Lecture 46

Graham.com welcome to another covid-19 Med cram update us continues to top the charts in terms of infections.

If you go to world ometer and sort by deaths per 1 million population, you can still see that the highest concentration of deaths are occurring in Italy at this point in terms of new cases. USA is still leading in the United States New York and New Jersey lead and California is a distant third and of course in New York, and now in California, we’re starting to have issues regarding saturation of healthcare Delivery Systems.

Okay, let’s discuss exactly what’s going on right now with covid-19. What we have here are three different populations. We have the entire population as a whole and we have those that are going to be infected and we have those that are going to need hospitalization and you may have noticed that the situation that we’re having right now in New York, especially also in other parts of the country is that this population of people who need hospitalization is not able to get

get into our tunnel here, which is in fact the hospital and because of that we’re having issues with shortages of ventilators of ICU beds Etc. And so right now all of the work is going into trying to increase the capacity of the hospital system to allow this type of bolus of patients if you will to get through and to be treated effectively now, of course, these graphs are not drawn to scale remember that there’s only a certain amount of the

Population that will become infected and the weights are reduced that even more is with isolation, but there’s a certain percentage of those people that become infected that will need to go to the hospital and as it stands according to the data that we have right now. That’s about 20%

Which means that 80% of the people that get the infection won’t need to go to the hospital and that is almost totally related to that patient’s immune system.

So the immune system is rather complicated and that’s why I want to talk about a little bit imagine your immune system is like this country’s Armed Forces. You have the Army the Navy the Marines the Air Force they all have specific functions, but they all work together to protect the organism to protect the country. Let’s face it. There are a lot of threats that can happen to a human being but in this case The tsar’s Cove to virus affects the human body in a very specific way. And so if we can learn

What part of the immune system is being diminished then we can learn potentially how to fight this virus effectively and reduce the number of people that might need to have hospitalizations.

So enter this article where they actually look at the immune responses to not only this coronavirus but the tsar’s cuff one and the MERS Coronavirus that was there previously. So this article was published in the Asian Pacific Journal of Allergy and Immunology immune responses in covid-19 and potential vaccines Lessons Learned From SARS and MERS. So let’s take a look and see what they found. They do a comparison in the number of cases between those three vital.

infections

they also break down the demographics.

And they show the issues here with the tsar’s Cove to the current viral infection in terms of the immune players that we were just talking about and the thing that they bring up in this article, which is very interesting is this first point here, which is delayed or suppress type 1 interferon response during the initial infection.

In fact in the article, they say here to mount an antiviral response innate immune cells need to recognize the invasion of the virus Often by pathogen Associated molecular patterns. So remember what the innate immune response is, it is those cells that do not require a little piece of the virus to be presented to them. And so these are not T cells and B cells that are making antibodies but rather in eight cells, so these would be like macrophages monocytes natural.

Sells this would be like the air force of the armed services and the things that activate them in this case are these PA MPS or these molecular patterns that are associated with pathogens in this case for the coronavirus. It would be viral genomic RNA they go on to say here that for SARS coven MERS cuff the response to viral infection by type 1 interferon is suppressed. Both coronavirus has employ multiple strategies to interfere with the signaling.

Leading to a type 1 interferon production watch what else they say here with similar changes in total neutrophils and lymphocytes during covid-19 SARS Cove to probably induces a delayed type 1 interferon and loss of viral control in an early phase of the infection. What they’re saying here is that the virus is able to down regulate your immune system in the early phase of the infection. And this may be the reason why most people with this infection are initially a symptomatic until the very

And when there’s a storm of cytokines in addition no severe cases were reported in young children when innate immune response is highly effective. This may explain why young children aren’t getting the disease as severely these facts strongly indicate that innate immune response is a critical factor for disease outcome analysis of tumors coven infected individuals with different severity found that the type 1 interferon response in the poor outcome patient, which

Died was remarkably lower than the recovered patients. So if we go back to our picture again, we see here that those patients that are ending up in the hospital are about twenty percent of those that actually get the infection. And the reason why we may want to say is that there is a decrease in the innate immunity. That is the specific problem with this virus.

And this seems to Bear out in a recent publication in nature medicine where they looked at immune responses and cells in a patient that had non-severe covid-19. In fact this patient never needed to go to the hospital and he recovered quite well, of course, we’ll link to this and the previous article in the description below. But what they did look at here was the amount of virus the symptoms the chest x-ray and then even more importantly for

Our evaluation these monocytes and natural killer cells. So here we have monocytes and natural killer cells and if you look at this triangle here, you can see where the patient’s monocytes were in relation to where they should be in a normal healthy patient the monocytes which are part of the innate immune system were much lower than they should have been even though this patient only had mild disease reaffirming that it’s the innate immune response that seems to be suppressed in

in these covid-19 patients and even more so it seems monocytes and natural killer cells seem to be the target. So the question is is what is it that we can do to increase the number of monocytes and perhaps gamma-interferon to elevate that early in the course of this disease and we’ve talked before about not treating a viral fever because we know that Viral fevers are involved with the immune response as well, but I’ve gotten some

Interesting comments wondering if a patient with coronavirus doesn’t have a fever would inducing a fever improve the outcome and the immune response. So knowing what we know already about what’s going on in covid-19 in terms of depressed monocytes made this German publication back in 2002 even more interesting and here are the authors Zellner at all says that thermal effect of fever has been associated with better survival and a shorter duration of the Z’s.

He’s in cases of infection and what they wanted to do was to understand better. What happened if they subjected 12 healthy Volunteers in a 39 .5 degrees Centigrade hot water bath to increase their body temperature and see what would happen to the expression of monocytes and tumor necrosis Factor Alpha, which is a cytokine that it releases and they looked at this both in vitro and in Vivo in humans that were actually put into a hot water bath and what he found was that

The in vitro data showed that definitely there was an increase in the amount of sites. They say here that the expression of the endotoxin receptor cd14 and the complement receptor CD 11 be increased After hot water bath furthermore when they looked at the healthy subjects after they were put into the hot water bath. They said here after three hours the response of monocytes to endotoxin was enhanced in an ex Vivo lippo polysaccharides.

Emulation assay, which is basically a stimulant from a bacteria that might have infected a human body when they stimulated the immune system. They noticed that there was greater tnf-alpha release which was statistically significant. So they conclude that the thermal effect of fever directly activated monocytes, the very cells interestingly that are deficient in covid-19 and that increased their ability to respond to in this case a bacterial challenge, but I’m sure they would be equally as responsive to a viral challenge as

Well, but this isn’t the only study that shows this there was a interesting article that was published around 2000 titled immune changes in humans during cold exposure effects of Prior Heating and exercise. They took subjects and they had them sit in a warm bath among other things and then they expose them to cold to see whether or not that would also improve immunity.

And you can see here for the seven subjects in the white boxes sitting in a 38 degrees Centigrade water bath increase their Core Body rectal temperature. And then after they were exposed to cold there was a drop in the core body temperature.

And here when we see the data in this second set of bar graphs, which are the ones where they sat in 38 degrees Centigrade water. You can see here for leukocytes, which are all of the white blood cells that there was a significant increase in the number of white blood cells care also for the granulocytes increase as well for the lymphocytes. There was an increase and also for the monocytes there was an increased remember the monocytes is the part of the innate immune system that’s deficient were finding out in covid-19.

What they concluded in this report despite popular beliefs that cold exposure can precipitate a viral infection. The innate component of the immune system is not adversely affected by a brief period of cold exposure. This is exactly the part of the immune system that we’re talking about with covid-19. They say indeed the opposite seems to be the case the Fallen core body temperature resulting from cold exposure led to a consistent and statistically significant mobilization of circulating cells.

Increase in NK cell activity natural killer and elevations and circulating il-6 concentrations moreover in agreement with one of our hypotheses prior exercise with a thermal clamp significantly augmented the leucocyte granulocyte and monocyte response to cold exposure prior passive Heating and exercise without a thermal clamp also tended to augment the effect of cold exposure alone. But because of the small sample size and enter subject variability these changes

Were not statistically significant so interestingly what they’re finding here is that yes heat can improve the immune system like we’ve seen before but then subjecting them to cold which goes against popular belief can actually enhance the immune system, especially the innate immune system, which I find very interesting because that’s the portion that’s affected in covid-19.

So all of this talk about being hot and then cold reminded me of the Finnish saunas that are so famous in that part of the world and actually in most of the Nordic countries, but not to the degree that we see in Finland. So here’s a study that looked at a single Finnish sauna session on white blood cell profile and cortisol levels in athletes and non-athletes and in this study. They only looked at nine people which is kind of a low number so we might not be able to see statistical.

But let’s see what they found.

So for those of you who don’t know what a Finnish sauna is, it’s quite extreme the Sonic can go upwards of 200 degrees Fahrenheit, which is very close to the boiling point of water during the sauna session. The human body is alternatively exposed to hot and cold stimuli hot air in the sauna room affects the skin and the respiratory system. This leads to a rise in body core temperature up to as high as 39 degrees Centigrade while the skin temperature might be as high as 42 degrees.

And then after this is done, there is a fast cool down and then they go back into the sauna to heat up once again, so what happened to the white blood cells in this situation?

They found here that there was a statistically significant increase in the number of white blood cells particularly more noticeable in the athletes than in the non-athletes. Some of these were statistically significant and some of them were not possibly related to the low number of subjects in this study. They found here that a significant increase in monocyte count was accompanied by a significant increase in the number of neutrophils and eosinophils only in the athletes, which could have been caused by a reduced cortisol secretion compared to the untreated.

In subjects remember, this is only after one session in the sauna.

So let’s take some stock about what’s going on. We’ve got the infection that occurs here at this point in time. And then we have at this point in time. Some of those about 20% will end up in the hospital with pneumonia secondary to cytokine storm as it has been often called. Why is it that people are asymptomatic early on and it may be that the immune system is being suppressed. Well if we inflame the immune system if we increase the immune system with thermal regulation and hyper

Hermia, is it possible that we could actually precipitate as storm situation and get the patients in the hospital sooner without actually helping out the patient’s well, that’s a good question and it’s a possibility and that’s why I found this publication. So interesting they talk about this interleukin il-6, which has been implicated in the cytokine storm that patients with pneumonia gets when they had covid-19.

The papers long but I found this paragraph very enlightening. Although febrile temperatures initially increase the production of pro-inflammatory cytokines by macrophages at sites of inflammation. There is also evidence that thermal stress dampens cytokine synthesis. Once macrophages have become activated this sequence of events is analogous to a natural fever which often occurs after macrophages and other and Nate’s immune.

initially encounter PA MPS, remember PA and peas from that first article that we looked at in this regard human monocyte derive macrophages produce less tnf less il-6 and less il-1 beta when exposed to febrile temperatures than heat and experience cells heat reduces transcription of pro-inflammatory cytokines and also lower cytokine mRNA stability thermal treatment of LPS a

Activated macrophages also appears to dial down inflammation. So what they’re showing here is that fever can actually reduce the cytokine storm and improve the innate immune system. Now, they actually have a model of this with mice who have arthritis collagen induced arthritis when they expose the mice to Fever range hyperthermia, they had significantly less joint damage. So they say that collectively these findings suggest that

Temperature shifts contribute to a biochemical negative feedback loop that actually protects the tissues against damage from excessive cytokine release following infection interesting. So in this period of time between when you have infection documented and hospitalization, if there were to be a higher temperature, it could improve the immune system which seems to be hamstrung already and it would reduce the cytokine storm.

Potentially that’s leading to pneumonia requiring hospitalization. Okay. So up to this point we’ve looked at real people. We’ve looked at cells though as surrogates for a good immune system against viruses. Let’s actually put it to the test. And here we have a article asking that very question does regular sauna bathing reduce the incidence of common colds. They took 50 people that had never been in a sauna before this was an Austrian study.

25 of them stayed out of the sauna and they were used as controls the other 25 had sauna bathing to see if they could reduce the incidence of common colds and what they found was this in the six months time that both groups were recording how many common colds they got there was significantly fewer episodes of common cold in the sauna group. This was found particularly during the last three months of the study period when the incidence was roughly cut in half compared to controls and so they concluded

did that regular sauna bathing probably reduces the incidence of common colds, but they felt that further studies were needed to prove this and you always need further studies to make sure that what you’re looking at is real here in an editorial. Dr. Ernst who was the one responsible for publishing this sauna Austrian study says here nevertheless. It seems unwise to Advocate sauna indiscriminately. Thus whenever in doubt a medical check-up is mandatory once this is done.

And it can be fun and relaxing. So we take dr. Ernst statement at its face value. But the question is a deeper one does this Keats and then cold help prevents and treats coronavirus 19. Of course, the answer to that question is we don’t know at this point because there hasn’t been a randomized controlled trial looking at that specifically, but then again there hasn’t been a randomized placebo-controlled trial in anything that we’re using for covid-19 at this point.

I know this is a long video, but I needed to get some more in here because it’s just so interesting. So this was a paper that was published back in 2016 by the Salk Institute and very interesting review of all of the data that was pertinent to their study that looked at this idea of hyperthermia and hypothermia. This initial proposal made by Kluger in the 1970s only considered the fever response beneficial for host defenses. However, we suggest that both

Fever and hypothermic responses are strategies of the host to optimize host defenses during infection indeed. There is evidence to suggest that both fever and hypothermic responses are beneficial for the host in the context of an array of diseases. So the more I thought about this the more I started to think about the Finnish sauna here is a population of people that use the sauna extensively.

So here you have the Scandinavian countries of Denmark Norway and Sweden. Finland is technically not a Scandinavian country, but they’re all considered Nordic countries. And so they’re all about in the same place. But while the fins extensively use saunas on a regular basis, maybe even two to three times a week not so much. So in Sweden and Norway and Denmark, although they are used to some extent there’s about 5.5 million people in Finland, and there is estimated to be about

Million saunas, so I got this idea to look up some of these Nordic countries on will domitor realizing of course that even though they’re very similar in nature. There could be some confounding variables that make them difference. But if this kind of hot and cold that is being experienced if this could help the innate immune system, and if in fact it’s the innate immune system that is deficient in a covid-19 case then we would expect to see some sort of improvement if it was worthwhile.

I’ll so let’s look at some of the numbers.

And so again this type of a study really doesn’t prove anything. It can be affected by when the virus started in each of these respective countries and where they are along the process, but it’s going to be interesting to see what happens. So what I decided to do was take the different countries, so Denmark Norway Sweden and Finland and I put here approximately the population of each of these countries. So Denmark being 5.6 million and so you can pull these numbers right off of world Dominator. What about total?

So this is an interesting question because perhaps if the immune system is Amplified with the sauna and the cold bathing, maybe it won’t prevent you from getting the infection, but it might prevent you from going towards cytokine storm and getting an ammonia. So we might see a difference in the total deaths. Let’s take a look and in Finland 11 interesting. What about total deaths per million? What about new deaths for today?

It’s going to be interesting to keep track of this data as things go on. There is another culture that also likes to have very hot baths and then cool down afterwards. And that is the Japanese and in looking at their numbers. They’re not doing too badly again could be confounders, but we need to look at this from the microscopic level and the macroscopic level as well.

Switching gears I wanted to also talk to you about a new publication that just come online regarding hydroxychloroquine. And this is by the same author that published the study that showed that the combination of is the throw my sin and hydroxychloroquine was effective. There was some criticism at the low number of patients in that group. Well now he’s updated his results with 80 patients and basically the results are very similar.

In conclusion, we confirm the efficacy of hydroxychloroquine associated with a zither myosin in the treatment of covid-19 and its potential Effectiveness in the early impairment of contagiousness given the Urgent therapeutic need to manage this disease with effective and safe drugs and given the negligible cost of both hydroxychloroquine and azithromycin. We believe that other teams should urgently evaluate this therapeutic strategy both to avoid the spread of the disease and to treat patients before the severe.

Irreversible respiratory complications take hold. You can see here. That black bar is the number of patients tested and the tan bar here is the number of patients with a CT value of less than 34. So the number of cycles that you have to do with reverse transcriptase PCR to actually get a signal. So what you really want here is a high number that means that the RNA is undetectable. And so when you have a less than 34

Is a bad thing and you want the number of patients with that to go down and that’s exactly what you’re seeing here is it’s going down and in fact it reaches zero around day 11 or so, and then you can easily see that with this green bar, which is the percentage of patients with a CT value of less than 34 and you can see that that’s a good outcome there a lot of stuff today more to follow tomorrow. Thanks for joining us.

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