developing cancers, heart disease and stroke in people who do not have a prior history of those conditions. So in the trial, there were 793 cancers occurring in the patients assigned to the vitamin D arm, compared to 824 cancers. Among the participants to the vitamin D placebo. So it’s a small but not significant reduction. Supplementation of vitamin D also did not reduce the occurrence of breast, prostate or colorectal cancer. However, there was a suggestive 17% reduction in cancer deaths, which came 25% in the analysis that excluded the first two years of follow up when patients may have had preexisting cancers. And although vitamin D didn’t significantly lower the risk of developing cancer in the total population, the black non-Hispanics assigned to the vitamin D did experience a 23% reduction in cancer risk. So again, further research is needed to confirm these findings. So let’s close with some recommendation and you raised that is some of the questions that our audience has. The Endocrine Society is the main source of guidelines. The lead author, again, was Dr. Michael Holick. There’s a large proportion of Americans who fulfill these criteria if they go primarily to the right hand side. There’s African-Americans and Hispanics. There’s women who are pregnant or lactating. There’s older adults who in the history of falls, there’s obesity. So it covers a lot of people, unfortunately. And then the next slide, the authors clearly express concern about nonskeletal benefits of vitamin D and reaching these levels will be difficult with food alone. So therefore supplements with everyone may be necessary to achieve levels of not only 30 but potentially even 40. Throughout this webinar, there have been a number of superscripts which refer to references. Those are available upon request and now I turn the mic back to you. Dr. Alagia. Okay, terrific. I think. Dr. McCollum would be impressed and Dr. Hope-Simpson would be happy and vice versa. So thank you very much, we’ve covered a lot. It looks like vitamin D is good for bone health, for baby health, respiratory health, immune health, general health and well-being. So let’s get to some questions. So just to be fair to the audience, when it comes to, you know, questions involving, you know, payment and insurance and things like that, I’d like to defer those to maybe questions afterwards because we want to keep this on a clinical level right now. Those coverage questions are important. Okay. So well, these are these are some pretty interesting questions here. So the reference ranges are on the last slide, you will be able to see the reference at the end of the webinar and record the webinar. Yes. The answer is let’s see, shouldn’t we see a seasonal variation in COVID infection corresponding with vitamin D levels? Are there too many confounding factors to tease that out? This is from B.R. Yeah, one would think that SARS-CoV-2 would show that pattern. Unfortunately, because of the transmissibility of the virus and how it sort of exploded, we’re clearly not seeing that pattern. An interesting curlat of that is what’s happening to influenza this season, and the reality is it’s either gone, or extraordinarily low. So looking at the CDC weekly reports, there’s approximately 30 or 40 cases reported each week. I suspect some of those might be false positives, maybe all of them, because the reality is they’re sort of scattered. There’s no transmission of influenza, it seems, in any particular geography, which is atypical. If there’s clusters, one would sort of see, you know, explosions in certain geographies. And we don’t see any of that. Looking at the Quest Diagnostics’ data, we see a very similar pattern of just rare cases showing up in one state, another state on a sort of weekly basis. It will be interesting to see what happens next year, next winter, particularly for influenza, whether or not we’ll see a full season or a somewhat attenuated season. Okay, terrific. And that’s the question from Z.S. - very practical question. What levels of vitamin D are considered to be protective? It’s unclear. So the focus of the Institute of Medicine and others has been on bone health. And so the focus is values less than 20 are considered deficient, 20 to 29 are suboptimal, 30 and above is considered optimal. The Endocrine Society suggests that for these other bone non bone conditions, values in the forties may be better. But it’s unclear. If you look at some of the cancer studies, you end up with different estimates, but again, they’re typically more in the forties than they are at a cutoff of 30. Okay, Terrific. Question from K.B., has anyone studied the vitamin D levels in the black and Hispanic community and how it relates to higher levels of COVID-19 in these communities? Yeah. So there was a slide where we looked at the relationship of SARS-CoV-2 positivity with vitamin D levels, and we separated out the individuals who were in predominantly black non Hispanic zip codes, so they have higher values, and there is that relationship. There have been some other studies that have looked at confounding variables that impact the black community, such as diabetes and obesity and the employment types that are more common in those communities as well as the population density. Now, we also have to be careful that as much as we’re stereotyping and it applies to the general population, it doesn’t apply to each person on an individual basis. Okay, terrific. And I’ve gotten this question a number of times, the studies and the science for the studies, we’re going to be able to provide a bibliography at the end of this for everyone, correct? Yes. Okay. Let’s see. It says in a week - this is from our technical people - in a week to ten days, the recording of the webinar will be sent to everyone who is registered. I’ve gotten a lot of questions about the PowerPoint slides. Should you avoid supplementing vitamin D before obtaining a vitamin D test? Probably not going to have much of an impact ... If one is deficient, one’s likely to be deficient and it will take a while to sort of get back to an optimal range so it can take anywhere from months to quarters. So I referred to earlier that I have celiac disease and my vitamin D was a bit low initially. I also had my PTH measured. Even after my vitamin D returned to a optimal range, my PTH was still elevated and it took a year and a half to really bring my PTH into the reference range, so there’s lags. Okay. So two general questions. This is from R.A. Number one, I understand vitamin D deficiency as a level below 30. Is there any optimal level of vitamin D we should be shooting for in our patients as opposed to the minimum level? And two also, are there any downsides for oral supplements with these three as opposed to sunlight? I mean, sunlight’s natural and it’s great. The downside of sunlight is the impact on our skin. So it does increase wrinkling, and more seriously, it does impact our cancer. So we do want to avoid cancer, skin cancer, so if one were to get the vitamin D through sunshine, it’s in moderation. The supplements for most of us, it’s sort of easier to take and more consistent than our sun exposure. Now, for some people who are more active in the summertime, that’s great. Be outdoors and then more indoors in the wintertime. So one can think about maybe supplementing for half of the year and not the other half of the year. There’s people who migrate, snowbirds to the south for the summer. So you have to consider all those things. And then the question of of the optimal value I get I said it a couple of times, which is although 30 is the optimal value, we got to think about that as you know, year round, not just in the summertime, that those in the winter time when our trough, we got to try to boost that level up. But there’s experts who suggest that those in the forties might be better for the non bone related health conditions. Okay, great. I’m conscious of the play clock here. We have about 3 minutes left and I’ve got a few great questions here. This is a question from San Diego. Many patients in San Diego are vitamin D deficient. You’d expect them to have the right type of sunlight, correct? Why might that be the case? There’s a host of factors. One is whether it’s one has is black, non-Hispanic or Hispanic or obese, or has a history of all those things. Also recognize older people synthesize vitamin D at a much lower rate than younger folks. So older folks produce vitamin D at about 25% of a individual in their twenties. That’s one of the side effects of aging. So there’s a lot of factors that play into that, as well as diet and the amount of sunshine we are exposed to. Okay, so this is an I’m going to stump the expert questions from a valued client. If I’m not mistaken. Dr. Michael Holick has suggested that clinicians can forgo testing patients in vitamin D levels and simply advise an empiric supplementation of 4000 international units per day without fear of toxicity. Would you agree with that suggestion? And also, you know, in addition to answering this question, I want you just briefly to talk about toxic vitamin D toxicity, and is that a concern here? Yeah. So Dr. Michael Holick is clearly a strong advocate for vitamin D supplementation. I take a more cautious view which is establish what the baseline is first. For those who are deficient, one basically needs to start with a booster dose to sort of get more quickly to an optimal value. Those who are already at a good level can take a lower dose and just maintain that dose, so establishing a baseline and periodically retesting whether it’s every year or less frequently, but just understanding where one is seems to be important. And then on that side, on the side of toxicity, when we looked at the Quest Diagnostics’ data and particularly the employer data, where we have a wellness program that we offer to hundreds of employers throughout the country, the only individuals who had very high levels, over 150, were all taking supplements. So I sort of caution taking the, you know, 10,000 units a day seems high, particularly if you’re not in that deficient category. So one can get there, but it’s rare and you got to work to get there. All right. We’re at the top of the hour now. Absolutely. Great presentation, Dr. Kaufman. We had hundreds of patients on here and hundreds and hundreds of questions. I want to thank everyone for your time today. Everyone stays incredibly well engaged. Thank you for your history lessons and thank you, really, everyone for participating. If you registered with the Zoom webinar, you’ll receive an email in about a week with a link on the online survey, please complete the survey, we appreciate your feedback. If you register on behalf of a group of colleagues, please forward the survey link to them and they will receive it. Again, thank you everyone for allowing us to share what I believe is the best of Quest with you all and have a wonderful day and we hope to see you at our next webinar. Thanks again, everyone. Thank you.