COVID-19 | Clinical Medicine

What's up, ninja nerds? In this video today, we're going to be talking about COVID 19 again as a part of our clinical medicine series. And if you guys are really enjoying them, hit the like button, comment down in the comment section, subscribe. You know the deal. If you want to see more, we offer more on our website. Go down the description box below. There's a link to our website. You can access things like notes, illustrations, quizzes. Lots to go and check out there. All right, let's talk about CO 19. So, uh, probably last time we talked about this was probably 2021. It's been a while. It's been a while since we talked about CO 19. This is going to be kind of like a little bit of an update, but it's going to again focus on the same style of the lectures that we kind of go through. So, big thing here, eeology of

COVID 19. You guys should know this. It's the SARS KV2 virus. Now, when we talk about SARS KV2, one of the interesting components about this is the genome. So, what is it actually inside of this? So, this is there's an envelope, right? So that's one of the interesting things about this virus is it has an envelope. And what does an envelope mean? All that means is it has a lipid billayer that makes it up. Inside of that envelope is a very important genome. And that genome is it's actually containing something called viral RNA. Right? So it's not a DNA virus. It's an RNA virus. But the important thing about that RNA is it's single stranded. Now we talk about singlestranded. There's negative sense like we talked about with which one? Influenza. What do you think this one is? It's positive sense. So it's positive sense singlestranded RNA virus. Now influenza had a enzyme in it. It had the RNA dependent um kind of RNA polymerase. This one doesn't have it. It actually is interesting where it's incorporated into the gene. So whenever this gets into the cell, it's going to use that gene to make that protein. And it's actually a critical component, especially when we talk about it in the pharmarmacology aspect of this. What's really important to the SARS KV2 virus structure is these proteins that are on the surface. There's a lot of them. I'm going to mention the less significant ones. So, we're going to skip this one, but we're going to go to the other ones. And I want you to remember those just mildly ones. This is going to be we're going to remember it via the pneummonic men. All right, men. And this is going to be you have membrane, right? So, you're gonna have the membrane surface glyoproteins. It's just critical to maintaining the structure of the virus. E is an envelope protein. This is important because the envelope protein can kind of act as an ion channel. N is a nucleio capsid. So, it's helping to be able to protect the RNA and kind of stabilize its overall structure. But the most important one and you can kind of base it by the look of it. This looks like a little I don't know like some kind of fish hook of some sort. This is called the spike protein. So this one is extremely critical. It is the most important one and we'll talk about why in a second. This spike protein is really the primary component of the virus that allows for it to attach to our host cells. So whenever this virus gets spewed into somebody's respiratory tract, it needs this protein to bind onto the host cells and we'll talk about how it does that in a little bit. Now that's the big thing I want you to know about the overall just virus name and structure. The primary virus that causes CO 19 is the SARS KV2. It's an envelope virus viral RNA which is inside of that and it has a bunch of different proteins but the most important one which I want you guys to remember is going to be the spike protein. This is the most critical and the reason why it's the most critical is because it attaches to the ACE2 and on top of that we're going to talk about things like antibodies which we give in vaccines that are going to target that one. All right. One of the things that's happened over the years since co 19 is you come up with variants. There's a bunch of different types of variants and we call them VOCC's or variants of concern. A couple of them is we started off with the alpha. All right. So we had alpha then we had beta and I'd say the primary two predominant ones that we've gotten to nowadays is delta and omacron. So these are going to be the two ones that nowadays we pretty much see these as the primary ones. This was probably the worst one, the original one. And then now we've gotten to these two which thankfully they have the lowest overall kind of like true mortality but we'll differentiate between these two in a second. So we start out with alpha then beta then delta then omocrron. How does this happen? It's not that complicated. What did I say was the most important protein the spike protein. What happens is here is the co 19 the sars kovv2 virus. So here is the viral RNA. In this viral RNA, it has different sequences that can code for particular proteins. Let's just pretend for a second that here is that sequence. And this is going to code for the spike protein. So what's going to happen is it's going to code for a very specific spike protein. We'll represent that spike protein right here. Here's the S, right? And that's going to then do what? It's going to be the primary protein that we talk about on the surface of the SARS KB2 virus. So what's going to happen is this will be incorporated into this virus. So now what we'll do is we'll represent this on the virus. This is our CO 19 or SARS KV2 virus. Now this is the spike protein. What happens is that this spike protein undergoes little changes. So what happens is let's say that this is the gene that's coding for that particular spike protein. And over time we have small little mutations. And now if I have a mutation, let's pretend here for a second that this gene under goes a small little change. I'm going to change it. I'm going to add in there's a small little mutation. Right? So here we undergo some small little mutation in the gene sequence. Now because of that we change a little bit of the spike protein structure. If we change the spike protein structure just a little bit, what's the problem with that? Well, the virus gained the ability to have two benefits of that. One is maybe it improved the ability to bind onto and get into epithelial cells. So, in other words, it increased its pathogenicity. So, maybe it became more pathogenic, meaning it can actually get into the cell. It can cause more damage. And so it gained it's had an increased ability to damage host cells. So maybe increase pathogenicity. Let's say pathogenicity. That's one component. Maybe it gain the ability for that spike protein to be able to bind on to this particular receptor which we'll talk about on the epithelial cell. Do you guys know what that receptor is? Just if I give you guys an information about this. This is going to be for right now I'll tell you it. It's called the ACE2 protein. What is this one called? It's called the ACE 2 protein. That is how the virus, the spike protein, binds to the epithelial cell. It needs the A2. Technically, what also happens is it needs a priming component here called the TM PRS S2, right? And that structure is what helps to prime the virus to get into the cell. What's happened over time is that this virus has gained the ability to maybe avoid priming mechanisms or improve its ability to get taken into this epithelial cell. So that's one downside here is that maybe over time especially something like omocron omccron it doesn't need that it doesn't need the priming it can use endoccytosis bind to the A2 and get taken up. Another problem with small mutations in the spike protein is that you generally have plasma cells and these plasma cells are supposed to produce antibodies and these antibodies are supposed to be generated based upon their exposure to maybe an alpha beta whatever it may be. They were exposed to a different type of spike protein. You undergo a mutation in that. That mutation may not allow that antibbody to bind to the spike protein and have the same immune response. And so the benefit of having the small mutation is that now when the spike protein tries to go, let's actually put it here. When it tries to go and do what? Bind onto these, it may not have that ability to bind as well. And so because of that, if this interaction doesn't occur as well, what does that lead to? It leads to an increased evasiveness evasiveness. And I think that is the biggest thing that we see as a result is that there's a increased pathogenicity we would may say and an ability to evade our immune responses because of these small mutations that occur within the actual gene sequence that leads to small changes in the spike protein that now antibodies in our host cells allow the virus to get taken up or they don't actually u they're not as susceptible to actually being attacked by our immune system. So why is that important? Well, since delta and omccron are the big ones. Now delta we associate this one as compared to omccron. Delta is believed to have more risk of pathogenicity and it has more of a predilction for particular respiratory epithelium. Same thing for omccron. This one has gained the ability to be more evasive and has a predilction for specific parts of the respiratory tract. Let me explain. So we compare this Delta versus omocrron which are the big ones that we really want to be able to know. Now Delta has increased pathogenicity. So it may cause more severe disease. Even though it's nowhere near as severe as alpha, it still can cause more severe disease than omccrron. Omron has less of that pathogenicity, but it's able to be more evasive. It's less pathogenic though. And so we're going to say that this one has increased pathogenicity. So, it gains the ability to do what? It allows for this one to potentially cause more damage. And this one has more evasiveness. And we could also just say in general, it's less pathogenic. All right, let's actually do that instead. Omron, we're I want you guys to actually remember that more specifically. Omron is actually going to be less pathogenic. All right, so it has decreased pathogenicity. The other component is the predilction. So which tissues of the respiratory tract do we see more damage from these two? The delta affects more of the lower respiratory tract, right? And so because of that, you'll see things like pneumonia more often because of that one. This one affects more of the upper respiratory tract. So because of that, you see things like upper respiratory tract infections. So that is the big difference here. Delta more lower respiratory tract predilction and then omocron more upper respiratory tract predilction. So again taking away from this if someone said hey Zach explain the eeology of COVID 19 I'd want you to say it's due to the SARS KV2 virus. If they said what's the most important part of it? Well it does have RNA but the biggest thing that makes this thing dangerous is the spike protein. Why Zach? Because the spike protein is literally the key that is going to bind onto a lock in our host cells. What kind of lock? I'll get to that, but it's called ACE2. Why is that such a big deal? The reason why it's such a big deal is that these viruses, they mutate. They change a little bit of their spike protein, which makes them able to evade the immune system against those antibodies. And on top of that, maybe they gain ways of being able to cause more damage or get into our host cells a little bit easier. Now with that being said, the next thing I need you guys to understand is anybody can get infected with the SARS KV2 virus, but not every single patient develops the scary disease that we see with it. And that's not just dependent upon the type of variant. It's dependent upon the individual, the host that the actual virus is going to bind to. And that's

dependent upon specific risk factors. So for example, if a person became exposed to this virus, the SARS KV2 virus, it got into the airway and it's got down here and it caused some damage. All right? So once this virus got down here, it has the ability to bind onto these different types of cells. What are these cells? These are called type two alvolar cells. And let's say here I have the virus. And again, how does it bind onto these alvolar cells or these epithelial cells in general? It uses the spike protein, which is this red structure here, binds onto the A2. Then what happens? It gets taken into the cell. We'll go over that, but it's going to produce some degree of tissue damage. That tissue damage is going to alert the immune system. The immune system will then bring inflammatory cells. What kind of cells? Well, once this tissue damage occurs, we should trigger things like a bunch of different cells, monocytes or what are the monocytes that are basically in the lung tissue, alvolar macrofasages. It may activate things like neutrfils. CD4 cells. And so you may get things like macrofasages that are supposed to be activated by that tissue damage. You may get neutrfils that are activated by the tissue damage. You may get T-C cells and B cells that are activated by that tissue damage. Right? But these cells are supposed to come in and help you to fend off that virus. They produce inflammatory cytoines. They damage those t the actual uh virus. But unfortunately sometimes they lead to tissue damage inadvertently. But this is supposed to go and activate these macrofasages. We want them to activate the neutrfils. We wanted to activate these cells so they can come in and generate immune response. My question to you is these will come in and help to generate that immune response. But what if a person doesn't have that proper immune response? And so what happens is these cytoines come into play but this response is lost and so I lose this ability. So now I'm supposed to be doing this and instead I don't have the macrofase response. neutrfil TE-C cell response for some reason. Because of that, now this virus can keep causing tissue damage without any ability of me being able to stop it. That's when this infection can get much worse. I'll end up with more tissue damage. As a result of more tissue damage, I end up with more lung disease. With more lung disease, I end up with a worse overall clinical scenario. So, the thing I want you to remember is this is supposed to be the we'll represent this as the cytoines. The cytoines are supposed to activate your immune system, right? That's what the cytoines are doing. But if I don't have the immune response, this tissue damage will continue to occur. And with that lung damage, what's going to happen eventually? The worry here is that it can pres progress to pneumonia. It can progress to ARDS, and we can get a pretty sick patient. And this is really oversimplifying it, but we'll go into more detail a little bit later. Patients who have a reduced immune response, they're at higher risk for things like pneumonia are. It's because they don't have the immune response. What kind of conditions would that be? That'd be anybody who is immuno suppressed of any sort. I mean, it doesn't take a genius to think that someone who has HIV, AIDS, they're on some type of medication, uh, TNF inhibitors, steroids, they are transplant rejection meds, you get the point. Pregnancy is also a really big one. So pregnancy has it's kind of multiffactorial. It's not just an immune response. They do have reduced tea cell activity but also they have other problems because of their overall I don't know how else to say it. The overall morphology of being pregnant and it kind of pushing the diaphragm up. It can create more of a restrictive physiology. So there's a couple different components to that. And the other one probably the biggest risk factor for developing severe COVID 19 is older age and we kind of define that by greater than 65 years. This is just by because they're becoming more immunoscent. Their immune system cells are just more kind of like bro I'm tired you know. So pregnancy can decrease their te- cell function. immunosuppressed patients. They may have reduced overall immune system activity in general and older age just kind of like some fatigued out tired immune system cells. Either way, because of that, that can lead to severe disease. And that's the patients we got to be careful for. Comorbidities. What this really does is if a patient gets this disease, let's pretend for a second. Let's say you have a patient who has COPD. So, they have a reactive kind they have kind of an overall obstructive airway disease. So because of that you bring in this virus and this virus produces tissue damage. That patient who already has a reduced pulmonary reserve can worsen their underlying lung disease. And so what could happen is if this virus gets in, it could worsen their lung disease. So it could worsen lung disease. So think about that for a second. If I have a patient who has COPD and I get a virus in there, this is the same thing. This is why we really support influenza vaccination and COPD years. We support COVID 19 vaccination in COPDers. Why? Because it can precipitate exacerbations. The other thing that's really interesting here is diseases like diabetes, CKD, um obesity, like morbid obesity, um CHF, you we can go down the line. These are all chronic diseases and probably to some degree these diseases create some form of inflammation or endothelial dysfunction. So at baseline here's what I want you to remember is these probably have a baseline they higher degree of inflammation than the normal individual. So they probably their inflammation levels are probably just a little bit higher and on top of that they probably have some degree especially CHFers, diabetes, CKD, they probably naturally have some degree of endothelial dysfunction or some form of cardiovascular disease. All right, that's probably just a normal thing is they probably have baseline increased inflammation and probably endothelial dysfunction. Here's what's interesting about CO 19. It prefers the epithelial cells of the respiratory tract, but it also has, look what I have here on the vessel on my blood vessel, on the endothelial cells, there's A2 receptors. And so, if this virus has the ability to get out here and bind onto these A2 receptors, it can get taken to the endothelial cells and produce endothelial dysfunction. And if I produce endothelial dysfunction and on top of that this disease worsens cytoine storm. So whenever you get inflammation of the lung tissue, cytoines get poured out. So the other component here is that they also get lots of cytoines. There's going to be immune system cells that'll come in here and they'll help to generate an immune response and they'll start pumping out lots of cytoines. So you get two things. we get lots of cytoines and you get endothelial dysfunction. The combination of these two things can promote severe disease. So then what I mean is I could get things like thrombosis. I could see things like ARDS. And so because of that is going to put all of these patients at high risk of things like thrombosis, ARDS, etc. So you get the point. These patients are very high risk for what? Not just having COVID 19, the worst case of COVID 19. You either don't got the immune response to fight them off before it gets bad or you have the immune system but you got so many coorbidities that put you at risk of exacerbation of your underlying disease and you just don't got the reserve to deal with it. Or you have a disease that has baseline problems with the vascular system and inflammation. You add more endothelial dysfunction. You tip them overboard into a lot of different problems. That's the key thing I want you to take away from that. All right. So far, Zach has said what CO 19 is due to SARS KV2 virus. The most important protein is the spike protein. Why? It's the key that accesses the lock to our epithelial cells of the respiratory tract by what? A2. Why is that such an important thing? Because as viruses start to mutate, they change their spike protein to evade the immune system, our monoconal antibodies. And on top of that, they also gain other ways to get into host cells without having to use the host cells machinery, which makes it dangerous. The other component here is that anybody can get kind of a SARS KV2 infection. The question is more important is who is at risk of the severe one that can kill them. If I get a cold, if I get an upper respiratory tract infection, that is important, but it's not as important as and it wouldn't be as concerning to me as something like, oh, I got pneumonia or I'm going to have ARS or I can actually get multiple clots in my body or I could end up dying. That's really important for me to know. The patients who have an impaired immune response are co-orbidities that could worsen their underlying lung disease or diseases that have baseline cardiovascular dysfunction and we add on CO 19 to that it can increase the risk of severe disease.

What I need to do now is I actually want to talk about this from the moment the respiratory droplets. So here you have patient zero. They sneeze, they cough, they aerosolize this virus. This virus is then transmitted via that respiratory droplets into the patient's respiratory tract. All right. So, what is the way that this gets transmitted? The route of transmission is called we say it's just via respiratory droplets. That's how the virus gets from point A to point B to cause the underlying infection. Once it gets to the respiratory tract, it can affect the upper respiratory tract. lower respiratory tract. Again, depends upon the virus, depends upon the patient. We're not going to get into that detail, but let's pretend that we zoom in here and we say, okay, how does the virus actually access the cell? You're probably like, Zack, dude, do I really need to know this? If you want to understand the pharmarmacology, I think it's important. So, here we have the virus. What did I tell you is the most important protein on that virus, the spike protein. I know you all said it. Here's my spike protein. The spike protein is going to bind onto this receptor. That is the lock. What is the lock? Again, we have our spike protein. I'll write it out here. Here's the spike protein. So, the first thing that we need is we need this virus to stick to the epithelial cell. So, it uses the spike protein. Sometimes it's even called the S protein, just so that we're aware. And it binds to something called ACE2. We already know this. That's on the host cell. This is just an epithelial cell of the upper or lower respiratory tract. This is the first connection. Now, technically, the spike protein has two subunits. The part that binds to the A2 is called the S1 subunit. All right? Or the receptor binding domain. And then there's another portion. The S2 subunit is really and this is this changes a lot with omocrron. I'll explain what I mean in a second. But there is this spike protein that binds with the A2. And this portion here that's binding to the A2, this like little curly portion right here, that's called the S1 subunit. This portion up here, let's just call that the S2 subunit. Like the little strand or the little stem that's holding this S up. Let's call that. So let's say here is your S1 subunit. Here is your S2 subunit right there. All right. Here's S1. Here's S2. There's a protein on the host cells called TM PRS2. SS2, sorry, SS2. This is basically a special kind of enzyme that is supposed to do what? Well, we want this virus to really fuse. We want it to kind of stick with this receptor and get taken in. So what happens is this TMPRS22 helps with the fusion process. So it basically kind of helps to cut the S2 subunit and allow this whole thing to fuse with the cell membrane. So now because of that let's actually bring this over here for an example. Let's say what that what will that look like? So it goes first thing binding of S1 of the spike protein to S2. Then from here S2 is still sticking to it but we got to get this whole thing to fuse. TMPRS 202 SS22 uh two sorry uh does what acts on the S2 protein cleaves it so that they can fuse then once that happens now my virus woo that was loud sorry is going to be like this you see how it fused so this is the third part here which is called fusion and that fusion is really the critical thing so we have first thing is the attachment which is going to be S1 subunit of the spike protein to A2. Then we need to prime it. So this is the fusion part. This is what's called the priming. This is the priming portion. If you really want to write that out, here's the fusion. I'm sorry, the binding. Let's actually call that particularly. Let's call this the binding component. So one is binding. Two is priming. Three is we're going to fuse this bad boy. All right. Once it fuses and it's really nice like this, now we have all of the genome, the viral RNA that can do what? It can get pushed right into this epithelial cell. So now this viral RNA can then uncote and release that viral RNA right into the host cell where it can start doing all of its bad stuff. And that's that positive strand singlestranded RNA. That's that part right there where it's kind of releasing the RNA into the cell. That's the uncoding process. Why am I mentioning all of this? The reason why I'm mentioning is, and I promise we'll get into this into the treatment part, but what if I had a way of blocking that spike protein from even sticking to the A2 and going through all of this to get into the cell? That's where drugs like vaccines or monoconal antibodies come into play to block that step. That's why so that's the clinical significance I want you guys to think about here is this is where we can bring in monoconal antibodies which we can either give to the individual like uh pimgarta or we can give vaccines to help them to generate amuno the monoconal antibodies against that spike protein that's why I'm taking the time to talk about that all right once we've gone from that stage this thing is now at the point where it's going to release the virus the viral RNA into the cell. Once it does that, the first thing that's going to happen is this viral RNA is going to go to ribosomes. When it goes to the ribosomes, the ribosomes will then take that viral RNA, that single strand RNA, translate it and make proteins. The key thing here, and I'm just going to make a big like, let's just say I make a big glob of it. Here's going to be a protein here. And I'll do it in different colors just so you guys get the point. There's going to be this component of the protein here. And then we'll do another component of it. We'll just do this part in purple. But this we're going to call a polyrotein. So this big structure that the RNA goes under goes translation makes a polyroin. This polyrotein has a bunch of different things that I need in order to make more viruses. All right. So this is called your polyroin. What I need to do is I need to cleave or break up eat this polyrotein into small individual pieces. So that's all I want to do is I want to take this polyrotein and I want to break it up into a bunch of small different types of proteins. All represent maybe like a couple dots here there's like a little protein. Again here in purple there's a couple different proteins and then here in red here's a couple different proteins. But I need these. If I don't get it cleaved out of that polyrotein, I can't make new viruses theoretically, right? So, I need somebody to come in and eat this thing up. All right, you'll never guess the name of this one. It's called a proteiase. Now, there is very specific types, but for right now, I just want you to remember it is called a protease enzyme. The protease enzyme is what's responsible for eating that polyrotein up and generating all of these different types of proteins. We'll call them for right now, let's call them nonstructural proteins. All right? So we technically what we'll call these is nonstructural proteins. This is not your spike protein, your envelope protein, your membrane protein, your nucleic capsule. They're very specific in their activity. One of these, and I'm actually going to draw this in orange now, too. Let me actually add a little piece on just so I can be very, very specific. I'm going to add like a little orange piece in here. All right. There's a very specific enzyme that's formed whenever we break these polyroteins up and this is the one in orange. This one is actually a very weird looking one. It's called RNA dependent RNA polymerase which we're going to put as R D RP RNA dependent RNA polymerase. What this does is that viral RNA that comes in, this dude can read it and make copies of it. And then on top of that, it can read the viral RNA and make mRNA. That's pretty interesting. So now we're going to do is we're going to take this viral RNA. We're going to have it go over to this dude and he's going to do what? Well, two things. One is he's going to make a bunch of copies of that viral RNA. So let me just draw a couple of these copies. So here I have a copy here. Copy here. But I'm making a bunch of copies. That's one thing. The second thing I'm going to do is I'm also going to make m RNA. So one thing is I'm going to make copies. That's called replication. The other thing I'm going to do is I'm going to allow for me to make very specific mRNA. All right. From this mRNA, this is going to go over to the rough endopplasmic reticulum where I have a bunch of ribosomes studded on the surface. All right. Whenever this mRNA goes to this rough endopplasmic reticulum where the ribosomes are studded all over the surface, I'm going to use that mRNA to translate it and make very specific types of proteins. Now, we need to be very, very particular. So from here, we're going to push these proteins in. And what are these different proteins? These are those structural proteins. So let's actually go back. What was the particular proteins on the surface? Well, the big one is the spike protein. That's one. What was another one? It was uh what color did we have this one? Blue. That was the membrane protein. So we'll draw here. We have a membrane protein. And then we have another one. Green envelope protein. But there's one that we do not make here. It's called the nucleioapsid protein. We don't make that one here. It's actually made over here. So technically RNA dependent RNA polymerase will actually use the mRNAs and make very specific proteins to bring that one over here. We represented that one in this pinkish color. So that actually made by cytoolic ribosomes, not the rough ER. And again, it gets into a little bit of a weeds here. So I don't want to go too crazy. But what happens is from here the spike protein, the membrane protein, the envelope protein, all of these are formed here. And then guess what happens? They get kind of pushed into the membrane of the rough ER. When it gets rafar, then what happens is this buds off. And when it buds off, look, son of a gun on this buds off here. And now it's got all these proteins studded on the surface. Right. Which ones? Well, we got the envelope protein. Studded on the surface. What else? The most important mac daddy one, which is our spike protein. And what was the other one? The membrane protein. These are all studded onto the surface. We almost have the virus though. So right here is our kind of our lipid billayer, which is almost like the envelope. And we have some of the surface glyoproteins. RNA dependent RNA pulymerase already made a bunch of copies with the nucleio capsid proteins. Guess what happens eventually? We'll talk about this in just a second. But these two will meet up at a very specific destination. And then we're going to start assembling all of this. Zach, why do I need to know all of this? When we have patients who have very severe COVID 19, we utilize drugs to inhibit the protease. If I inhibit proteases, can I break down polyroteins? Can I make all of these different things that I need in order for all this process to occur? No. And so all this viral replication and proteins that I need to make the virus stops. What if I had another drug which I inhibited the RNA dependent RNA polymerase? I wouldn't be able to do all of these processes where I make new viral RNA or I make mRNA to make new viral proteins. So this is where drugs which we'll talk about a little bit later called paxelvid nomemetrovir and ritanavir come into play to inhibit the proteiase and then rememir inhibits dependent RNA polymerase again that's the significance of that now at this point this is this this uh co man it's using our cells to be able to do a lot of stuff we already said just as a recap RNA dependent RNA pulymerase is copying it's undergoing replication it's making mRNA the mRNA is and actually helping to make structural proteins. These structural proteins are then being incorporated into a vesicle from the rough endopplasmic reticulum. These two things, all the viral RNA and this vesicle from the rough endopplasmic reticulum meet at what? The Golgi. And when they meet at the Golgi, the Golgi is going to package all these puppies together. And then now we're going to have our final thing that we need to really get this virus assembled. And then to piece out in this membrane bound vesicle, we'll have all of the particular proteins. Again, just to recap it, we'll have our spike protein. We'll have the membrane envelope protein. We'll have the nucleioapsid protein. And then inside is going to be tons and tons of copies of the viral RNA. We've made it, my friends. Then what happens is this is going to move up and it's going to say, "Yo, membrane, I'm going to need you. I'm going to fuse with you, but you're going to give me another envelope. " And then what happens is this thing fuses with the actual membrane. And via the process of exocytosis, we then pop this virus out. So that's the exocytosis process. Now from here, what's the downside of that? We made a new virus to go ahead and spread to other different cells. And on top of that, whenever this happens inside of this cell, it produces a cytoathic effect. So not only causing tissue, you're not only causing cell injury, you're also making new viruses to go and further cause more cell injury. Is there any particular thing that we can use at this stage? No. But what I want you to know is once this happens, what's the end result out of this? Two things. This is going to result in cell destruction and further spread. And at this point, we're having problems, right? So this is where you're going to get cell injury and spread of the virus. So if theoretically we could target this thing very early at the attachment site, we could utilize ways of not allowing that virus to actually spread via different things like N95s and isolation or we can give drugs that block these. We won't have to worry about that stage. But if it happens here, we already got cell injury and we got the spread of the virus. Now once this happens and we've damaged the cell, we're going to have a response. This is pretty straightforward. But I don't want to go too crazy, but again, I'm using the epithelial cells here, the type 2 pneumocytes. Once this thing binds, it's going to use all of that to make more viruses and replicate, and it's going to go through that cell lis. That's going to cause cell injury. That cell injury, I already kind of talked about this. What do these cells do? They release things like damage associated molecular patterns, DMPS. The DIMPs then go and activate your immune system. When you activate the immune system, the biggest response initially is from what? Your alvolar macrofasages. When you activate the alvolar macrofasages, they're going to say, "All right, bro. I'm going to come on over here and check out what's going on. " So, these DMPS come over here and activate the alvolar macrofasages. These say, "All right, let me come on over here. " And they can go via the pores of con and come into this area. When they do that, the alvular macroofasages are kind of like your little alarm system. They'll try to start eating up some of the viruses. But one of the things that they do is they say, "I'm not going to be enough for this job. " And they release a bunch of different cytoines into the bloodstream. Right? So these cytoines get pumped into the bloodstream. Things like interlucan one, interlucan six, TNF alpha. Now in normal individuals this is shouldn't be like too bad but they're going to pump some of these cytoines out and that's going to go and alert your immune system. It's going to bring in more macrofasages more monocytes right so what this should do is bring in more monocytes bring in some neutrfils because it even releases things like interlucan 8 which neutrfils love and then on top of that lymphosytes. So I'm going to activate all of these different types of cells. Bring them to the area. It's pretty much going to be these two first though. So let's get rid of the lymphosytes. We're going to bring these two primary ones to the actual area of injury and we're going to trigger a response. Macrofasages will undergo fagocytosis. Neutrfils will actually release proteasis and reactive oxygen species, things of that nature. And it even under goes fagocytosis. But these are going to come and try to cause they're going to try to clear the virus. But unfortunately, when they attempt to try to clear the virus, sometimes these guys, especially the neutrfils, they can cause tissue damage as kind of an overall bystander effect. It releases things like reactive oxygen species, proteasis, etc. So that's our first response, the innate response. And this is going to just cause an inflammatory reaction. Depending upon where it occurs, that's going to cause the overall symptom. If it occurs in the upper respiratory tract, they'll have upper respiratory tract symptoms. If it occurs in the lower respiratory tract, they'll have the pneumonia like symptoms. If it occurs in the body, you'll have the appropriate organ tissue effect there. The adaptive response is also really critical. When this virus gets down into the alvoli, again, this is the most concerning area if it can get into and it damages these type 2 alvolar cells. When you damage the type two alvolar cells, we already said that that's going to cause those damage associated molecular peptides, right? But what we did say is that those damage associated molecular peptides, let's get rid of this blue marker. It sucks. It's going to do what? It's going to tell your Oh, that's good. That's good stuff right there. That's going to tell your alvolar macrofasages. Alvar macrofasages are going to release all of those cytoines. What were those cytoines again that we talked about? We just talked about it. Come on, guys. Here it is. It is interlucan one, interlucan 6, TNF alpha. That's going to bring in a bunch of different immune system cells. When these immune system cells get to the area, especially things like macrofasages, more macrofasages or monocytes and dendritic cells, these are called antigen presenting cells, APCs, bro. When they come into the area, they're going to undergo fagocytosis of the virus. So, they'll take this virus that's all going to be out here in this these purple dots I'm going to represent it as, and it's going to undergo fagocytosis. When it underos fagocytosis, it's going to take bring it inside and express it on its surface. So it under goes fagago cytosis and then it under goes antigen expression. So it's going to express a very specific piece of the virus on its surface. What's the very important one? It's the S protein and it's going to present it on its MHC2 complex. So it presents and presents that on its surface to the T- cell receptor that's present on the T- cell. Based upon this interaction, when this occurs, the T- cell becomes activated. When that TE-C cell becomes activated, it does two things. It releases cytoines that push B cells to become plasma cells. And it also helps to form different types of other TE-C cells. Maybe it forms memory tea cells and cytotoxic tea cells, but it's going to help to form different types of memory tea cells are going to be formed. And on top of that, it's going to cause a B cell to become a plasma cell. And that plasma cell, as a result, whenever it releases the very specific cytoines to make more memory tea cells or to stimulate the formation of plasma cells, these plasma cells will now make antibodies. And these antibodies are going to be just perfect to be able to bind on to what specific protein that's present on the viral surface. Come on, I know you guys know this. What is it? It's going to be the spike protein. This is a way that we should have a normal immune response. So, if you think about this, you get infected with the virus. If you have a person who doesn't have the appropriate immune response, are you going to be able to generate antibodies? fight this virus off? No. And this is why this virus can keep replicating and replicating causing further damage without a proper immune response. It's going to cause the patient to get really, really sick. All right. Now, this is kind of how things should be happening. And this is kind of a normal inflammatory response. But what I really want you guys to take away from this is whenever that SARS KV2 virus attaches onto these different cells, it uses the AE2 receptor. That was the common theme. These A2 receptors are present all over the dang place. The primary targets is the upper respiratory tract and the lower respiratory tract. Think about this for a second. It's very straightforward. It's not that hard to imagine. If I attack the upper respiratory tract, what kind of uh symptomatology should I be concerned about? Well, if it's upper respiratory tract versus the lower respiratory tract, the upper respiratory tract, I would be worried about upper respiratory tract infections. What does that look like? I'm talking about a person who has rhinocyitis, nasal congestion, nasal discharge. Uh maybe they have a headache, maybe they have facial pain and pressure, maybe it's affecting the throat, so they have a sore throat. On top of that, maybe they even have a little bit of post-nasal drip that's causing a cough. They have a low-grade fever. All right. If it's lower respiratory tract, we're talking about things like the concerning feature like pneumonia, right? They have cough, dysnia, typnia, increased work of breathing, fever. These are the concerning features, right? A secondary target again that has lots of those ACE2 receptors I already told you is the endothelium. So another really important part here that also has lots of those A2 receptors. So because those uh viruses bind onto these cells, they'll produce replication and damage those cells. What can that result in? If I damage that, I can lead to endothelial dysfunction. Whenever you have a damaged or dysfunctional endothelium, my friends, why is that really important? The endothelium is supposed to make things like prostaglandin I2 nitric oxide prevent platelets from sticking. It also is supposed to kind of shield vonwilderron factor. If those things are all happening, von wildbrron factors exposed. I can't make those anti-thrombotic things. What's going to happen? I can get clots. And that's the concept of what we call veros triad, right? And so that's another big thing here. All right. Endothelial dysfunction can lead to thrombosis. And that thrombosis component is what really scares us with this disease. And that can be direct damage from the virus and it can also we'll talk about a little bit later due to cytoine storm other targets. There's lots of A2 receptors that are present on the interosytes. If it's present on the interasytes, what kind of thing could happen? These are supposed to be involved with absorption. So what could I potentially see? I can see abdominal pain and diarrhea. All right? So diarrhea may be a potential thing that can happen if it's affecting the git, right? the interasytes of the git. It also can affect the myo cardium. So what could I see as a result of this? Myocarditis. Dude, this thing can cause what? Potentially cause acute heart failure. Sorry, Rob's over here screaming at me to put two Rs in here. That's right. Diarrhea. So git, the interasytes are getting damaged. The myioardial cells are also getting damaged. that's causing myocarditis. Now, this is why we can see potentially things like diarrhea and even like abdominal pain and even abdominal pain with this disease. Now, myocarditis is pretty scary. And if you get an inflammation of the myioardium, that could lead to a lot of different problems. You can end up with I mean, it can cause acute heart failure. That's probably the most concerning feature. So if a patient came in with acute heart failure sometimes it can cause ST changes as well. The other thing that we get worried about with myocarditis is arhythmias. Now the other thing is on the kidney the proximal tubular cells there is also lots of A2 and so the kidneys especially the proximal tubular cells have a heavy amount of that and that can lead to something called acute tubular necrosis which can precipitate something called a AKI and AKI is mainly going to present with things like a bump in the creatinine potentially less urine output called aligura and so these are all possibilities of the virus's intrinsic ability to damage these cells. cells by what? By binding that does this by binding what particular thing I need you guys to remember this binding the ACE2. If it binds onto it, it can cause it to replicate and damage the cell. If it damages the cell, you can get all of these potential effects. And then on top of that, if that's the base effect and then you add something on to that like cytoine storm in other individuals who have very high risk factors of getting really bad, that's when we see the severe cases like really bad myocarditis, really bad kidney injury, really bad pneumonia, really bad clots. So that's the key critical thing that I want you guys to take away. There's also one other thing. It's kind of a part of the upper respiratory tract and that's what makes this kind of like it's kind of like a unique thing to co. There is a olfactory epithelium right here. And there's also within our tongue, there's a gustatory epithelium. All right, I'll just let's represent it in green. A little gustatory epithelium. If the virus has A2 receptors on those epithelial cells, binds onto it and damages them. Unique types of symptoms that can result as of the damage of the olfactory epithelium is called anosmia. All right. And then damage to the gustatory epithelium is called azia. — I knew you spell it wrong. That one you're not getting. I It's okay. You spell it wrong every time in your Google doc. I'm sorry. — Okay. What is it? — Spell out the word age and then guzzia. So the word age. A ge. — Okay. — Gui. So age. Guzia. I don't know how you want to say that. — UA. — Yeah. Gu. — Okay. Gu i a — gu ia. — No. — Oh, — here. Let me just make sure. I correct it every time the Google doc cuz I'm like it's so weird that sometimes it — All right. So, a g e. — Yeah. You spell age and then almost like USA but us a. — Okay. Gotcha. — Make sure age us a. — All right. Gotcha. — Okay. — All right. So if we damage this gustatory epithelium, it's going to lead to a decrease in taste. So this is a decrease in smell or absence of smell. This is going to be a decrease or absence of taste. And this is called auzia. All right. I like to say azia. Either way, this is the unique components where if you see something like this, not a lot of viruses or infections cause this type of presentation. So again, it can have multiple different targets. The primary ones is the epithelial cells of the upper respiratory tract like your goblet cells, your pseudoratified ciliated columnar and then again the lower respiratory tract the type 2 n pumocytes. All right, but again you can see this all over the place. All right, so at this point we've really gone in just as a quick recap up to this point. SARS Cob V2 is the virus spike protein is the most important one. It's an RNA virus. Again risk factors that are important for the progression to severe disease is those who have immuno compromised states age greater than 65 pregnancy which is kind of a multiffactorial feature coorbidities that can either exacerbate their underlying disease or make that ards possibility thrombosis possibility more likely. We talked about how the virus is transmitted via respiratory droplets. Once it gets into the airway it binds on to epithelial cells via the AC2 in the spike protein connection. Sometimes you need priming. Once it gets into the cell, uses enzymes to replicate all of the viral RNA, make more proteins, assembles, it pops out of that cell, damages the cell, goes and spreads to other cells. We get an innate immune response which should normally occur with macrofasages and neutrfils. We get an adaptive response. Our body is supposed to produce antibodies and generate memory cells, T- cells and B cells. And then on top of that, once these um viruses attack these different tissues, it's going to cause cell damage. If it's of the upper respiratory tract, upper respiratory tract infection, lower respiratory tract, pneumonia, endothelial cells, you can get thrombosis. All these other different tissue cells can have direct cytotoxicity. The big thing that I also want you to take away from this is we can have most patients live with that primarily upper respiratory tract infection like presentation. Some can get that pneumonia presentation. Some can have other organs being affected. What I really want to understand is how does that direct cytotoxicity translate into a way worse way more severe disease. It's not just now the damage from the virus. It's two other mechanisms that make it much worse. So one of them is related to angotensin 2. Normally you have this sorry guys that's ACE2 normally what happens is angotensin 2 is supposed to be acted on by ACE2 and converted into angiotensin 7. All right, angotensin 17. This is a normal reaction. And angotensin 2 is supposed to be acted on by ACE and converted into this, right? Angotensin 7 is kind of like it's nice because this one is not really a pro-inflammatory type of molecule. Angotensin 2 is when a person gets infected with that SARS Kovv2 they have that spike protein. The spike protein will bind with the A2 and what happens is once that happens you get fusion. When you get fusion what happens to the A2 level. So once you have this fusion reaction that occurs between the spike protein and A2 what ends up resulting is that this A2 levels they get taken inside of the cell they get down reggregulated so then what happens is I have a reduction in the A2 levels that means that this reaction is not going to occur that means I don't make as much of the angotensin 17 and instead I end up with a buildup of angotensin 2. If that happens, the problem with this then is what's really interesting. Angotensin 2 is kind of like a it's an inflammatory molecule. One of the things that it can do is it can act on our pulmonary vascule and it can do two things. One is it can cause the pulmonary arterials to undergo an intense vasoc constrictive mechanism. So now this vessel is going to clamp down. Woo baby, that ain't good. All right. So that's the first thing is we're going to undergo pulmonary vasoc constriction. So the first thing is pulmonary vaso constriction. Now think about why that's important. If you have pulmonary vasoc constriction, this is going to be really difficult to bring oxygen or actually bring blood. I just say just bring blood which is rich in CO2 and then undergo gas exchange which will then move the oxygen through here. That blood flow is going to be affected. And so what's going to end up happening is you may have a reduction in that perfusion concept there. And that reduction in perfusion may lead to a VQ mismatch and that can worsen a patient's lung function, right? They can end up with a kind of an acute lung injury at this point. This pulmonary vasor constriction when it kind of reduces that profusion by clamping down, you cause VQ mismatch. On top of that, it also can cause the pressure inside of the pulmonary circulation to go up. So, think about this. If it's really hard to squeeze blood through there, right? Then what's going to happen is you're going to end up with a back pressure. And as a result, if I have a back pressure, all the pressure built up prior to this little vasoc constrictive point is going to trigger pulmonary hypertension and that can put a lot of strain onto that right heart. Right? So two things can happen as a result of this. A back pressure causing pulmonary hypertension and reduced profusion which can cause VQ mismatching. The other thing that it will do is it'll make the pulmonary arterials super leaky. And now if I increase this capillary leakage, now not only do I vasoc constrict affecting the profusion, but guess what else I do? Any plasma that's running through here is going to leak out and it's going to leak into the interstitial spaces. alvoli and if I start filling up this alvoli that's going to be a particular problem. So then what's up happening is I end up with alvolar consolidation alvolar and we can just call this like filling if you want but we'll just for right now we'll call this a consolidation. The combination of this, the pulmonary vasoc constriction and the capillary leakage effect is what leads to acute lung injury in these patients. So all this does is these two things lead to acute lung injury and this is what's going to make a patient be more likely to progress to ARDS to develop a severe case of pneumonia. So that's one concept. One of the concepts that's really critical here is that we think that the virus we know it's downregulating AC2 increasing angotensin levels which are causing pulmonary vasal constriction and increased capillary leakage which are contributing to a worsening of their lung function via an acute lung injury alvolar filling and VQ mismatching that's going to increase the risk of this patient developing a severe case such as ARDS and that's we get work we worried about is the end result is this pushes a patient's risk of developing ARDS to be a little bit higher. All right. Now, that's one concept. The other thing about angotensin 2 is it's not just if I really wanted to keep going. This is the two big things, but we've also seen that angotensin 2 can cause lung fibrosis. So, if you really wanted to add that on there, you can even add a little bit more. I'm just going to say it's a plus or minus if you'd like to remember it. one pulmonary vasic constriction, two is the capillary leakage and the third thing is it can cause lung fibrosis which can end up making the disease just overall a little bit worse. All right. That's the big things I want you guys to take away from the angotensin 2 accumulation. What about the cytoine storm? This is by far the most important thing. Normal individuals when they get that virus if it gets into the airway it causes damage to the type two numocytes when they're damaged they have less surfactant that's a big problem. So one thing that happens is you get damage to the type two pumices. So whenever pumytes two things happen. One is damage. Two the type two alvolar cells are the pumocytes and that results in one concept here. One is it results in a decrease in surfactant production. Surfactant is supposed to reduce surface tension which is the alvoli is wanting to assume the smallest size possible. If I don't have that ability to make surfactant to reduce surface tension, what happens? the alvoli want to collapse and that's a pretty stinking big deal. All right, so this triggers alvolar collapse. So that's one problem. The other thing is once this is damaged, they release damage associated molecular peptides, a bunch of different types of cytoines and all of this is supposed to do what? activate your immune system, activate your macrofasages, your neutrfils, you'll bring in teac cells, all of that stuff that I talked about. Normally, these cells are pumping out something called interlucan. So, here's what happens. These are supposed to I'm going to go up so I don't get in the way of this whole arrow process, but these are supposed to go here and supposed to go here. And they're going to activate things like your macrofasages, te- cells. And these are supposed to pump out what? Cytoines. What are those cytoines that they pump out? I told you guys this interlucan one, two neocrotic factor alpha, interlucan 6, and even interlucan 8. But these are going to be the most significant ones. And out of all of these, probably the most important one is going to be interlucan 6. Now, in normal individuals, they shouldn't be producing crazy high levels. But in individuals who have things like diabetes, CKD, um, obesity, they have uh impaired immune responses where they're not able to fight this thing off. And what happens is you just get a very bad cytoine storm. These things are in super high levels. Like I'm talking super high levels. Because of that, they get a more amplified immune response than most individuals. And why is that important? Well, one is we already have the alvolar collapse. These cytoines are going to come here to the lungs. And what they're going to do is they're going to make these capillaries, the vessels dilate a little bit, but they're also going to make them super leaky. If they get super leaky, what's going to happen? The alvoli are going to fill with a bunch of fluid. So now I have the alvoli filling up with a bunch of fluid. And now I have alvolar filling. And on top of that, that was the one component. Alvolar filling is right here. What was this one? That was due to the decreased surfactant. Guess what? These cytoines cause lots of fluid to leak in and that washes the surfactant levels even more. So, not only do you get decreased surfactant from type 2 damage, but having fluid come into the alvoli washes or dilutes the surfactant that makes the surface tension go up even more and you get alvolar collapse. So, we have a combination of these things, right? So, two things are happening. But here's the big difference. These cytoines aren't just going to be released in a localized area like right here. It's going to be all over the lung. Because of that, I'm going to have damage here, here, here. You guys get the point. I won't be super annoying, but it is all over the place. And all these red X's indicate is these are areas of alvolar filling and alvola collapse all throughout the lung. This, my friends, is what we refer to as ARDS. Acute respiratory distress syndrome that is due to alvolar filling and alvola collapse. How will this patient present? If I haven't told you guys this enough, you guys should know it by I don't need to write this dang thing down. What's happening is the patient will have multiple areas of where they can't have gas exchange. Because of that, the primary manifestation will be hypoxmia, right? a low sp2 a low pa2 and respiratory distress typnia disna increased work of breathing that is going to be the big thing that we see here all right so that's one effect one of the effects of this cytoine storm is I have damage to the type two alvular cells that we talked about over here and then on top of that I got the cytoine storm that just makes everything worse that's what leads to diffuse alvular damage and ARDS another thing here is these cytoines. They have a lot of especially interlucan 6. They have little receptors on the liver and whenever it acts on the liver, the liver will respond by producing a bunch of different things. Some of these aren't super important, but some of them could be. One is it produces a lot of acute phase reactant proteins. One is called CRP. The other one is it can release something called feritin. But there's another one that is really important and this one is called fibbrronogen and fibbrronogen we know is really important in the coagulation cascade. So we have fibbrinogen, we have feritin, we have CRP and even ESR is all it's a result of having a lot of proteins. But what you'll notice about these is that patients who have these heavy cytoine storm, they'll have these high levels of these acute phase reactant proteins. And these are things that you can measure to determine, hey, there's lots of inflammation. There could be a cytoine storm brewing in this patient. But here's another component. I told you what was expressed on these endothelial cells. I represented it in pink. What was rep what was actually expressed on these cells? The ACE2. So if the virus which we represented here in purple binds to this endothelial cell via what protein here? The spike protein. What's it going to do? It's going to cause damage. So now there's endothelial injury. Whenever there is endothelial injury that leads to a couple different things. So there's a couple things that result out of this. So here's the virus, right? Here's our SARS KV2 virus binds with the ACE 2 on the endothelium that results in endothelial injury and a couple things result as of that one is I damage the cells. What do I expose? Von wildderon factor. So now I'm exposing von wilderbron factor. So it results in increased von willilibbron factor exposure. The other thing is normally these endothelial cells are supposed to release what kind of things? PGI2, nitric oxide. But it's releasing that when they're normal, it's damaged. Am I going to be able to produce PGI2, produce prostyc? No. So if this is damaged, I can't do this. and these levels drop. So now I have exposure to von wilderon factor anti-thrombotic um molecules are released. So there's uh or not released. So we have decreased PGI2 and nitric oxide. And there's one more thing. Whenever you have tissue damage to a vessel, the vessel responds by pumping out a very specific molecule. Do you guys remember what that is? Tissue factor. So there's another molecule called tissue factor. This is also known as factor three. These levels go up because it's a vessel injury. If there's endothelial dysfunction, the vessel is injured. And so tissue factor levels go up. So the fourth thing is we also have increased levels of tissue factor. The problem with all of this, my friends, is absolutely catastrophic. I have endothelial injury. So I I'm exposing von wilderbron factor. I can't release PGI2 and nitric oxide and I have tissue factor on top of that. So now here's the vessel. Let's say here I kind of represent this area here that's injured. Here's the area that got kind of injured by the virus. I literally lead to everything in this area not being able to stop platelets from sticking. I have something that platelets love to bind to and on top of that I release tissue factor which likes to push the coagulation cascade towards making a clot. All right. So now I have this endothelial area of injury exposed to von wilderbrron factor tissue factors released and on top of that I got fibbrronogen that's being pumped out from the liver all of these things here and fibbrinogen here is one of those really critical things that we need to make fibbrin lead to what type of effect oh dude I'm going to get a clot thrombosis and that's really the concern here is Now I have a person who can present with a thrombosis and that's because we're kind of creating a hypercoagulable state. That thrombosis can then flick off embey and if that emblei flicks off then I can spread these all over the body and then I increase the risk of emblei. Why is this an issue? The reason why is when a person has SARS KV2, the cytoine storm is really perpetuating all of this. The virus is causing it damage on the endothelium. The cytoines are worsening pretty much everything. On top of that, cytoines are also driving this process too. They're also not only is the virus doing it, the cytoines are also worsening all of this. When you get emblei and thrombosis, you increase the risk of what kinds of conditions? Well, the result here is I can end up with things like uh DVT, PE. Um I could end up with a um es schemic stroke. I mean, the list goes on. You're basically increasing the risk of getting clots all over the place. And that is what makes this disease even worse because if I have a clot that's in the pulmonary artery and the patient also has um ARDS and pneumonia, oh my gosh, I'm going to worsen everything. All right? So that's why I'm trying to get you guys to understand this. The benefit of this is that when a patient comes in who has um a positive COVID 19 testing and they have symptoms of maybe pneumonia or ARDS, you're going to need to get a chest X-ray to really see if they have any features of diffuse infiltrates. If a patient has labs drawn like CRP and feritin and fibbrinogen levels and another one here's another thing whenever you have a heavy clot burden what's one of those factors that's actually made as a result of a little bit of fibbrinolyis there's one other thing that's actually made and that is d-dimer. So a d-dimer is basically a breakdown product of fibbrinolyis and that occurs when you have a heavy clot burden. So you're also going to notice that these patients will have a elevated d-dimer. So sometimes what we'll do is in patients when they come in we'll get their CRP levels we'll get their feritin fibbrronogen levels we'll get their d-dimer levels because it tells me do they have a lot of this cytoine storm going on which increases a risk for hypercoagulable state getting thrombbo emblei okay the next thing is these cytoines can also act on your systemic vasculature and when they act on the systemic vasculature they do two components here One is they make the vessels super dilated. All right. So now what I'm going to do is I'm going to make these I'm going to overexaggerate it. Obviously we're going to make this thing super dilated. On top of that we're going to make it leaky. All right. So two things happen here. One vasoddilation. Two is systemic capillary leakage. Right? So let's write this down. vaso dilation and a increase in the capillary leakage. The problem with both of these mechanisms, if I make the vessels really dilated and I really make them leak, what happens to my blood pressure? Well, systemic vascular resistance goes down, effective arterial blood volume goes down. Either way, the patient's blood pressure, which one of the best ways that we can look at blood pressure, especially as a profusion component here is mean arterial pressure. Mean arterial pressure, that's their blood pressure that determines the profusion to the organs. So their mean arterial pressure will go down. If they have terribly high levels of these cytoines, mean arterial pressure will go down from vasoddilation to capillary leakage. That mean arterial pressure. If I don't have enough perfusion to organs, the organs begin to come become eskeemic. Oh shoot. If I have organ eskeeia or I'm not delivering enough oxygen to the brain, this can lead to encphylopathy. If I'm not profusing the kidneys, I can end up with an acute kidney injury. If I'm not profusing the liver, it can end up with an eskeemic hepatitis. If I'm not profusing the myocardium, I can end up with myocarditis. And sometimes in severe periods of this, I can even have arrhythmias. This is what I'm trying to tell you guys is you'll notice something kind of interesting here. The virus itself has the capability of causing acute kidney injury, myocarditis. If I add a cytoine storm into the mix here, I can worsen their acute kidney injury. myocarditis. The cytoine storm causes three big things I need you guys to know. When a patient gets infected with SARS KV2 and they develop CO 19, what really makes it dangerous is not just the direct damage of the virus. It's the cytoine storm that can cause diffuse alvular damage which can cause ARDS indotheliitis or endothelial dysfunction which can create a hypercoagulate state and systemic hyperrofusion which can lead to multi-systemm organ dysfunction. I mean, here's another thing. Look, if I don't peruse tissues, one of the easiest ways for us as clinicians to check to see if tissue profusion isn't occurring. It's just easy for us to do is a lactate level. Even that would be a potential sign of poor profusion to tissues. But obviously looking at the patient to say, hey, they're confused. They have an altered mental status. They have an increase. So here, this would cause altered mmentation. This would cause a bump in the creatinine, a decrease in the urine output. This would cause LFTs to go up. This may cause I mean heck you could see ECG changes. You could see an increase in their troponins. You guys get the point is if I look at all of these, I may have a patient who has an elevated lactate, altered mental status. They may have some abnormalities in some of their labs or testing. So I may see increased creatinine, decreased urine output, a bump in the LFTs, an increase in the dropponin, EKG changes. This is a sign that a patient has more of that critical COVID 19. All right? And that's what I want to move on to next. The next component is when a patient comes in, they get infected with SARS KV2, it binds onto the A2, it creates a cytoine storm. They can get the potential to be really, really sick. Some patients don't present sick at all and they don't have any symptoms. That obviously depends upon the patient and depends upon the variant that SARS KV2 variant. We know that omocron

technically has less of that pathogenicity. asymptomatic individuals really all we're saying is they have a positive like testing and the most common one which we'll talk about this later is they have a positive PCR or nucleic acid amplification test but it's obvious no signs and symptoms mild COVID 19 is they have a positive PCR nucleic acid amplification test but they have more uh so positive PCR nucleic acid ampl amplification test and upper respiratory tract infection symptoms signs and symptoms. So this is an individual who comes up positive for COVID 19 but their symptoms are really fever maybe a low-grade one maybe malaise maybe myalgia maybe anosmia maybe aia maybe they have a sore throat cough maybe they have congestion maybe they have diarrhea it's very mild symptoms there's no lower respiratory tract involvement for the moderate one they have a positive testing so their PCR nucleic acid amplification test which the gold standard is going to be positive and they have lower respiratory tract signs and symptoms. What do I mean? Maybe some pneumonia findings. What would that be? It could be things like a cough. It could be disna on exertion. You may even get a chest x-ray of this individual and find that they have some type of like ground glass opacities. The key thing here is not enough to cause hypoxia. So their SPO2 is greater than 94%. So they have a cough, they have dysnia, maybe on exertion, but their SPO2 is fine. In the severe COVID 19, they have a positive PCR nucleic acid amplification test, but at this point and they have the pneumonia signs and symptoms, but at this point it's more severe. It's enough that it's starting to cause damage to the alvoli. It's starting to get to that ARDS point where we're really affecting oxygenation. And now we're seeing the individual developing some of those similar findings. So what could this be? They could have again dysnia but that dysnia maybe is at rest which is not normal. They can have a increase in their respiratory rate. We say greater than 30 which is typnia right? So an increase in the respiratory rate also known as typnia or they have an SPO2 that is less than 94%. So do you see how here no symptoms very mild upper respiratory tract symptoms no hypoxia and signs of increased respiratory distress beginning to occur. Then we get to critical. At this point, they have a positive PCR nucleic acid amplification test, but they have a couple different things. One is they can have things like respiratory failure, so ARDS, but now they're requiring heavy oxygen support. So the way I would say that is they have respiratory failure requiring and I'm going to abbreviate this invasive mechanical ventilation. They have to be tubed. The second thing is they have multi- system organ dysfunction. This is probably because they have hypotension. They have thrombosis. So this is probably a combination of due to thrombosis from the endothelial dysfunction creating a hypercoagulable state and hypotension the shock state from the systemic hypoprofusion the vasoddilation increased capillary leakage kind of like a it's like a distributive shock kind of presentation this is what you get worried about so if I had to tell you Zach hey I mean Zach hey can you tell me again the particular clinical findings that help me to stratify where the patient lies in having COVID 19. Asymptomatic, it's just a positive test, no symptoms. Mild is upper respiratory tract. Moderate, lower respiratory tract, but no hypoxia. Severe, lower respiratory tract with hypoxia. Critical, they have severe respiratory failure that they're having to utilize. Either they're rapidly deteriorating and they're on high flow BPAP or they're intubated or they have hemodynamic instability and multiple thrombotic uh kind of complications that are causing multi-systemm organ dysfunction. Now, we've talked a ton about COVID and really what it is, how you get it, how does it actually cause disease, the mechanisms of severe disease, what that could look like, and really the overall

classic clinical presentation, but complications, we again, we kind of covered that intrinsically, right? And what do I mean? The big complications that we get worried about first is ARDS. We talked about that. That's with the diffuse salvular damage. So you get direct injury of the lung tissue from the virus and then a cytoine storm. The other one is you get thrombosis. This is that hypercoagulable state that's due to the again cytoine storm and damage from the virus. And then on top of that you can end up with the multi-system organ dysfunction. And this is probably due to systemic hyperrofusion and clots that are occurring in those vessels that are causing organ eskeeia. And again we use this example as things like AKI, myocarditis, right? Um es schemic hepatitis the list goes on. So this has already been discussed right? We don't need to go hypatitis. through that part again. What I do want to talk about is some very unique interesting complications that can occur as a result of co 19. One is called multi systemm inflammatory syndrome in children. Um we are seeing this in adults. It just happens to be one that we get really concerned about in children. What happens is probably a um probably a couple weeks. So what happens is the first thing is they usually they get COVID 19 infection and then probably two to six weeks later they end up with worse symptoms. And what I mean by that is they look absolutely terrible. All right? They usually the symptoms that they'll present with is things like a fever, rash, um and low blood pressure. Honestly, it kind of looks like a Kawasaki. Like they can have like a fever, they can have a rash, they can have um conjunctivitis, they can have cardiogenic shock. They literally almost look like a Kawasaki uh Kawasaki disease or toxic shock syndrome kind of presentation and it's actually it's pretty concerning. And then abdominal pain. Abdominal and abdominal pain. Um that's a pretty big one. Abdominal pain. The concept behind this is kind of really weird. What's thought, and I don't want to go into too crazy of a detail here, but it's thought that the virus can live in these interases for a while. So, you get the infection, you think that you clear it, but you actually don't clear it. And what happens is the viruses, they're living in these interases. So, some of these viruses are living in the interases. And then what happens is the virus releases things. It triggers the epi the inter interasites to release something called zonulin which is the theory behind it is these epithelial cells or these interasittes they increase the expression of something called zulin and what zonulin does is when it's released by these cells is it kind of increases the permeability it kind of makes spaces between these uh interasittes. So that's what zonulin does is it kind of creates these little spaces if you will between the cells. If I increase the spaces between these cells I increase the permeability and things can cross over. And when these things can cross over especially even from these cells you can release these viral antigens. And when you release these viral antigens I'll just represent them in purple here. they get into the bloodstream and then what happens as a result if I can kind of slowly release these viral antigens a couple weeks later I create a inflammatory response right because I'm going to expose them to things like spike proteins and that's going to cause this inflammatory response and that inflammatory response is what leads to this multi-systemm inflammatory syndrome in children. So again the thought behind this is they get an infection the virus survives and kind of acts as a reservoir. Your in your intestinal epithelium acts as a reservoir for that virus. They release zonulin as a result of being infected by the covid-19 or kind of holding it there and reserving it there. The zonulin increase the permeability of the gut lining. Viral antigens can get into the bloodstream and increase this inflammatory response. And that's why they'll end up getting symptoms two six weeks later. And I'm not kidding. It's terrible, terrible symptoms where they can actually like look terribly, terribly bad. This one you have to treat with like IVIG. All right. So, introvenous imunogloabbulin. Sometimes we even have to do like steroids in combination with that. All right. Long COVID. This one's interesting as well. Long COVID is kind of a similar concept to this where what happens is the virus basically you think that you clear it and what happens is the virus lives in these areas. It's just like this. The virus kind of like has like these little reservoirs where it lives in the intestinal epithelium. It lives in your central nervous system. lymph nodes. It lives in the endothelium. And then every now and then after you've actually so you have again it goes like this. You have one is the coid9 infection and then the component of this is second is you have symptoms for greater than four weeks. It's continuing to persist. So you end up with COVID but these symptoms just don't particularly go away and they're very unique symptoms. And so what happens is the thought is that these viruses are living in particular reservoirs like your git primos common in your brain, your lymph nodes in your endothelium. And then just small amounts of these viral antigens are being released into the bloodstream. And when they're bloodstream, it's creating an inflammatory response. That inflammatory response is causing dysfunction in the microirculation and you end up with particular symptoms that persist for a while. But again, this is what leads to that inflammatory response is that they're kind of just these reservoirs are just leaking this stuff into the bloodstream that's activating an immune response and that immune response is causing microvascular dysfunction. Some of the symptoms is things like brain fog. So they kind of just have like they don't remember things. They have post-exersonal malaise. They're just really tired. Maybe they have persistent loss of taste and smell. They can have dautonomia where they can have an increased heart rate and a low blood pressure. It's just very prolonged symptoms that are continuing to occur even after they've been infected with COVID for at least four weeks or even longer. Um and that's what makes this one kind of interesting. So that's what I want you guys to take away from all of this with CO 19 is we talked a lot about the virus. We talked about particular components of the virus, the risk factors for severe disease. We went through the life cycle. We went through what tissues it damages. We talked about the mechanism of how you can actually get a very severe type of COVID 19 infection. We talked about the classic findings that you would see with an asymptomatic, mild, moderate, severe, and critical COVID. And we talked about complications already with this. these unique ones. What I want to do now is I want to put all of this together and come up with a way of

being able to approach COVID 19 as a clinician and then talk about how we treat it. Let's do that now. All right, my friends, let's talk about the diagnostic approach to CO 19. So, we've talked a lot about the pathophys, we talked about the clinical manifestations, we went over the complications, all of those risk factors. The key thing here to remember is the patient presenting with signs and symptoms of COVID 19, right? And we talked about a lot of that. So that's the patient who maybe presents with potentially upper respiratory tract infection symptoms. Maybe it's a sore throat, maybe it's a runny nose, maybe it's congestion, maybe it's a headache, maybe it's some muscle pain, maybe it's a high fever, a nausea, aia, diarrhea, things of that nature. That's one reason that you'd want to test this patient. Another one is that they have close contact. So they were around somebody that tested positive for COVID 19. CO 19 is very easy to be transmitted from one person to another via respiratory droplets or fulommites. So again, close contact or signs and symptoms, you need to test them. Now, when you test a patient, there's two different tests. You can do the rapid antigen test. It's just the sensitivity for that one is a little bit lower. So, if it is negative, you can't completely rule it out. You may have to repeat it in a couple days later or just go to the gold standard, which is the nucleic acid uh amplification test or that PCR. Um, and that's going to be via a nasoperial swab. You're going to swap back there. You're going to take that actual sample and you're going to test it to see if I can find that particular virus. All it does is it takes the specimen, it actually isolates the actual nuclear material, amplifies it and sees it comes up particularly on these particular probes to say, "Oh, I definitely have the actual genetic sequence in this case for something like COVID 19 or the SARS KV2. " So that's the key here for that one. Now if that test comes up positive for that nucleic acid amplification test or let's say that you get the rapid antigen detection test and that is positive then you can say with relative certainty that the patient has COVID 19. So if they have symptoms or they have close contact you get the PCR nucleic acid amplification test comes up positive good you have COVID 19. The next question that you have to determine because it determines your decision making is how sick are they? because that determines if you're going to hospitalize the patient. have to do more testing on the patient and so that's really critical. So first thing we want to know is are they maybe asymptomatic and this was just a close contact exposure. I'm not going to do anything except hey maybe you should quarantine and just watch for supportive care right? So if there's no symptoms there's no hypoxia that's great. For the mild one, they probably have upper respiratory tract symptoms. Again, that's sore throat, fever, maybe they have an osmia, azia, maybe they have some congestion, some runny nose, a cough, things of that nature. Okay, as long as they're not hypoxic, cool. Send them home, quarantine, supportive care. The next thing is the moderate one. This is the patient that maybe is starting to show some lower respiratory tract involvement. Maybe they have some pneumonia symptoms. Maybe it's a little bit of a disna, right? cough, but they don't have any hypoxia. All right, that's still a patient I'd want to keep an eye on. I might need to just do some imaging and maybe some labs just to see where they are. Depends. But the biggest thing is that they're not hypoxic. When I get to the severe CO 19, that's when I'm worried that the pneumonia symptoms are progressing. So they have cough, they have dysnia and on top of that maybe they're showing some signs of a little bit of increased work of breathing. Maybe they're a little bit tipnic. The respiratory rate's going up. They're greater than 30. And that big parameter, the easy one to remember is that they're hypoxic. Maybe the SPO2 dropped to less than 94%. So when a patient starts showing signs of hypoxy or increased work of breathing, that's a severe COVID 19 patient and I'm starting to get concerned. critical is a patient who presents with like I'm talking very severe symptoms and what I mean by that is they're showing signs of like ARDS right they're acutely hypoxic there's refractory hypoxmia they are really working hard to breathe they're hypotensive tacocardic that's another person that I'm worried about maybe a multi-systemm organ dysfunction or failure and the other one is when I actually have evidence of organ failure Maybe this is altered mental status. Maybe this is acute kidney injury. Maybe this is I have ARDS and I'm involving a bunch of other organs as a response to that. That is when I'm concerned that the patient has critical COVID 19. So again, the big thing to determine out of this is why I'm doing all this is it determines what's the next step. Anybody who falls within that kind of moderate to critical range, I probably am going to want to do a little bit more work up on. So if they fall within that range, the next thing I'd want to do is just, hey, let me get some labs, imaging. The big p purpose of doing this is that sometimes the labs will give you some kind of concept. It's always good to get some baseline labs, especially if the patient gets admitted and they need some kind of followup. CBC for these patients, especially the sicker they get, that tends to show lucopenia, so a decreased white blood cell count. when you get that patient who has that again maybe signs of multi- systemm organ dysfunction um we know that co 19 has the ability to attack the kidney cells on its own but it also produces that cytoine storm that can also worsen kidney injury and so in these patients it's very critical to look at their renal function sometimes they can have an acute kidney injury due to the virus cytoathic effect on its own and that cytoine storm so look at the creatinine look at the bun the other thing is in patients who have that cytoine storm that they lead to severe hypotension. They don't peruse their liver. You want to watch out for any evidence of increased LFTs. So that could be an indicative of an eskeemic hepatitis. The other thing is it's really important to look for these inflammatory markers. A lot of them out there. There's so many of them. But all these tell us is the risk potentially of micro emblei or multiple micro throi all over the place. And it's really kind of a marker of badness due to that cytoine storm. So it's really good to look for things like CRP which is that acutephase reactant protein, feritin which is an acute phase reactant protein, fibbrronogen protein and LDO which LDH which is kind of a marker of overall injury to a tissue. If these things are elevated, it really pretends potentially a higher risk for things like a hypercoagulable state. it pretends a higher risk of things like maybe multi-systemm uh organ dysfunction and that's really really critical to kind of identify these. The next thing is also a coagulation panel because co 19 again has the ability to damage the endothelium. It can cause potential endothelial dysfunction. It can increase tissue factor production. It can also cause exposure of bombwrun factor and on top of that from the cytoine storm it can cause the liver to increase its production of certain types of acutephase reactants like fibbrronogen. All of these things increase the risk of forming thrombi and that is really important to be able to get an idea of that. So fibbrinogen is a really good one and a d-dimer to look at. The higher that fibbrinogen the higher the d-dimer the higher the risk of that hypercoagulable state. Again, it all goes in line here, this whole component with that cytoine storm. And again, proalcetonin is one of those that people may throw out there. You got to be careful. It's been shown that sometimes CO 19, for the most part, it may be normal. It could be a little bit lower. That could suggest more of a viral pneumonia, but that's not always perfect. The reason why we like this is that sometimes if you have a higher proalceton level, it could potentially suggest a bacterial pneumonia or a concurrent bacterial pneumonia that resulted as a postcoid kind of like a pneumonia. So again, the big things I want you to take out of getting these labs is look for potentially acute kidney injury and look for evidence of that cytoine storm. That's really going to give you some information of whether you need to be a little bit more on alert for this patient. Okay. The best thing to look at is the imaging. If I have a patient who has a chest X-ray, especially um who isn't presenting in that moderate anywhere to the critical range, I'd like to get a chest X-ray first. It gives you a lot of information, especially if a patient is distic, especially if the patient is hypoxic, if they're working hard to breathe. And what you're going to look for is these bilateral ground glass opacities. When you look at this patient's lung, you'll be able to tell. Look at how diffuse this actual kind of like overall opacity is. It's very diffuse. You compare this to a normal chest X-ray. It's night and day. You can see crisp costic angles, the heart kind of like overall contour and you can appreciate that lucency. Over here I have all of this kind of like white opacities diffusely spread throughout the lungs. It's kind of shading out the heart borders, maybe shading out a little bit of those costic angles, but that's a clear sign of a diffuse interstatial infiltrate and that's something that you would see for CO 19. All right. The other thing is if you ever did get a CT scan for these patients, you'll still see those groundclass opacities and they're kind of interesting, but sometimes you may see this what's called a crazy paving pattern. And sometimes this is somewhat kind of like somewhat pathonmonic, but it's not always perfect. So here you can appreciate these ground glass opacities. It's this kind of grayish appearance here of the lung. You can see maybe a little bit of normal lung area to tissue and all of this is kind of evidence of that diffuse kind of infiltrate. And then over here, you can appreciate it really well. You can see these lines that kind of are separating the lobules apart from one another. That's that crazy paving pattern. And that's kind of basically the thickening of the lobular walls. And on top of that, intermixed in that is the ground glass opacity. And that's pretty suggestive for COVID 19. So first thing, symptoms or close contact, test them if they're positive. Next thing, assess the severity. If they have pneumonia symptoms or they have hypoxia or they have critical findings, they have respiratory failure, they're hypotensive, there's organs that are failing, you get labs. You check the labs mainly to look at the inflammatory markers in the coagulation panel. This is going to be your big thing that you want to see. And you get the images to find diffuse infiltrates in the form of ground glass opacities and sometimes interlobular thickening with that crazy paving pattern. That is the goal for this. Now once you find those things the next thing that you have to determine is

do I need to do more of a workup on this patient and that really comes down to their symptomatology. So this is where we can get kind of like really in depth. If a patient presents with that refractory hypoxmia then the concern is have they progressed to ARDS? That's always the concern. And again the workup here comes from getting that AG. You've already had the chest X-ray showing the diffuse bilateral infiltrates. You have to then show again do they have refractory hypoxmia that's present on their AG. So a PAO2 less than 60 mm mercury. If I get the PF ratio it's going to be less than 300. If that's the case and I've and it's acute onset and I ruled out a cardiogenic source that's my concern is that they have ARDS. Other things that you want to watch out for is that in patients who have underlying conditions things like CAD or CHF they can end up with exacerbation. So if a patient presents with chest pain, you want to watch out because CO 19 can also damage the myocardium itself and when it damages the actual cardiac muscle, it can lead to myocarditis that can push the patient into acute heart failure. It could cause arrhythmias and so that's what I want to watch out for. So I like to get an ECG, make sure that they don't have any ST changes and get the troponins to find any kind of injury to the actual myioardium. So you'll see maybe an ECG will have some ST changes. They may have some arrhythmias but the tropparonin also usually in myocarditis because there's damage to the myioardium they may have a tropponin leak as well. Another thing is that if a patient has hypoxmia they have puritic chest pain they have typnia and that concern here is pulmonary embolism which is very common with co 19. CO 19 because it has that again ability to increase the hypercoagulable state. It can cause micromboli thrombi especially within the pulmonary vessels but it can form all over the place. So a pulmonary embolism is definitely concerning. So in this patient I would have to get a CTPA a CT pulmonary androgram and look for evidence of a filling defect that's kind of blocking off that particular area. And that's another thing I would actually want to consider. The next thing is if a patient had a productive cough, if they had a lowbar consolidation on their chest X-ray and maybe they had a fever, well then my concern is do they have a secondary bacterial pneumonia? This can happen just like you get post flu pneumonia, you can get postcoid pneumonia that actually is due to a super infection by things like MRSA or streptoccus pneumonia. So what I would do is again if I haven't already I get a chest X-ray and I would probably get some sputum cultures and to see if it comes up positive for the particular likely pathogen. Things like MRSA and things like streptococcus pneumonia are very common as a postviral bacterial pneumonia. All right, that's really critical to think about these when a patient comes in. So again to recap what I want you guys to think about with this patient has symptoms of CO 19, you're going to test them. If they have close contact, test them. do with the nucleic acid amplification test or PCR. It's the better test. If it's positive, they have CO 19. Then you determine their severity because if they're in the moderate to critical range. So again, pneumonia symptoms, hypoxmia, multi- systemm organ failure. Get the imaging. Get some labs. The big thing for the labs is looking for signs of inflammatory markers. That tells you that they got a cytoine storm. That's a kind of a brewin. They may have high risk for thrombi. ARS. They may have a high risk for systemic hyperrofusion. If you look at their chest X-ray, you see the bilateral ground glass opacities, you see that crazy paving pattern. That's also really suggestive of a COVID 19 kind of pneumonia and they can progress to ARDS. The big thing is that you need to be willing to work these patients up if they show signs of ARDS, getting an AG, ruling out a cardiogenic source, making sure that if they start having arrhythmias, chest pain, ST changes, you work them up and consider things like myocarditis. If they start having puritic chest pain, typnia, refractory hypoxmia, consider a PE study. And if the patient also is showing signs of a productive cough, they have a lowbar consolidation that's really getting dense, um, and their fever is really going up, maybe they have a luccoytosis, maybe their proalcitetonin has shot up, then you may want to consider like a bacterial pneumonia that's secondary to that postcoid infection. Get the sputum

cultures. And again, the goal of all of these things is it could change the patient's management. That's why it's important. All right. So now let's talk about how we treat CO 19. In order for us to do that, we need the actual life cycle in front of us. So again, you remember in this epithelial cell, we have that A2. A2 binds to the spike protein on the SARS CO V2 that allows for them to attach. Once they attach, there's two ways by which the virus gets into the cell. If it's the alpha beta delta variant, uses the TMP RSS2 to primeate. It cuts the S2 subunit and allows for it to fuse with the cell membrane and that'll release that viral RNA in. If it's the omocron variant, it's gained an ability to avoid the TNRSS2 priming and it actually just under goes direct endocytosis. All right? Either way, they get into the cell. From here, they release their RNA right into that cell. Once that RNA is in, that RNA then needs to be able to utilize particular processes to replicate itself and make more viral proteins to assemble a new virus and then go spread to another cell. How does it do that? Well, that goes to the actual host ribosomes and translates some of that singlestranded RNA into a big polyrotein. The other thing that happens is there's a protease enzyme. The protease enzyme then takes and eats that polyrotein and breaks it up into small pieces. These nonstructural proteins that we're going to utilize as kind of enzyatic processes. One of those is going to be helpful because it's the RNA dependent RNA polymerase. And what this dude is going to do is what? It's going to take the singlestranded RNA and it's actually going to convert it into mRNA. mRNA is then going to go find ribosomes that are present on the rough endopplasmic reticulum and get translated and make the actual structural proteins. It'll make the spike protein. It'll make the membrane envelope protein. Right? And then those are going to get packaged by the rough endopplasmic reticulum into a vesicle. The RNA dependent RNA polymerase is also going to take the singlestranded RNA now and it's going to replicate it make multiple strands of that singlestranded RNA. Now what happens is I have the RNA, I have the proteins. I'm going to have them do what? meet at the Golgi. So it's right at that actual complex between the rough and the Golgi. They meet and they move into the Golgi and everything gets assembled. From there it then goes to the cell membrane under goes exoccytosis and you pop out that virus. This is where we need to understand something. What if I could now attack this virus at multiple different stages? So we have antivirals and this is going to be things like nuromemetrovir and ritonavir also known as paxlovid. So it's a combination drug that's actually really kind of cool. What these drugs do is very interesting. Now the liver has an enzyme called the CYP3A4 and that metabolizes nurmmetral into its kind of broken down form. So it's going to be less effective in that scenario. Well, what if I gave a drug like ritonavir that inhibits the cyp3a4 enzyme? Now nurmatrovir won't be metabolized as much and the levels of nurmat will go up. All right. Now that nurmatrovir what does it do? It actually comes right over here and inhibits the protease enzyme. If I inhibit the protease, can I break down the polyroteins and make my non-structural proteins? No. Can I make the RNA dependent RNA polymerase and other proteins and enzymes I need? No. Can the virus then go through and make its RNA and make its proteins it needs to form a new virus? No. The next drug is rem desave. Remmes desave is great because it directly inhibits RNA dependent RNA polymerase and now it can't take that singlestranded RNA and make mRNA. So then it can't undergo the translation process. It also can't replicate the RNA and by that default we can't make new viruses. That's the benefit of these two antivirals. All right. Other drugs that we want to give is again the virus produces a cytoathic effect itself on the upper respiratory tract, the lower respiratory tract, the myioardium, the git, the um it also works on the kidneys. It works all over the place, right? The endothelium, it can damage a lot of tissues directly. And so this may reduce the damage from that. But sometimes when the damage has already been done, you trigger a massive inflammatory response referred to as that cytoine storm. What if we could give drugs that could modulate that cytoine storm? Well, again, you got to remember this virus. It attaches to these epithelial cells. The biggest and scariest one that we get worried about is these type 2 numocytes, the alvolar cells in the lungs. When it does that, it gets in there, it triggers damage to the type two alvular cells. What we know is that the type two alvolar cells make surfactant. If you can't make surfactant, what happens to your surface tension? Goes up. If your surface tension goes up, can you keep the alvoli open? No. What do they do? they collapse. That right there contributes to an overall effect in reducing recruitment of the alvoli and now it's harder to oxygenate your blood. The other concept here is that whenever these cells are damaged, they release damage associated molecular peptides. They release pathogen associated molecular patterns. All of these things act on macrofasages within the alvoli. when it acts on those alvol um alvolar macrofasages they then respond with a very aggressive hyperimmune response and they pump out things like interlucan one they pump out interlucan 6 and they pump out tumor necrotic factor alpha the big culprit here that we find is interlucan 6 tends to be a little bit more problematic than I think the rest of them but we'll get to that what these things do is they basically create this systemic and localized uh vasoddilation pulmonary capillary uh permeability and a hypercoagulable state. I'll explain. Let's say that this works in the lungs. So all of these cytoines are being released all over the lungs. It's going to basically cause the pulmonary vessels to become dilated and leaky. The fluid is going to leak out of those pulmonary capillaries into the alvoli and now the alvoli is going to be consolidated and filled. So now you got alvoli that are filled throughout the lungs and collapsed throughout the lungs. That is a recipe for ARDS. All right, that's where we start to see ARDS is from this diffuse alvular damage due to the damage from the virus and the cytoine storm. Now the other thing is that these cytoines also act on your systemic vessels and cause them to dilate and also become leaky. Now fluid starts leaking out of the vessels. If you dilate your vessels, what also happens to your systemic vascular resistance that goes down. Then your blood pressure goes down. If down, what happens to your organ profusion? that can decrease and you can start to see multi-systemm organ failure. This could be the brain. You're developing an altered mental status. You could see lactate elevation. You could see an acute kidney injury. You could see es schemic hepatitis. You start to see a lot of issues arise. All right. The other concept here is that these cytoines also do work on what? Well, you have to remember that the actual virus itself can induce thrombosis via endothelial cell dysfunction. That's one thing that we said, right? It does that by damaging the endothelial cells. They no longer can release prothrombotic uh anti-thrombotic molecules like PGI2 and nitric oxide. Platelets stick the exposed von wilterbron factor platelet stick. You also cause these cytoines to trigger the production of fibbrronogen and maybe other coagulation proteins and all of these things the cytoine storm and the direct viral and injury itself to the endothelium leads to thrombosis. The problem with thrombi is that they can pop off right. So again, tissue factor, fibbrinogen, indothelial dysfunction, we talked about that. But the biggest thing with thrombosis is the popping off of it and forming imoli. And these can form all over the place. If you get a big one in the leg, you get a DVT. If it breaks off and flies up to the pulmonary arteries, you get a PE. If they get stuck somewhere within the actual circulation, you can get a cerebrovascular accident. And you can get micro emblei that are all over the place. It could be in the fingers, toes, it could be in the kidneys, it could be in the liver, it could be literally anywhere. And that's what makes this condition super dangerous. Now this is really the effect of these this cytoine storm. But I want to zoom in and say okay how a lot of this stuff happens really comes down to how these maybe work at the cellular level. But the big culprit that we tend to look at a lot is interlucan 6. Interlucan 6 tends to actually act on these cells by binding onto an interlucan 6 receptor. When it binds onto the interlucan 6 receptor it's supposed to activate a jus kinase enzyme jack 2. Jack 2 then activates stat the signal transducer activator of transcription that then signals the nucleus to then trigger the production and undergo its process of making particular proteins and cellular responses that are very critical and in this case the cellular responses is everything that we just talked about it leads to this crap what if I had a drug that could block interlucan 6 all right that would be super helpful so now let's see how we utilize these drugs to come into play the first one that is the most recommended has been shown to reduce mortality is dexamethasone. Dexamethasone really works by kind of shutting down the cytoines very high up. So what dexamethasone does is it kind of shuts down the cytoine production and so you may see a reduction in interlucan one and interlucan 6 and tumor necrotic factor alpha and by default you'll see maybe reduced diffuse alvular filling reduced systemic profusion you'll see a reduced hypercoagulable state. You're trying to reduce the mortality factor that comes with corticosteroids or dexamethasone. All right, that's a beautiful thing. But what if I can now block it at this stage? That's where tosselymab comes in. Tossel tosselymab is an interlucan 6 receptor blocker. So it's going to basically be a monoconal antibbody that binds onto this and blocks the interlucan 6 to interlucan 6 receptor connection. Now you can't signal the jack enzyme, the stat enzyme and you don't produce a good cell response. The other one is baracit. Paracitib directly inhibits the Jonis kinase 2 enzyme. If you inhibit this enzyme, you can't activate the signal transducer activator of transcription and you can't produce that cell response with these. And so by default, what do you do? You reduce the diffused alvular film. You reduce the stemic hyperusion. You reduce this hypercoagulable state that's caused by this cytoine storm. So that's the concept that I want you to understand. When as a patient gets really sick, you're probably going to be on an antiviral and maybe one or two of the immunom modulators. If you're not as sick, you probably don't need these imunomodulators because you probably don't have that intense cytoine storm. So, you probably only need one of these. As the patient gets really sick, using these drugs definitely helps to reduce hypercoagulable state, but they're still super high risk for clots. And so oftent times we need to use things like low molecular weight hepin as an anti-coagulant to basically prevent that risk even more. And so these basically work by again not treating the underlying issue, they treat the symptoms. And so they're basically working to inhibit things like thromben um from actually well particularly actually inhibiting factor 10 which then would inhibit the actual production of thromben and again reduce the risk of thrombosis. So that is where this low molecular weight comes in is any patient who is kind of maybe showing elevated cytoine storm ris risk factors. So maybe you're looking at that inflammatory panel, their coagulation panel and you're seeing that those things are on the rise. They're looking a little bit sicker, they're in that moderate kind of category, you probably start low molecular heperin prophylactically right away. All right, that's the thing I really need you guys to understand here. All right. Now, with all of this being said, the next thing that's also really important is that CO 19 pneumonia and ARDS can cause hypoxia. That hypoxia needs to be addressed. Anytime the patient has an SPO2 less than 94%, you put them on some form of oxygen. That probably can just start off as a nasal canula. As the patient's hypoxia gets worse and maybe they're on nasal canula, then you can give them something like high flow nasal canula. This is giving them maybe upwards of 50 to 60 liters where this may cap out at around like 10 or 15. And sometimes if you have like a um a non-rebreather, those can go up a little bit as well. But nasal canula maybe potentially a non-rebreather would start off with. Then you go to the high flow if they're really hypoxmic and you need to give them a heavy amount of flow and very high amounts of oxygen. Sometimes in certain scenarios you can consider BiPAP. This is by level positive airway pressure and you're going to be generating not only you can control their oxygenation but you're helping to ventilating them. You're giving them a good amount of what's called positive and expiratory pressure because those alvolola are collapsing. You want to keep them open and recruitable so that oxygen can run into them and then run into the pulmonary blood. So BiPAP would probably be another thing that could be considered. Usually when a patient is really struggling to breathe the refractory hypoxmic to all of these above the therapies then we may have to intubate them. So we'll do an endotrachial tube intubation put a tube in and then control their ventilation with a mechanical ventilator where we control their tital volume their respiratory rate their PEEP and their oxygenation. So that's all things that would be controlled in these patients. And in worstc case scenarios sometimes if the patient has progressed to ARDS we start to consider things like prone positioning. Now in certain patients that maybe are in that kind of like let's say they're in the severe COVID 19 they're hypoxmic they have some infiltrates they have shortness of breath we do actually suggest things like awake prone positioning. So that can be utilized before you're even intubated are extremely critical. But again, the concept of prone positioning, I don't want to go into too much detail here because we talked about an ARDS, is again what you're doing is you're taking a patient who's in the supine position. When you have this COVID 19, what happens with these patients is that their lungs are consolidated in that posterior kind of dependent portions. And because of that, you have changes in the transvular pressure. And because of that, the blood flow going to those areas, you're getting mismatches in ventilation and profusion. All we want to do is improve that ventilation profusion matching. So when you flip them over, what you do is you allow for that dependent posterior portion of the lung to open up. And so now when it opens up, it's not going to be collapsed as much anymore. It's recruitable. And by doing that, you actually allow for this alvoli to participate in gas exchange better. So now there's a better transpulmonary pressure difference and because of that the perfusion and ventilation no longer have that significant mismatch and you get improved oxygenation. So that's something that we definitely have to consider but again we talked about that in ARDS. So a lot of stuff what I want you to do

is we understand now why we give these drugs but it's important to have a systematic approach of when we give these drugs. So again that patient who has the mild to moderate COVID 19. So this is the patient who is in the mild category. Maybe it's upper respiratory tract symptoms but they don't have any hypoxia. The moderate one is they have maybe some pneumonia symptoms but they don't have hypoxia but maybe they have some an abnormal chest or x-ray. In those patients it's probably best to just do something like what well if they're high risk on hospitalized you could probably just do the pulavid. So, Numatrovir um or with the ratanavir is probably going to be the go-to. Rem desavee is also a second alternative and sometimes they even consider malnir as well but we don't often use that as much anymore. So, nometravir pax is probably going to be the number one or rem desave could be a second um kind of runner up in that scenario as they get to that severe covid 19. Now, this is the patient who has the pneumonia symptoms. They're hypoxic. They have an abnormal chest X-ray, CT scan, they're kind of a little bit more complicated. In that scenario, anytime a patient is hypoxic, they're going to need oxygen. So, you're going to have to keep them in the hospital. They're going to then be admitted. If that's the case, the best scenario here is I could actually give something like dexamethasone because now they're showing signs potentially of a cytoine storm. The other thing is rem desave because I want to give an antiviral agent to prevent the continuous viral application and further damage. The other thing is I may need something like what respiratory support. This could start off with nasal canula. This could also potentially maybe escalate to high flow sometimes, but ideally you're probably going to just have them on nasal canula, maybe a non-rebreather. And again the goal here is use the one that top down effect the dexamethasone is going to really treat that higher up kind of cytoine storm. Rem desave is the antiviral agent and the respiratory support here. Start off with your nasal canula and as you start to titrate up and you need things like high flow. We're starting to get into the critical time frame. Also cytoine storms not only increase the risk of things like ARDS and potentially systemic hyperprofusion but they also increase the risk of clots. And so what would I want to have this patient on to reduce the risk giving it prophylactically low molecular weight hepin. So again this patient probably doesn't have a cytoine storm. All we need is antivirals nometraville paxvid or rem dese. This patient they have the viral infection but they probably also have a little bit of a cytoine storm that's starting to brew. Give them that topdown amodulator dexamethasone. Give them an antiviral to reduce the replication. Give them a little bit of oxygen nasal canula non-rebreather. If you have to start kind of dipping into the high flow, you're starting to get worse. You're starting to move into the critical range and reduce the risk of developing thrombi prophylactically by giving them something like low molecular weight. All right. So, if they have critical COVID 19, it's really important to remember that they obviously have that cytoic effect of the virus, but the cytoine storm is on full-fledged alert. So, because of that, this patient is likely experiencing RS. They're probably experiencing systemic hyperusion. They have a very intense hypercoagulable state. Because of this, they're probably either on high flow nasal canula and it's rapidly starting to increase their FiO2 requirements, the BiPAP, they're requiring high PEEP settings, high FO2, their work of breathing is starting to get worse and maybe in certain scenarios, they have to be intubated. Often times, the patient may start off in this severe kind of CO 19 category and then bridge themselves over into that critical CO 19 category. Now, in this scenario, it's important to remember dexamethasone is still going to be needed. you have an intense cytoine storm. This is going to give that top down effect. The other thing that's really important here is that rem desae if it was started when a patient had severe COVID 19, maybe they were on nasal canula, a little bit of high flow, maybe they were on byp right away. In technicality, rem desave has shown to have no mortality benefit when the patient is already on invasive mechanical ventilation. If they were started on it when they were in the severe state or while they were on high flow or BiPAP, all you do is you continue rem desave. That's really important to remember. You don't give it if they're intubated because it showed no mortality benefit. The next thing is because the cytoine storm is the really problematic issue here. You need a second amun modulator. That is where tosselyab or baracetitanib come into play. So if you remember anything for critical co 19 treatment is that you need two amun modulators. That is the most important critical step here. Dexamethasone for the top down tosselymab at the interlucan 6 blockage baritib at the jack 2 blockage. That is the key. The next thing is obviously respiratory support. At this point they're on high flow. They're on BiPAP, they're intubated. All right. And lastly, low molecular weight hepin for that anti-coagulation control. So again, looking at this patient, they have no cytoine storm, just the antiviral. Here they have a little bit of a cytoine storm. Antiviral and give them an amodulator, little bit of oxygen if they're hypoxic and anti-coagulation. Here, full-fledged cytoine storm. Two amun modulators. Only continue remover if it was already started when they were on nasal canula. high flow biap if they were intubated already you don't really need to start rem desave only continue it if it was already started again respiratory support it's more aggressive

high flow byp mechanical ventilation and anti-coagulation control all right that covers the treatment approach it would obviously be ideal if we could prevent a patient from even developing co 19 right that's the goal so how do we go about doing that well that's where vaccination comes into play my friends and there's mrna vaccine If you guys want to know a little bit about them, you can see that on our other videos where we talk about things like Madna, Astroenica, etc. But there's mRNA vaccines and there's actually novivvax, which is kind of like this protein subunit. Essentially, it's kind of the same thing. One is you're kind of like giving them a way of being able to produce these antibodies via the mRNA that's introduced. One of you're giving them proteins to produce antibodies. But either way, you're introducing a vaccine to the individual for them to produce antibodies against what? Against this son of a gun, the spike protein. Other things that we may give in certain scenarios is pimabart. It's a chemoprilactic agent. Essentially, it's the amunogloabbulin. You're not even giving the opportunity for the patient to produce the antibbody maybe because they can't. you're giving them a monoconal antibbody in this scenario or an IGG antibbody against the spike protein. You're not giving them a chance to produce it. So either way, in both of these scenarios, you're giving them a antibbody. The vaccine, the body makes the antibbody. The chemoplaxis is an artificially alreadymade antibbody. But what do they do? They bind to the spike protein. They block the spike protein from connecting with the A2. They can't attach. They can't get into the cell. can't undergo that viral replication process. That's a beautiful thing. Now, with this being said, who do you give these to? The mRNA or protein subunit vaccines, it's any patient greater than equal to 6 months of age. All right, that's really the key. That's the really important thing to remember for the chemoprilaxis. It's a patient who's not capable of responding to the vaccine and mounting a strong enough immune response to produce those antibodies. So, you give it to them. you say don't worry put the immune system at rest I got you that is the thing that you want to remember so again for chemoprilaxis you're giving the patient the actual antibbody you're not letting their immune system generate vaccine you're giving it to the patient expecting their immune system to generate the antibodies against that spike protein that is the key thing here my friends we talked a lot about co 19 we went over the pathophysiz complications those who are at risk we talked about the downstream consequences of this condition and what it really can do. We talked about the approach that whenever you have a patient who has symptoms or close contact, what's the testing? How do you assess the severity? When do you get labs and imaging? What do those labs and imaging tell you? And then what are the potential complications of this that I may need to do a further workup? How do I treat it and understand that treatment based on why I do it? And then understand it in a systematic approach of who I give this to and then finishing it off with the prevention. What is the best way that we could attack this mechanism right from the beginning and how do we do that and who do we give it

to? I hope at the end of this you understand that and answer those questions and man I love you guys for sticking around, hanging out and uh as always my friends until next time