Influenza | Clinical Medicine

What's up, ninja nerds? In this video today, we're going to be talking about influenza. This is a part of our clinical medicine series. If you guys are digging these videos, you like them, they help you, they make sense. You know the deal. Hit the like button, comment down in the comment section, subscribe. You want to take some time to really understand things though, and I think this is critical. We have things like notes that are extremely detailed. We have some illustrations that I you guys can follow along with me. We have some quiz questions. We're trying to develop some flashcards for you guys all on the website. So, go check it out at ninjer. org. Without further ado, let's dig into influenza. Influenza is one of these kinds of viruses that it can potentially cause some severe infections. And so, we have to first off understand a little bit about the viology. Then, we'll talk about the risk factors. So, anybody can get influenza. It's more about identifying the severe cases of influenza. So, influenza related complications. And so we'll talk about that. Then we'll get into once this virus kind of accesses our epithelial tissue, particularly of the respiratory system, how does it actually cause damage? And then what does that tissue damage look like of the upper the lower respiratory tract? And then worst case scenario, what are the most complicated concerns when we talk about influenza? So let's dig into it. First things

first, influenza virus, it's a part of a family. It's probably not super high yield for you to know this. I just think it's kind of cool to know. It's a part of what's called the ortho Mixo verde family. All right. So it's part of what's called the orthomix verde family. Now when we talk about influenza a couple different things is really critical to it is its structure. So its overall structure is really important. When you look at it it's an enveloped virus. All that means all that literally means is that it has a lipid billayer. That's all it is. It just means that it has this lipid billayer and in that lipid billayer there's a bunch of different kinds of proteins glyoproteins that are plugged into this surface. All right, the next thing is it has a particular genome. This is the nuc the actually the DNA the RNA different types of things that are really important for a virus that once it accesses a host cell our epithelial cells it uses our kind of overall cell to generate its overall kinds of nucleic acid structures. That genome is really, really critical. When you look inside of this, it's got some very, very specific types of nucleic material. And that is what's called singlestranded RNA. But there's two different types. And so one is you have what's called a negative sense, and positive sense singlestranded RNA. This is a negative sense singlestranded RNA. All right. So, so far, what do we got? We have a enveloped virus. All right. All that means is it has a lipid billayer inside of it. It's got some genetic material which is called the singlestranded RNA and it's got different types of we'll call them RNA dependent RNA polymerases and so they're going to be very helpful of being able to make new RNA. The other thing is on the surface so within this kind of like overall envelope or that lipid billayer it's got different types of surface glyoproteins and we'll kind of color coordinate them. The red one is probably the most important one and that is called hemma glutin. And this one is a weird one where it's got two G's. Sometimes hemoglutin and we'll abbreviate this HA. So hemoglutin is a very specific type of glyoprotein that's on the actual surface of this virus within the lipid billayer. Really important one. Why is this one so important? Well, we'll kind of illustrate it. What it does is I'll kind of go through it. I promise we get into the overall life cycle and how this actually infects cells. But this structure, what's critical about it is that it allows for attachment component. It's an attachment component. So what it will do is it'll allow for this virus to stick to our epithelial cells and it does that by binding to these things called P scialic acid residues that are on our epithelial cell surfaces. The next one, so that's the hemoglutin, right? So this is basically the hemoglutin. There's so many different types of these and that's what we'll get into. There's different subtypes of influenza and that subtype is really dependent upon the hemoglutin and the next component. The next component is called nuraminadase. And we'll write that as NA. And again, you'll see here that's that blue particular protein. This one, we'll get into it a little bit later, but this guy is really, really critical for allowing for the release of the virus from the host cell. So, basically what happens is, we'll get into it, I promise, but the virus gets into the cell. So it uses its hemoglutin to attach to the host cell, gets inside of the cell, replicates it all of its kind of machinery, its proteins, its different types of RNA, repackages it, kinds of buds off of the cell, but it gets stuck and so it needs to cleave and release the virus. So it's critical component here is it allows for the cleavage and releasing of the virus. So it completes a role what's called a it's a cleavage component. And all that's going to allow for is it's the release of the virus. And again, this is the nuraminadase. And there's multiple different subtypes of these. And I'll explain that a little bit later. The next one is this green protein. And this one's called the M2 ion channel. It used to be really, really important that we knew this because it used to be a drug target. We just don't use this drug anymore. it's no longer recommended because resistance to that drug, especially with the current influenza A strains, the drug is pretty much like it's almost like no efficacy whatsoever. Like there's greater than 99% resistance to the drug. So, we don't really use it, but there is an important component to it. So, here's the M2 ion channel right here. And what it allows for, and I'll write it again, we'll go over this, but it's going to allow for what's called uncoding. That's all I want you to know. It's critical to the uncoding. It's an uncoding component. And I swear we will go over this when we get into the life cycle. What's the most important ones out of these is the hemoglutin and the nuramadase. And we'll talk about this, I promise, when we get into the types of influenza. But there's so many different subtypes of hemoglutin. nuramadase. And what happens is we put these together to give you a specific kind of subtype of that influenza. And so we get into what's called like H1, N1. We can have uh another one called H3, N2. You get the point. There are different types of hemoglutin and nuramidase. And that gives you the type of influenza. For example, this is the most common type of human flu. This is the second most common one. And then there's other ones like bird flu, swine flu. So they have differences in their hemoglutin and the neurodase. And that's why they're super critical. All right. So we got the structure and again inside you see how inside of that lipid billayer what do we have? We have all of the singlestranded RNA. That's a really important point. So this is our single stranded RNA. And again what type? Negative sense. Which one is it? It's all of these. But here's one other thing I want to add on to it. How many uh of these do you see? Eight. That's one really important point. Another thing that I need you guys to remember and that's comes into play when we start talking about things like antigenic shifting and antigenic drifting. But more specifically the concern is when we get into like antigenic uh shifts is there is eight different segments. So there's eight segments in the virus and that's really really important because obviously these segments determine the types of hemoglutin amidases M2 all of these things that we need. The other thing is we need a particular protein. And I told you about it inside of the virus. And what is this one? That's that orange structure. This is called RNA polymerase. And it's technically an RNA dependent RNA polymerase. And that's this little orange structure. And we're going to need this because it's basically going to take the RNA. Eventually, what will happen is it gets converted into very specific types of RNA and then we can transcribe it. We can replicate it and make more RNA so that we can make more viruses. All right, we got overall the basic component of the virus. The influenza virus is an envelope bio virus. Has a lipid billayer. It has what type of nucleic material inside of it? RNA is it single strand or double stranded? Single strand. Is it negative or positive? Negative. How many segments do we have of this? Eight segments. When we look at the structure, what kind of surface glyoproteins are present? Hemoglutin, nuramidase, M2 ion. What is the most two important ones? hemoglutin and nuramidase. Why? Because it determines the subtype of that influenza. The next thing is how in the heck does this thing get transmitted? Well, it's primarily via two different ways. One is it spread via respiratory droplets. So in other words, someone coughs, they sneeze. And that thing is just airborne. Another one is fulommites. All that means is and we'll get we'll kind of explain this. Let's say that I have a person here who's infected. This is the infected individual. All right. So, infected. And let's say here is the normal person. What I mean is normal is they're not infected. All right. What happens is this person decides to go ahead and just sneeze away or cough away all of these different types of viruses into the air. This can obviously travel into the person's respiratory tract and cause damage. Another thing is it could land onto different types of hard surfaces. And so let's represent that. Let's say it lands onto a doororknob or it lands onto this handrails and then someone walks by this individual touches it and then touches their face, touches their nose, touches their mouth, they then allow for that virus to access their airway, their respiratory tract and that's where allows the damage to actually occur. This is the example of fommites. the respiratory droplets that have aerosolized. All right. The other thing I want you to know is that influenza there is different types. But when we really think about this, it's influenza A and there's three other ones, but these other two are less common. So it's influenza B or C. What I want you to know is this one is much more common. These are less common. All right. So there's two things I want you to get out of this. Influenza A is more common. The other downside about this one is it can actually be more severe. So, it's more common. It can cause a more severe disease presentation. And we'll get into another thing. Because this is more common and more severe, it has the possibility of causing more things like antigenic drift and antigenic shift, which we'll explain. Influenza B or C are less common and oftent times cause more of a less severe course. And it's likely due to it has less antigenic drift and antigenic shift. All right. So that's what I want you to know is that influenza A is likely to be the more common type that we're going to discuss. All right. So influenza A is the most common type of influenza most often spread via respiratory droplets or fommites has this specific structure that we talked about that makes it really easy for it to cause a lot of damage. The next thing I got to talk about before we really start getting into particularly risk factors and its life cycle and how it causes damage is I

talked about these two different terminologies and we have to be able to understand the differences between these two between antigenic drift and antigenic shift. The big thing I need you to know is when if you take anything away from this antigenic drift is more associated with what's called epidemics. So localized kind of outbreaks that occur within a particular community due to small changes in some of the hemoglutins or nuramidase protein structure. That's really all it is. Antigenic shift causes global pandemics because what happens is you're not having small changes in the hemoglutin and the neurodase. You're making a novel type of virus. Let me explain. Let's say that a person gets infected by this virus here. And let's just say that this is your H1. All right. So this is your H1N1 influenza. Right? And this is which type? More often influenza. How do you get it? Respiratory droplets or foommites. Gets in here binds on to this epithelial cell that we have here at the respiratory tract. Gets taken in via endoccytosis. Once it gets under goes endo endoytosis it actually under goes uncoding and viral release releases out its nuclear material which is it singlestranded RNA and its RNA dependent RNA polymerase. These move into the nucleus where it under goes some specific modifications. One of those modifications is we turn it into mRNA. That mRNA then goes to a ribosome and the ribosome will then synthesize these specific types of proteins. The other component here is that this um genetic material, the singlestranded RNA, we convert it into what's called complimementary positive strand RNA and then eventually we then use that as the template to make a bunch of negative stranded singlestranded RNAs. All of these will get repackaged and then what we'll do is we'll release a new virus. What if along the way you developed a mutation? So in other words, let's say somewhere in this process as the RNA polymerase is reading the RNA and making new strands, it causes a mistake right here. You get a little point mutation. So what is this usually due to? There's something called a point mutation. So really the trigger here is a point mutation. That's son of uggon. It that point mutation. The problem with this is because it's very common with RNA polymerases, this is now going to get read by the ribosome. When it gets read by the ribosome, the ribosome is going to read that particular RNA strand and make a maybe a different type of amino acid. It may substitute, it may delete. And because of that you create small changes in maybe the hemoglutin and the nuramidase structure. That's the key. And so there is a small change in maybe the hemoglutin or neurodase structure. That's why this is really important because this can be prevent. We usually we have vaccines and these vaccines are manufactured based upon the current circulating strain and that's why this is really important to make sure that you're actually getting vaccinated because we want to be able to stay up to date with the current strains that are out there and because these small little mutations can occur that may also slightly reduce the efficacy of that potential especially if you use inactivated forms of the influenza vaccine. Let me explain one more time. Let's say here we kind of have this virus come in. It's still going to be H1N1, right? So it's still H1N1. The only thing it changed is still the is I'll put a little asterisk to it is that it's a small change in the overall structure of the hemoglutin and the neurodamase, but it's still an H1 subtype. Still an N1 subtype of the influenza. So all that happens is here's the RNA strand. Let's say here you have a mutation. that mutation whenever it actually occurs and it gets read by the mRNA it's going to be red and it may swap out a nucleic acid I mean or delete a specific type of amino acid in that protein structure and so all that happens is maybe it kind of causes a small little configurational change and that's really important and that's why we want to be able to stay on top of our vaccines make sure that we're actually making vaccines against the current circulating strains all right so this is antigenic drift This is extremely common, completely normal. This happens a lot. Antigenic shift is your nightmare. All right, this is an example and this is why when we talk about epithelial cells, this is usually what happens pretty much normally in a human cell. Our human cells as RNA polymerases are reading RNA, they make mistakes. They're not great proof readers. And so because of that, they make mistakes. those mistakes is then maybe put on the wrong type of um nucleotide that gets read by the um ribosome and gives you the wrong amino acid but you still have the same hemoglutin and aramadase structure. It's just a slight confirmational change. This is I have a pig cell. Usually this is the perfect examples because pigs have different types of receptors that combine different types of influenza viruses. So let's say for example I take one like let's say I take H3 N2 which is a type of influenza. It's just a less common strain. And let's say that I take something like the bird flu which is H5N1. H5 is what makes hemoglutin 5 is a really scary one. All right they have they bind to special P scialic acid residues that are usually in the lungs as compared to the upper respiratory tract. But let's say that this all happens inside of a pig. So let's say that a pig catches the human flu, catches the bird flu. Both of these simultaneously get taken into the cell. They undergo endocytosis. Then what happens is they undergo viral uncoding and they release their nuclear material into the actual cytoplasm. This material then does what? Gets into the nucleus. Once it gets into the nucleus, this uh RNA and the RNA dependent RNA polymerases will make mRNA that can then synthesize proteins. The problem is that if I read this one, I'll get these types of proteins. So, this may be the H5 and the N1 proteins. H3 and the N2 proteins. Over here, I'll synthesize some RNA. And this RNA could be the negative stranded RNA for the human flu and bird flu. So now look what happens here. I can have some H3 and N2 and over here I can have some H5 and some N1. And then again I'll have singlestranded RNA that comes from the human and the bird flu. Then what happens is when I package these, I package all of these together and make a virus. I may have a virus that unfortunately maybe it grabbed all of the H5s, but it stuck with the N2s. And you guys get the point. That's what makes this kind of scary is this is no longer the same virus with a small little change in its overall structure. This is a completely new type of virus. This is a novel virus. This is what keeps probably like your microbiologists and epidemiologists like up at night because now this is a novel virus that we could theoretically call H5N into. And I'm making this up. I'm not saying that we actually have one of these, but this is now a completely new virus because it's by random chance when we try to assemble these viruses together. We may grab some of the H5s, H3s, we may grab some of the N2s, the N1's, you may grab some maybe five of the RNAs from the bird flu, maybe three human flu. It's not like an exact science. It's by random assortment. That process can lead to a possibility of this new virus having completely new different types of hemoglutin and nuramidase proteins. So again another concept here is just again imagine here here's the human version. So here is the H3N2 version RNA right? So here's the RNA of that one and here is the H5N1 RNA. There's no point mutations here. What's happening is this is making these types of proteins. It's This is again which types? This is making your H3. N2s. This is making your H5. This is making your N1. But then what happens is when we go to reassort these and actually repackage them, you get a mixture of these. That's the danger is that now we can have a mixture of all of these. And maybe what I do is I take mainly these two and that is where I get the new virus. This is what makes this extremely scary and dangerous. And oftentimes we use the pig as the perfect example because it has epithelial cells in its intestine that can bind to all different types of hemoglutins, especially things like the human and the bird. And then what happens is you create a new virus that has the capability of attaching into human cells. And it was actually from a you know usually a zooonautic one. So something like the bird flu. So it has that hemoglutin that allows it to attach onto epithelial cells that it couldn't attach on to before. That's what makes this scary. That's what causes global pandemics. So now that we understand that, we get the point that influenza is a part of the orthomixir day family. It's an envelope virus. It has surface glyoproteins like hemogloin and remedies. We understand now why that's so important. Usually the most common type is influenza A. Not as common for influenza B or C. Why? Because again influenza A is the more likely one to cause things like severe disease. It's more likely to undergo antigenic drifting. It has the possibility of undergoing antigenic shifting. When it undergoes a lot of these processes, hemoglutinates are the key elements. But what is the genome? It's because they have eight different segments of RNA. And what kind of RNA? Negative singlestranded RNA that really again contributes to the production of those specific types of proteins. Now we went through this I think pretty well.

What I want to do now is I want to talk about because again anybody can get influenza. It's not the fact of if you get influenza it's the fact if you get a severe case of influenza. And one of the severe ways that I would consider influenza is you end up with like a primary viral or primary influenza pneumonia or like a secondary bacterial pneumonia or you have some kind of a chronic diseases and it exacerbates those diseases. That's probably the more severe cases and this happens obviously in a very specific patient population. So what are those? It's any patients who have an impaired immune response. So for example, probably the ones that I would be the most concerned of is anyone who is immuno compromised. Anyone who's im imunocmpromised. So that could include your HIV, your AIDS patients. They're on some type of immunosuppressive therapy. So this could be I mean you could go down the line TNF inhibitors, steroids, you guys again we can go down the list if they're transplant and usually that kind of goes along with the imunosuppressants because a person who's a transplant recipient usually they're on anti-rejection meds. So imunocmpromised individuals definitely I would kind of fit into this category. The other ones that I would fit into this category is pregnancy and pregnancy causes impaired te- cell function. So, believe it or not, in those who are pregnant, there's actually kind of two concepts behind the pregnancy. One, it's not being mean, but they got this fetus that they're growing in that's growing in them, and it pushes the diaphragm up. And so, that basically kind of creates like more of a restrictive physiology, if you want to think about that, because their lungs can only expand so much. That increases the risk that if they get a bad infection, it could actually be harder for them to breathe than a normal individual. Plus, pregnancy does kind of change your overall TE-C cell of function. So they may have more of an impaired te- cell function that makes them less able to kind of fight off these infections. And the next one is extremes of age. And so this is what kind of age range. Well, usually anybody greater than or equal to 65 years of age and anybody less than 5 years of age. So usually anybody within the 5 to 65 year um anybody 5 to 64 year range is probably going to be at less risk of a severe type of infection. If you're less than five or greater than or equal to 65 you're more at risk. The concept behind this is something called amunosineessence that it's probably especially with older individuals they have immunoscins meaning that they kind of have I'd like to think about it as like you got some sleepy grandpa grandma types of immune cells. They're overall just exhausted and they don't have the capabilities to fight off infections as well as someone who's younger. All right, this one you're just your immune system is a little bit more naive. You haven't had the opportunity to build up immunity. All right, so the concept behind this is pretty straightforward. Let's say that you get exposed to this influenza virus, gets into an airway. When it gets into the airway and it starts causing what? Tissue damage. This tissue damage is going to do what? It's going to alert your immune system. That's really, really important. So, you should be able to activate things like lymphosytes. macrofasages. But because you have an immunompromised or impaired immune response, guess what? When you're supposed to stimulate this, this is supposed to basically activate macrofasages, right? Or lymphocytes, activate macrofasages and lymphocytes to kind of come here and kill this potential virus and really mount a proper immune response. What's going to happen? you ain't going to get debt. So, you're supposed to do this, but in patients who have this impaired immune response, guess what? That impaired immune response alters this process. And so, you may have in some scenarios, maybe you're imuno compromised, so you just don't have the actual immunity response to bring in the lymphocytes or you have some type of imunosiness or novel naive immune system. You can't activate those macrofasages. And so, in those scenarios, I actually inhibit my lymphocytes. I don't stimulate them. I inhibit my macrofasages and I don't allow for them to come to actually do their job. And because of that, the combination of these two things is you lead to that virus continuing to be able to replicate. So the virus survives and if it survives, it can potentially keep replicating. And if it can do that, it can theoretically cause more damage. And in that potential scenario, what happens? you can end up with a severe infection and that is why we get really concerned. So they can end up with severe infections. Usually this is an example of something like pneumonia. This could be you know bacterial primary viral influenza. I mean primary influenza pneumonia. But again that's why we get really concerned about these patients is they're super high risk of getting a severe case of influenza. The other kind of patients who are at risk of severe infections is those who have chronic diseases. The concept behind this is that it's probably going to exacerbate some of their underlying diseases. So what are some of these patient populations? I they say the big one is probably going to be those who have COPD, asthma. This is why we often times really suggest especially for the COPDers that they get keep up with their annual influenza numacco vaccines because if not they get infected with something like influenza or numacco it can really push an exacerbation up increase their mortality and morbidity. The other one is probably those who have underlying coronary artery disease or maybe underlying CHF. We'll talk about why in a second. And then anybody who is morbidly obese and we kind of define that morbid obesity especially when the BMI is pretty high. So greater than 40. This is probably the patient population that you want to be really on the lookout for. The concept behind the morbid obesity is actually kind of interesting. It's kind of similar to the pregnancy. It probably creates in general it probably creates more of a restrictive uh physiology. So it causes more of probably restrictive physiology and that restrictive physiology in combination with an influenza infection something like a pneumonia can make it harder for the patient to be able to breathe. Kind of similar to pregnancy but COPD asthma CAD CHF is kind of interesting. So let's talk about this. Let's say a patient gets has COPD. They have asthma. Normally their airways, they're not like super hyperactive, but they have underlying disease processes. Let's say that this virus gets into the airway. And when it does this, it causes some airway damage. We'll talk about how it does that, but usually it damages the epithelial cells. It damages the mucosilary apparatus. And so, you're going to get damage to these tissues. It's going to create an inflammatory response. That kind of damage is going to trigger cytoines that are going to trigger something called bronospasm. So it's going to cause increased mucus production. bronco spasm. So what's going to happen as a result here? You're going to get two things. One is you'll probably get more mucus production or actually you'll have destruction of the mucosilary escalator because you damage the cells and so you can't beat the mucus as well upwards. So it may cause a little bit more of mucus and on top of that it's going to cause bronco spasm. So two things happen as a result here. One is an increase in mucus and the other one is it's going to cause something called bronco spasm. The combination of these two things can push a patient into what's called an exacerbation because it causes a dynamic kind of airway obstruction. So when you cause this type of effect here, you're going to push them into an exacerbation because what you're going to do is you're going to obstruct their airways even more. One is you cause bronco spasm, one is you fill it with mucus. If you cause a worsening obstruction, you're going to exacerbate their already obstructive lung disease. That is why we get concerned about these patients because it can make their condition worse, increase the risk of underlying disease exacerbation. All right? So again, it can pump out the mucus. It can cause the bronchi to spasm that causes worsening airway obstruction and precipitates an exacerbation. All right, the other concept here is what if the influenza gets down here and you get something like a pretty bad kind of infection here. Let's say that you get a good really good infection here. You get an infection of the lung tissue and two things happens as a result of this. All right, one is your immune system responds and when your immune system responds, it pumps out different types of cytoines. All right. So we'll explain this here for a second. It pumps out some cytoines. So what are some of these different cytoines? One is you can have things like interlucan one. You can have interlucan six. You can have TNF alpha. All of these guys are getting pumped out. And what happens is these cytoines they definitely cause a lot of stress. All right. They cause things like vasoddilation, right? That's one really problematic issue. They can also create changes in the overall plaque structures in patients who have CAD. But one of I'd say the biggest thing here is that it can cause hypotension. It may cause in certain scenarios hypotension. That's where I'm going to leave it right now. That these kind of cytoines especially in high amounts they can precipitate something called vasoddilation and that can drop the patient's blood pressure. The other thing is that whenever you have this severe infection, you alter the gas exchange process. When you damage the type 1 epithelial cells, you cause fluid and you cause the thickening of the respiratory membrane. you alter gas exchange. And so because of that, I'm gonna make it harder to get things like oxygen into the bloodstream. So now because of that, I'm going to have less oxygen. If I get less oxygen in the blood, that's called hypoxmia. You know, hypoxmia is a sucky thing because one of it is just you don't have enough oxygen delivered to the tissues. The other concept here is that it actually causes a reflex sympathetic response. And that sympathetic response is to trigger something called tacocardia. So that hypoxmia may you have two concepts from this. One is that you have hypoxmia just in general. So you have less oxygen to theoretically be able to deliver and then on top of that your patient's going to try to breathe faster. Their heart's pump more blood to the lungs to hopefully undergo more gas exchange. But here's the issue. If I have hypoxmia and tacocardia and hypotension, all this does is it can create mismatches in a person who has underlying heart disease. What do I mean? Well, hypoxmia is going to do what to your oxygen um supply. It's going to decrease your oxygen supply. What about hypotension? You're happens in tacocardia? It increases your O2 demand. So now as a result of me getting a really bad influenza infection, I am going to cause reduction in my O2 supply and increase in my demand. That's going to create a mismatch. And when you get mismatches in oxygen supply and demand, you create opportunities for myioardial eskeeia. And if I cause maybe some eskeeia to the moardial tissue that could push a CAD patient to end up undergoing something like maybe they develop an end stemi maybe they develop something like unstable anga worstc case scenario I may even trigger it to push them into a stemi all of this is under that umbrella of what's called acute coronary syndrome that's one thing that theoretically could happen because I may cause myioardial eskeeia due to oxygen demand mismatch and again I told you sometimes these cytoines they can actually cause the plaque to rupture too so that's why stemmies are probably less common you'll probably see more and stemmies unstable engine but again I want you to think about that and the other thing is if a person has heart failure and you cause eskeeia you're going to decrease their mocardial ejection fraction and so theoretically if a person has a CHF you decrease their left ventricular ejection fraction even more you can put them into acute heart failure here. So then what would acute heart failure look like? Well, they may end up having things like pulmonary edema, jugular venus distension, they may have more disnia. This patient may have chest pain, elevated troponins, EKG changes. You get the point. This is worsening their underlying heart disease in severe cases. So we don't want them to get severe infections. That's why these patients usually have co-orbidities, have this type of immune uh impaired immune response. We're very consistent with getting them vaccinated and if we notice that they have signs of an infection of influenza, we don't want them to get a severe disease. So we may treat them with antivirals ahead of time. And again, this last one is just paying homage to the morbid obesity. If you have restrictive physiology, so you have a person who's very, very obese. In obesity, what it does is, you got to think about this. In obesity, it does two things. One is it adds a thick layer on top of the patient's chest. All right? And so that basically increases the let's say the chest wall thickness and that makes it harder for your chest to be able to expand against and so it wants to be able to go and expand outwards but it's got this thick fat layer that's restricting that. All right. So that's one concept. The other one is when you have a person who is obese, what does it do to the diaphragm? Well, if you got a big old belly, it's going to push the diaphragm upwards and that's going to make less space with inside of the thoracic cavity. So, it's hard for it to be able to expand and you have less space in general. It makes the lungs much smaller and hypoventilated in general. So, that's another thing is chest wall thickness impairs expansion. But on top of that, you also have the diaphragm bows up into the thoracic cavity and that's how you kind of get that restrictive physiology. And when you have that type of restrictive physiology, the concept behind that is that you kind of cause hypoventilation. That's why patients can get what's called obesity hypoventilation syndrome. And if you have that in combination with a pretty bad influenza infection, imagine how much harder it is it's going to be to breathe. All right, I spent time talking about this and really harping on this because again it'll come in really handy when we talk about this because again these things are basically all if I'm kind of combining this concept here this is causing exacerbations. So all of this is really triggering an exacerbation of their underlying disease. All of this over here. All right. So again, this is really important because this is triggering an exacerbation of the underlying coronary artery disease, heart failure or making it much worse scenario if they have morbid obesity and COPD asthma again triggering worsening exacerbation. I spent a lot of time on this because again it's going to come in handy when we determine who we test, who we really have to be aggressive with vaccines and then which ones we treat with antiviral agents regardless of when their symptoms started or not, if it's severe or not. We have to make sure that we know that. All right, let's

dig into the next step. The next step here is talking about this virus gets spewed out into the air. It hits a fomite. You touch it, you touch your kind of respiratory tract and it attaches onto an epithelial cell. Once it does that, how does it go through its normal life cycle? And then from there, once it damages this cell, what does that look like within a patient? So, first things first is here's the virus. It gets taken up, spread via respiratory droplets, gets in here, gets into the airway. Either way, it's going to cause some tissue damage. We'll talk about this. It can cause damage to the upper respiratory tract and lower respiratory tract. All right? And usually that kind of breaking point of where the you know we kind of determine upper lower respiratory tract is at the level of the generally larynx right at the lingial inlet kind of we kind of consider that at that point we're changing it up from upper respiratory tract to lower respiratory tract. So once this gets into these airways and attaches onto an epithelial cell can cause upper respiratory tract infections. So if we really wanted to we could say that this could trigger a upper respiratory tract infection or it can cause a lower respiratory tract infection. Right? Boom. And boom. But it has to attach onto the epithelial cells of the upper respiratory tract or lower respiratory tract. How does it do that? Well, here's the virus. On that virus, I told you there was a very specific type of protein. What was that protein? It was hemoglutin. The hemoglutin is basically it's kind of like your glue. So, it's a really, really important structure. So, again, which one was it? This is your hemoglutin. Hemoglutin allows for you to attach to a receptor that's present on this epithelial cell and that's called P scialic acid. So the first thing that happens is the virus which has hemoglutin binds to the P scialic acid. Then from here it starts to undergo this membrane of vagination. Right? So it's going to stick here onto the scalic acid and then it's going to start undergoing a process called endoccytosis. So first thing is it kind of creates a little invagination. Then from here it brings this whole thing inside and puts it into this thing called a endoome. But in order for this virus to even get into this epithelial cell of the upper and lower respiratory tract, it needed what? the P scialic acid residue on the host cell and the hemoglutin on the virus to be able to bind. That's the first step. All right. Second is uncoding. So here's the endoome and then again it's binding to the P scialic acid that's again on the actual host cell but it gets brought inside of this endoome and it's doing that via the hemoglutin. Once this happens the endoome under goes something called acidification. All right. So what happens is there's little channels that are present on the endoome and this is called just your acidification channels and what's going to happen is protons are going to rush into this little vesicle. When it does it then acidifies the center basically inside of the endoome gets acidic. All right. There's channels that I told you about that are present on the viral membrane. What were those called? The M2 ion channels. Once protons come into this space, they make it acidic. So, what I'll do is I'll show that there's some positive ions here. It makes it acidic. Once it gets acidic, these M2 ion channels open up. When they open up then all the protons do is they rush into the virus. They run into this lipid billayer and then they make the inner center of this acidic. The benefit of doing this is that it basically enhances the ability of this hemoglutin to fuse with this cell membrane. It's going to trigger the release. All right. So first thing is we have to have the hemoglutin to bind to the scyic acid residue come inside make an endoome. Then once it gets inside the endoome undergoes acidification. So we're going to say acidification of the endoome. And then after the acidification of the endoome, what happens? That's this first part. The acidification of the endoome is this first part here. Then the second part is the M2 ion channel allows for the positive ions to come into the virus. So then what we're going to do is we're going to say that this part here is we have M2 ion channel opens. Why? Because of the acidification. Because the protons come into the endoome, they change the pH of that area. The M2 ion channel is very pH sensitive. Boom. Opens up. Protons rush in. Now we create a perfect environment for the virus to say, "Okay, I'm going to come out now. " That's the next step. From here we go to genome transcription replication. So right now it's going to start fusing. So what happens is this basically this whole thing fuses. We're going to fuse this kind of membrane here with the virus. Boom. It's opened up because of the acidification process. So the acidification process allowed the M2 ion channel to open up. Protons came in and then now we have a fusion of the endoome with the viral envelope. From here what happens? we release out that genetic material into the cytoplasm. And what are we going to release out here? We're our RNA polymerases, which are going to be right here. Here's my RNA polymerases. And then I'm also going to release out what? My genetic material. What is that genetic material? Come on. Say it again. It is the single stranded RNA. Is it negative sense or positive sense? Negative sense. Once this happens, where does it go? Right into the nucleus. This is going to go into the nucleus. Now, when it go here, let's actually do this. What happens here is it's going to have two highways. One go to this highway and the other one is going to go to this highway. Once it goes in here, we have this RNA polymerase. We already talked about it. Here's the RNA polymerase. It has different subunits on its surface. The subunits basically allow for it to do different types of things. One is we can take this negative sense singlestranded RNA and I'm going to add a little fiveP prime cap on it. All right. So, what I'm going to do is I'm going to show you now. It's going to undergo what's called cap snatching. I ain't capping, bro. I ain't capping. And all it's going to do is it's going to add on this little piece and that's called the fivep prime cap. So, it's going to do two things. is one is it's going to add on this fivep prime cap and it's also going to kind of basically turn it into um a piece of mRNA that's capable of now being translated. So, it's going to add this fivep prime cap and it's going to turn it into an mRNA and this mRNA strand now it's going to hopefully it's going to try to make it more positive sense and then it's going to run to our ribosomes and now this fivep prime cap that's on that previous negative sense singlestranded RNA is made it into something that's actually readable. Now the ribosomes can actually read this nuclear material can read the nucleotides. When it reads the nucleotides, it then synthesizes what? All the proteins that it needs to be able to make a new virus. What are those proteins? It makes hemoglutins, which we're going to represent here in red. Where is my markers? Here we are. Out of frame, in frame. It's going to make neuronidases, which are these blue proteins we represented it with. It's going to make M2 ion channels, which are those green proteins that we represented. It's going to make more RNA polymerases which we represented in orange. All of these are the proteins that we need to make new viruses. All right, so that's the first thing. RNA interacts with an RNA polymerase. It basically adds a fivep prime cap and turns it into a positive sense mRNA that then can be read by the ribosomes and make viral proteins. This is my viral proteins. And we already talked about all these different types of viral proteins. The other thing is another subunit on the RNA dependent RNA polymerase is going to basically take this singlestranded RNA and convert it into something called positive sense complmentary RNA. All right, that's not a certified anesthesiologist. This is we're going to go uh from here we're going to have positive sense RNA is now able it's basically here's what I want you to think about this as this is a template we can't really um replicate negative sense single stranded RNA we need it to be in a positive sense and now this is going to act as the template and this template we can then use this enzyme this RNA dependent RNA polymerase now that we have this template form it can basically add it can make new strands off of that template and so now what will happen is it'll use that and it'll pump out a bunch of new singlestranded RNA. How many pieces you say? I'm just going to represent it here, but I'm you're going to yell it back at me. Is it's going to make negative singlestranded RNA? A bunch of them. But how many? Eight. All right. It's going to make eight of these. From here, we have basically used the cell's machinery to make viral proteins to make multiple RNA pieces. And that's just off of this one example. Obviously, this virus is going to make tons of viral proteins, tons of these single stranded RNAs, and make tons of viruses. But that's how we start this whole process out. All right, next thing. We've made the pieces. Now, we got to start putting them together. So, again, how did this all work? It went this way and made my caffra made the positive mRNA with the fivep prime cap. Then that went to the ribosomes and we made our proteins. From here we also took this RNA dependent RNA plyase converted in this into positive sense complimentary RNA which got used as a template to make tons of singlestranded RNA that are negative sense. This is adidles. Then what happens is we're going to take all of these proteins. these RNA molecules and we're going to start shoving it. What happens is they all congregate to the cell membrane. And then what happens is they form kind of like this little bud. So this is a little bud, if you will, that's kind of bulging off of the cell membrane. From here, we need to get this thing to break off because here's what happens. It's kind of really cool. Here's the virus, and it's getting ready to butt off. when it buds off, guess what's keeping it stuck to this epithelial cell? The hemoglutins. So, the hemoglutin allowed for it to stick to the epithelial cell to cause the infection, but it keeps it stuck to the epithelial cell so that it can't actually release the virus. Why? Because what's it bound to on the epithelial cell? P scialic acid. What is this one over here? Psyalic acid. So the scyic acid is keeping this stuck, this virus, this butting off virus stuck to the actual cell. So guess who comes in to save the day? Nuramidase. You're probably like, "Yeah, we haven't talked about this dude yet. How's he coming into play? " Nuramidase basically cuts the P scialic acid residue connection. So it basically here, let's actually do it like this. It actually makes more sense to cuts this connection. So now what I'm going to do is I'm going to cut this little connection off. And off here. And now I rip this piece apart. If that happens, now this hemogluten is no longer stuck to the epithelial cell. It can actually separate from the actual epithelial cell and this causes the virus release. So this is now you're going to have a new virus that is then freed away from that cell. So the nuramidase is basically what does what? It cuts that connection between the P scialic acid and the hemoglutin. We need that. The reason why I spent so much time talking about this guys was not for nothing. When we get into the pharmarmacology section, we're going to talk about a couple different drug groups. One is nuramidase inhibitors. I can give drugs that can inhibit the nuramidities. And if I inhibit it, would it be able to cut this connection and free that virus to go and infect other cells? No. I can give drugs that can basically inhibit the M2 ion channels from uncoding and releasing the virus into the cell. We don't really use it anymore, but again, that's the you get the point. I have drugs that can inhibit the RNA dependent RNA pyraases and prevent them from assembling new viruses that we need to package and make new viruses. blocks it here. We'll get into all of this when we get into the mechanism of action of those drugs into the treatment section, but I didn't cover this just for nothing. All right, the next component here is once we've actually released this virus, it basically unfortunately it causes destruction. So, what happens is this cell as a result may undergo some lis. All right? So, it may undergo cell lis. So, once this thing gets released off, it busts the cell. So now this cell is unfortunately dead and now we end up with some cellsis. That cellis is what we see as a result here. We're going to get tissue damage. So now these tissues are going to be damaged. And this could be of the upper respiratory tract, the lower respiratory tract. You get the point. When there's tissue damage, these tissues release different types of like small pathogen or damage associated molecular peptides. And these basically when they get out here, they're supposed to go and activate our immune system. And so what it'll do is it'll stimulate our immune system. And again, which cells primarily? It's going to activate your lymphocytes. macrofasages. And they're going to try to come to the area to help out and kind of fix whatever is going on. So that's what's going to happen is you're going to activate this these immune cells. They're going to release these different types of damage associated molecular peptides. These little bad boys are going to come over here and say, "Hey, immune system cells, come do your dang job. They're going to come and they're going to try to help to clean up the area. " But one of the things that they do is they alert the other immune system cells. And so, as a result, they pump out a bunch of different types of cytoines. And we already talked about them a little bit. This is interlucan one. It was a little cheat there. Interlucan 6, TNF alpha. And you also release another one called interferon gamma. Now what happens is these little bad boys can cause a bunch of different issues. One is that they have the capacity especially interlucan one and TNF alpha they act on the hypothalamus and when they can basically change the hypothalamus's ability to control your body temperature. So essentially what they do is they activate the hypothalamus and the hypothalamus is going to then do what? Oh, we're going to have to go a little bit at an angle here guys. Let's actually do this over here. Let's put uh stimulates the hypothalamus here. We're going to come down here a little bit. Stimulates the hypothalamus. So, when we activate that good old hypothalamus, that's going to increase your patient's body temperature. And we'll talk about what that looks like in just a second. The other thing is that these cytoines, especially TNF alpha, is going to go and act on the muscle tissue. And when it acts on the muscle tissue, it's going to cause some types of metabolism and it can cause a little bit of meioitis. And so you could get some inflammation of the actual muscles. And so what happens is it may stimulate some muscle irritation. So it may cause a little bit of meioitis. All right? and it's going to

change the metabolism of that. The whole reason I tell you this is when we have all of this happening, it's going to cause specific types of presentations that we look for. What are those? Well, it's going to be findings of systemic inflammation. So that could be well if you increase the body temperature, what would that look like? Fever. So a patient could have fever. They may also have just generalized malaise, right? which is just kind of just overall kind of like physically you don't feel very good. It could even cause myalgas. So it can cause fever, malaise, myalgasalgas. You get the point. All right. The other thing here is because these tissues are damaged, they cause a couple different things here. But when these tissues are damaged, it depends upon which tissue are we talking about. If the tissues were damaged of the upper respiratory tract, like things like the nasal cavity, maybe the sinuses, maybe the fernx, maybe even we get into a little bit of the larynx area, that's going to cause signs of the upper respiratory tract to be damaged. What would that be? Well, the big thing here for the upper respiratory tract is you can get things like, for example, if I inflame the nasal cavity and the sinuses, I can get something called rhino sinocitis. If I damage the fairings, I can get something like fngitis. Let's actually bring this one down just a little bit. This could be fngitis. And if I damage maybe the larynx, I can get something called laryngitis. You get the point here that the upper respiratory tract is much more common usually to get damaged especially in the influenza strains. But you're going to get rhinocyitis, fngitis, and you can even get laryngitis. How would that theoretically present if I damaged the upper respiratory tract? Well, oftentimes rhinocerositis, and we've talked about this like on end, we know this stuff. We're so good at it now, is you're going to get things like congestion, right? You may even get some nasal discharge and we even can get dripage into the back of the throat called post-nasal drip. All right? So congestion, nasal discharge, maybe some facial pain and pressure of post-nasal drip. Fingitis you can get a sore throat right laryngitis you may get maybe horarsseness of the voice and sometimes due to the actual dripage or even due to the langial irritation you may even get a cough. And so in a patient who has the most common presentation of influenza, it's usually a combination of systemic inflammation, fever, malaise, myalgas and maybe some type of upper respiratory tract involvement. So in other words, they can have congestion, uh they have some nasal discharge, post-nasal drip, sore throat, and maybe a little bit of a horse voice and a cough. That's probably the most common presentation. This is going to be the more common. So more common among most individuals. This is going to be less common. However, you could say that this would be a higher risk for those individuals like what who have an impaired immune response like what pregnancy amunos suppressed extremes of age. On top of that, they can end up with a disease exacerbations if they have underlying coorbidities, especially which ones? COPD, asthma patients. When you get damage of the low respiratory tract, we're talking about things like the trachea, the bronchi, the alvolar tissue. And so because of that, you could get things like, for example, you can get things like bronchitis. But the concern, so bronchitis is definitely one. And sometimes that'll just cause maybe some coughing and some wheezing. So cough, wheeze. If you got a chest X-ray on this patient, it would look completely normal. They won't have any infiltrates or anything of that nature. The one that we really get concerned about is pneumonia. So influenza, and we're going to talk about this one in just a second up on the top, but influenza pneumonia is the concern. All right. This is the one that I would say is really concerning in those individuals who have immunos impaired immune responses, pregnancy, extremes of age, imunocmpromised. And on top of that, if you get influenza pneumonia, it can worsen underlying diseases, things like COPD, asthma, it can worsen things like a CAD, CHF. That's why this one is really, really important for us to be able to identify. All right. So when we talk about patients who usually present oftentimes it's usually a combination of systemic inflammation, upper respiratory tract involvement. If they have systemic inflammation and lower respiratory tract involvement, it's more often to be something like bronchitis. This one here, this is the one that can increase mortality. This is why we really, really need to know about this one and that's what we're going to talk about next. So this one can increase mortality. So it's critical to know those patients who are at high risk of severe infection and also it's really critical to know if they get this what kind of diseases

could it exacerbate again worsening the mortality and morbidity complications of influenza. This is probably the scary one. This is the one that I really want you to know. Primary influenza pneumonia can kind of cause an ardsike presentation which is really terrifying. So, let's say that the virus gets in, gets in here, gets down here, and starts getting into the alvoli and starts jacking things up. It's going to jack up two different types of cells that line the alvoli. Let's see if you guys remember these. So, it's going to cause alvolar damage, but we actually have to go and discuss this. So, it's going to cause alvolar damage. Well, what is the alvoli? There's two different cells. There's what's called your type one cells. They call them type two numacy, type one pumices, type one alvular cells, type two numites, type two alvolar cells. The type one are the squamus cells. Right? So if you were to actually kind of look at these cells and we looked at this part here, these are going to be your squamus cells. The type two cells are going to be the cubuidal cells. This one is for gas exchange. surfactant production. All right? So they're two different things. So again, we're going to have alviolar damage. It could be of the type one cells. two cells. What would this result in? If I damage the type one cells, these are critical for gas exchange. This is critical for surfactant production. So this would lead to a decrease in gas exchange. And on top of that, this is kind of a barrier. So what happens is the type one uh cells basically prevent lots of fluid from leaking into the alvoli. So they're important for gas exchange and they act as a good barrier. They're a good component of our respiratory membrane. All right. If I damage those cells, right? So if I damage the type one cells, what's going to happen? I'm going to decrease my gas exchange and I'm going to impair my barrier. All right. If I damage the type two cells, what do they do? They produce surfactant. So they're normally supposed to play a role in surfactant production. What does surfactant do? It's supposed to decrease surface tension so that the alvol doesn't collapse. If I damage the type 2 cells, I lose the ability to produce surfactant. So then what happens to the patient's surface tension? It increases. And that does what again? Increases surface tension. What does the problem with having a increase in the surface tension? it's going to cause the alvoli to collapse. So we'll explain what that looks like in just a second. Okay. So virus gets in, it starts damaging the alvolar cells. This alvolar damage can look like damage of the type one cells and two cells. So now as a result, this is what we should see here. I've damaged the type one cells and I've impaired the gas exchange and I've also limited the barrier and type two cells is I got rid of the surfactant. So now the alvea wants to get smaller. See how it's this size and it got smaller. So it's going to try to collapse. When I damage the type one cells, not only do I impair the gas exchange, but guess what else I do? That damage, whenever you get that damage, basically what it does is it increases capillary permeability. So whenever there is that, let's actually represent this as some red X. Here's the damage to the aviolar cells. This is basically going to trigger increased capillary permeability. Now, as a result, guess what happens? This is going to cause fluid to leak into the alvoli. A son of a gun. So, we damaged the epithelial cells, triggered an increase in capillary permeability, caused fluid to leak in. So, now it's fluid is leaking into this and the alvoli is getting smaller because the surfactant's not as present and the surface tension is going up. So, it's going wanting to collapse. As a result, you end up with something like this. as a result. So this is your end result is that because this doesn't just happen in one alvoli, it happens in tons of alvoli. You get something called as a result here, you get what's called diffuse alvolar damage. So we actually write this as dad a dad. So diffuse alvolar damage. These capillaries become leaky. fluid exitate starts leaking. Protein rich fluid leaks into the alvoli. The surfactants not as present. So the alvola wants to collapse. As a result, your lungs start to have diffuse infiltrates bilaterally all over. So now I have these infiltrates that are all over the lungs. Right? So what is this called? This is called diffuse bilateral infiltrates. This should sound like something. When I have diffuse alvolar damage that it's causing infiltrates all over both of my lungs. Dude, I know this. This sounds familiar. What is this? ARDS. And that's what can happen with these patients. Usually what happens, the end result from these diffused bilateral infiltrates is it impairs gas exchange over the entire lung. It's not just one alvoli. This is millions of alvoli. And as a result, the patient can present with ARDS. So acute respiratory distress syndrome, right? And that's what we get worried of because you have tons of alvoli that can't participate in gas exchange. And so what's the the way that these patients would present? If you have diffused bilateral infiltrates, it's going to impair gas exchange. These patients oftent times present with things like um hypoxmia, right? That's probably the first thing is the first thing that you'd be worried about is that you'll have a patient who presents with hypoxmia, right? And so how would we look at that? Usually be their SPO2. So if we look at their pulse occimmetry, we would expect this thing to be pretty dang low. That's one thing. So that's going to be more of an objective thing. The other component is that they may present with signs of respiratory distress. So what would that look like? Well, they may have things like disna. So they may just be generally short of breath or they could potent potentially present with um increased work of breathing. And what does that look like? So increased work of breathing is the patient's working harder to breathe. So in other words, they could be breathing really fast to kipnic. So fast and deep. They could be using uh accessory muscles. They may have nasal flaring, intercostal retractions. These are all concerning signs that a patient's exhibiting respiratory distress. The third thing is if I ended up having this patient get a chest X-ray, this is what I would see. I would see diffuse bilateral infiltrates. But on top of that, this patient can exhibit ARDS that progresses to multi-system organ failure. That is what we get concerned about is because they could start causing things like hypotension and multi-systemm organ dysfunction. The kidneys could start failing. They could have reduced profusion to the brain. They could have injury to their liver. They could have elevated lactate. You get the point. So this is what I want you to remember for primary influenza pneumonia. The virus causes alvolar damage. Type one, type two. As a result, the alvoli collapse because of the surfactant not being present enough. On top of that, the damage here triggers increased capillary permeability. So fluid exodate leaks in here and you get diffused alvular damage. That causes diffuse bilateral infiltrates. You can't perform gas exchange at all. So these diffused bilateral infiltrates causes what we would refer to what's that physiology called? When you almost have zero gas exchange, what's that called? Almost very little uh exchange. This is can lead to what's called a pulmonary shunt. So we call this a shunt. And that shunt is what leads to this degree of respiratory distress. All right? And if I got a chest X-ray on this patient and we look at this in the diagnostic section, this is what you would expect to see diffused bilateral infiltrates. This is really important. And the reason why is because this patient, you're going to tell the difference in this. This is really acute. They're going to get worse. They're going to be hypoxmic. They're going to have respiratory distress. they're not going to really have this extreme productive cough. And when you get a chest X-ray, you'll see diffuse infiltrates. Secondary bacterial pneumonia is a little bit different. What happens is they get the viral infection and the virus damages the bronchioles, right? And the reason why it damages the bronchios is because it loves to damage these pseudoratified, you know, siliated epithelial tissues. And so you're going to damage these tissues. When you damage these tissues, right, we're going to damage these tissue cells. You get two effects here. One of the effects is you'll obviously damage the cells, the epithelial cells, but what happens when you damage epithelial cells? What do you do to the psyia? You lead to decreased siliary function. And so this can lead to what's called psilio stasis. The other thing is whenever you have tissue injury, this is basically a activator of goblet cells. Gobblet cells respond to that and they pump out mucus. And so what are you going to have a result of here? These gobblet cells are going to say, "Don't worry, bro. I got you. " And it's going to start pumping out tons of mucus. And so you're going to get an increase in your mucus production. And so the second effect is increase in mucus. So you get silostasis, you get an increase in mucus production. The combination of these leads to what? An impaired mucosilary escalator. And because of that, you have a hard time being able to clear things out of the airway. And so what this does is this basically traps bacteria. It keeps the bacteria that maybe you inhale, you get exposed to, it traps them in the airway. What kind of bacteria? Oh my gosh. Usually it's stafllocus aras. But this isn't just your typical. We see this in MRSA infection. So methasylone resistant stafloccus. On top of that it can trap one of the most common typical community acquired pathogens. This is called streptococcus pneumonia. So these can basically be trapped inside of your airways and then if they're there they have the perfect environment. They already have a damaged tissue. They love damaged tissue because it exposes underlying tissue membranes that they can stick to. On top of that lots of mucus. It can provide an environment for the them to grow and keep them trapped in that area because it's harder to clear them. That's a perfect environment. On top of that, it's not just that though. Here's what else is crazy. These damage epithelial cells, when you damage these epithelial cells, not only do you damage their psyia and lead to changes in their mucous processes, but again, I told you it activates these cells to release things like damage associated molecular peptides, right? And these damage associated molecular peptides go and activate your immune system cells. And what happens is immune system cells a bunch of them they can release different types of cytoines. But this cytoine is really special and this is called interferon gamma inter. So there's different types of interferons. There's interferon alpha and beta and those basically they the epithelial cells tells the other epithelial cells to make antiviral peptides to protect them against influenza. Interferon gamma really looks to activate your macrofasages, your lymphosytes. But what it can do in high levels is it can inhibit your neutrfils. Son of a gun. If I think about this, I create the perfect environment for these bacteria to grow and get trapped in. And then I remove the very cell that's supposed to be able to eat and kill bacteria, and that's neutrfils. Dude, the combination of these two things is probably everything that you need to allow for not only the trapping of the bacteria, but the growth of the bacteria. So traps and you get growth of bacteria from these two effects here. And this can lead to a post like a what's called a super infection. So now the end result here is that these pathogens if they're trapped and they're allowed to grow they often times these like to behave more in an alvolar fashion. So they infect an alvoli they consolidate the alvoli they damage the alvoli they draw in the immune system cells. What ends up happening is you're supposed to get more of an exodative um effect here, but this thing can continue to grow from alvoli to alvoli and you get more of a socked in type of consolidation. It's not diffuse, it's more lowbar. And so what ends up happening is you get what's called a lowbar consolidation. And this is a bacterial pneumonia, right? And so that's the difference here is I got a patient who can get this kind of like socked in consolidation which I would be able to see on a chest X-ray right sometimes especially with um MRSA not only can it cause lowbar consolidation but sometimes in these infections it can cavitate and so sometimes you may even notice like this cavitating like lesion and that's very consistent with staflacaris and sometimes it can actually cause them to cough of blood and then get hemopsis. So watch out for the possibility of cavitation especially with MRSA. So with this being said, if I had this type of problem, how would they present? Well, they'll present with basically it's a community acquired pneumonia presentation. That's pretty much it. And so they'll present they'll have like a community acquired pneumonia presentation. And that's pretty straightforward, right? I mean, when you think about this, it's going to be cough. fever. It's going to be white blood cells are going to be elevated, right? And so, they'll probably have some type of productive cough. They'll have a fever. They'll have an increase in their white blood cell count. All right? That's all definitely going to be a possibility of this presentation. You got a chest X-ray, it's going to have a low bar consolidate. But what's the big difference here? I'm going to write it down, but I want you guys to think about this. So when a person gets the flu often times what will happen is they'll get better. They'll have a quick period where they get better maybe around days three probably like day three day four they get better and then all of a sudden after that they have this acute worsing it's just like acute bacterial rhinocinitis. So we call this a bifphasic illness. So the big thing here is they'll have the symptoms of influenza. Maybe it's kind of like a fever, malaise, myalgas, maybe they have some rhinocinitis, cough. And then what happens is a little bit later they have this really terrible worsening of their presentation. That is the key thing I need you guys to remember. It's called a bifphasic illness. All that means is when they have the first kind of flu onset, they'll have these symptoms that we talked about, but then maybe around day four or so after they get better, they get acutely worse again and they present with these types of symptoms. That's when you start thinking about the possibility of secondary bacterial pneumonia. For this one, you'd probably want to do sputum cultures because this one will talk about you're going to be testing for the virus. This one they'll definitely maybe already you knew that they had the viral infection but you're going to test the sputum for what? Stafforius strap numo sometimes if it's a really severe infection which usually they are you even have to do blood cultures and things of that nature. All right so it's going to be like you're working for the community acquired pneumonia which we already talked about. Now this is the most concerning and common complications of influenza. Can there be other ones? Yes. It's just I don't think that they're as important. What I want you to remember though is again here's a couple of the other complications that can occur but they're just they're not as important and also they may be relatively rare. One is it can cause exacerbation of chronic diseases. It can basically worsen things like COPD, asthma. We already talked about that. It can worsen things like CHF, worsen things like their underlying coronary artery disease. That's one easy thing to be able to remember, right? For those ones, you may have to do a little bit more of a work up and look for these patients. Again, you they'll have an underlying history. That's key there. That can get worse when they have the influenza infection. Sometimes you can see things like rye syndrome. Ry syndrome is extremely rare, but if I had a very young individual at least less than 19 years of age, they had a fever and maybe the parent gave them aspirin and all of a sudden they have things like altered mental status, confusion, seizures, vomiting, they have increased LFTs, they have um maybe changes in overall blood work because of ammonia buildup. That could be something like ry syndrome. So it's very common for viral infections who got aspirin they can get worse. Another one is called gillon beret syndrome. Gamma syndrome is something that can be seen but it's usually after they have um the flu or they get the vaccine less common two to four weeks later after that infection they develop antibodies against that vaccine or against that flu and because of that concept of molecular memory they attack other tissues like the myelin on your peripheral nerves and it can lead to demolination of those peripheral nerves that can cause ascending symmetric flaccid paralysis um with a reflexian so that'd be gonet syndrome and again The last one is rabdtomyis. This is less common. Influenza is not just able to damage the lungs, but it's also has myotropic kind of functions. And so it can damage the actual myioardial tissue and can also damage the skeletal muscle tissue. And so you can get things like enough meioitis that it actually damages the muscle tissue and spills out things like creatinine kynise. It can spill out things like potassium and myoglobin. The damage to the muscle can cause pain out of proportion. That's the difference between your basic myalgas and something like rabdo. On top of that, they'll have very, very dark urine because of the myoglobin. And on top of that, because of the myoglobin getting into the urine, they may have something like an acute kidney injury. So, those are the possible complications. Again, less common. I really would prefer you to

remember these. Now that we've talked about this, let's put all of this together and go through a diagnostic approach. All right, my friends, let's talk about the diagnostic approach to influenza. So, when we think about this, the first thing that I need you guys to remember is you have to look for those influenza symptoms. And we also want to have the particular concepts of risk factors coming into play. And so again, influenza symptoms are primarily going to be those upper respiratory tract infection like symptoms. This is primarily going to be things like congestion. You may have some rhinora. They may have a sore throat. cough. They also may have a fever. They may have myalgas. Sometimes you can get those lower respiratory tract symptoms, but it's just way more common to experience those upper respiratory tract symptoms. So if you see that plus the patient is high risk. There's so many different components that I told you determines a high-risisk patient. Oftent times it comes down to kind of putting them into easy remembering buckets. And I like to remember those who have more like an immuno compromised or a decreased immune response if you will. Usually those are individuals who are really young maybe less than like 2 years of age. The other ones that are going to be a little bit older greater than 65 years of age. And on top of that, probably individuals who are immuno compromised in some way, shape or form. HIV, AIDS, they're on transplant rejection meds, they're on other kind of immunosuppressant medications. Pregnancy is also another one because it also does decrease your TE-C cell function. The other thing is it's usually those who have comorbidities, things like COPD, coronary artery disease, um they have maybe some type of restrictive lung disease due to their obesity. Those are things that just puts them at high risk for exacerbations and we just don't want that to happen for these patients. Another thing is that any person who has influenza symptoms and requires hospitalization. So that's usually if a patient is presenting more often with these lower respiratory tract like symptoms. This is a patient who presents with hypoxia. They present with dysnia. They present with typipia and they're also showing some signs of increased work of breathing and you're worried that maybe they have some kind of influenza pneumonia and you need to watch them and that patient it's really important to be able to pick them out. So again influenza symptoms and if they're high- risk influenza symptoms or they're being hospitalized. The other one is if that symptom onset has been very recent. And the reason why this is important is in patients who are high- risk or hospitalized, you really want to be able to know that patient because that determines whether or not you can give them very specific drugs like oelttemir or blox. Symptom onset also comes into play with this. Even though maybe their symptoms are very mild, you really want to get that particular medication like ocelmavir to them sooner than a 2-day time span from symptom onset because it's going to reduce their symptom overall timeline maybe by like a day or so, but still that's beneficial. So again, when you're looking at an influenza patient, examine them. If they have symptoms and they're high risk, you should start considering I should test them and make sure I identify it and consider giving them oeltamir. hospitalized, they're going to need ocelmover and I'm going to have to test them for influenza. Is their symptom onset recently within at least two days? I need to test them because I could give them ocelavir. All of these are questions that you need to ask yourself. Why am I testing a patient? Because if I'm going to test them and I'm not going to do anything about it, sometimes what's the point? I'm testing them because if I determine that it is influenza, what am I going to do about it? and I'm going to treat them with the appropriate medications if that kind of scenario comes about. So in that scenario, we have a patient who has those symptoms, they're high risk, they're hospitalized or their symptom onset is recently, you should test them for influenza. Get the PCR test. It's a reverse transcriptase PCR. We're going to do a nasoparential swab. We're going to send it off to the lab and we're going to do a PCR. You can also do rapid antigen tests as well, but the PCR is going to be the gold standard. Now, if that patient comes back positive for influenza, this PCR will tell you if it's influenza A, which is most common, or influenza B, which is the less common form. And right there, you have the diagnosis of influenza. The next question that you have to ask yourself is, what am I going to do about this? I determined that they have influenza. A lot of cases, especially if they're not high- risk, they're not being hospitalized, sometimes if their symptoms are a little bit past 2 days, you just do supportive care. So you did that test and you determined what they had, but you're not going to treat them any differently than you would if they had a common cold. So in this patient population, you need to know why you did this. If it's very uncomplicated, they don't have a lot of symptoms. It's maybe they have again that runny nose, the sore throat, the congestion, the cough, maybe a little bit of a fever, then you don't really have to do much except maybe send them home and you kind of tell them, "Hey, take and rest. Make sure that you stay hydrated. Take some Tylenol for any pain or fever. " and you let that kind of work its course. If they fit within that particular symptom onset of less than 48 hours though and it is mild, you can consider giving them oel tem and that's why I put this plus or minus antiviral agents. All right, the next question is what about in that patient who is complicated and what that means is most importantly is the ones who present with very severe symptoms. They're presenting with hypoxia. They're presenting with tacipnia. They're presenting with some form of dysnia and respiratory distress of that ma matter. That is a concerning patient. Another one is a patient who's high risk. That's a complicated patient because they are high risk for developing a severe course like influenza pneumonia and on top of that exacerbations of underlying coorbidities. So in that patient it is extremely important to make sure that you do a good and thorough ass assessment in the patient that presents with any signs of hypoxia, dysnia, they have shortness of breath, maybe they have like diffuse crackles, wheezes, they just don't look normal. I would get a chest X-ray, maybe an AG if they're really hypoxic. And sometimes when a patient presents like this, you don't know if they have pneumonia or not. If it's complicated enough that they're having respiratory failure and we have to hospitalize them, I would get sputum cultures to make sure that I rule out bacterial pneumonia because it is very hard sometimes to actually completely differentiate between a primary influenza pneumonia and a bacterial pneumonia especially if it's a secondary form. So get the chest X-ray. That's probably the most important thing here. You could get the AG if they're very hypoxic and the sputum culture is going to be a good one anytime you're hospitalizing a patient in this form. Now when you get that chest X-ray it's really important to know what normal looks like and what abnormal looks like. So you can see here in this patient they have very clear obvious loosency of the lungs. I can see the costtophrenic angle. heart borders. Everything looks really obviously healthy and normal. When you get a patient who has primary influenza pneumonia on the other hand, you can see here now why it's so important to compare normal versus abnormal you to see all of this diffuse kind of bilateral infiltrate. This definitely a little bit more in the hiler region, but you can 100% those primary kind of forms of infiltrates throughout the actual both lungs. That's pretty obvious for influenza pneumonia. So if you see a patient that has those symptoms, they present with maybe some shortness of breath, some dysnia, maybe they present with hypoxia, you got the PCR to say that they have influenza pneumonia and they have this type of presentation on their chest X-ray, you should be very concerned for primary influenza pneumonia because this can progress to ARDS. All right? And it's very common for this to happen in those high risk patients and they'll need to be hospitalized. Now if you got the AG, it would again show you hypoxmia. That's why I say looking at the SPO2 is going to be the most beneficial. And if it's continuously low, you could get an AG to see where exactly they fall. And then on top of that, getting that sputum culture to show, hey, there is no bacterial growth. So that could suggest again that primary influenza pneumonia. All right. Now, the reason why I tell you to kind of do these things is because if I got a chest X-ray and this patient and I saw this and I went through all of these steps and I have primary influence and pneumonia, the best thing to do is get them on something like oeltemap here because that is going to help to not only reduce their symptoms but also potentially reduce the progression of this disease. You're going to treat them supportively. You're going to give them obviously certain types of oxygen therapy for respiratory support. Maybe this isn't the flow for above nasal canula, high flow nasal canula. Sometimes you may have to intubate the patient, but getting those antiviral agents on board is going to help to potentially reduce the progression of the disease. And that's really critical. And the reason why I spent that time is because if I got a chest X-ray on this patient, they came in with shortness of breath, typia, they came in with some hypoxia, their influenza test was positive, and I got the chest X-ray and I saw something like a lowbar consolidate. So now if you look here, I can definitely tell that there's definitely this opacity here somewhere probably in that right middle lobe of the lung. And I even can see kind of some cavitation. If the patient came in where they presented like this, let's say initially they had a little bit of shortness of breath, maybe disna at some point in time, maybe they had some upper respiratory tract symptoms and a fever and then it kind of went away and then a couple days later they got worse. So maybe four 14 days after their initial symptom onset they develop cough and it's productive. They have shortness of breath. They have typnia. They have hypoxia. This could concern me that they developed a secondary bacterial pneumonia. So they had a viral infection and it was complicated by a bacterial super infection and that can't happen. So if I see a low bar consolidate, I see any kind of cavitation, that really concerns me for potentially in this patient having some type of bacterial pneumonia. If I got the AG again, it would show hypoxmia. But here's the key, the sputum culture. What does that tell me? And if that sputum culture shows me things like MRSA, which is very common post flu or strep pneumonia, very common post flu, that would make me think about a secondary bacterial pneumonia. All right. So, usually this has that bifphasic appearance where the patient appears with some kind of non-specific upper respiratory tract symptoms, maybe some lower, they get better, and then all of a sudden they get worse. That's common of secondary bacterial pneumonia. And for this one, it's completely different. We don't really kind of go only with the antivirals. You may treat them with those antivirals to clear up any residual, but it's really the antibiotics that are going to be the key thing that are needed here. All right. So again, the whole point of talking about this is that influenza is one of those kinds of common upper respiratory tract infections that you can test for if you really need to, but try your best to keep it to the high-risisk patients, those who need to be hospitalized, those who have very early symptom onset. And the reason why is if you get that test and it shows influenza, you can actually do something with that. If it's down the uncomplicated section, doesn't matter if they're not high- risk, they're not hospitalized. You if they're symptom onset with less than 40 hours, you can give them something to reduce the actual course time frame. And if they are complicated, they're high risk, they have to be hospitalized and they present with respiratory failure, you then need to differentiate between a primary influenza pneumonia and a

secondary bacterial pneumonia because they have a difference in their overall treatments. All right. So, the next thing I want you guys to understand is we can do complication workups. They're just very uncommon. I think it's important in the logistics of understanding that how influenza is a viral infection that sometimes can worsen underlying comorbidities. And that's really what I want you to think about. So let's say that a patient has influenza and they present with a disna. They present with cough and they have an underlying history of COPD and asthma. How do I know that it's not a COPD exacerbation or an asthma exacerbation as compared to the just maybe an influenza pneumonia? Well, you would get that chest X-ray. You would get an AG. Maybe you would even consider doing sputum cultures in this patient. The things that you're going to be looking for in this patient is they may have some hypoxmia. Heck, they could even have hypercapnea. But you're going to look at the lungs and you're not going to see any kind of like diffuse infiltrates, secondary kind of like findings of low bar consolidation. You'll see maybe hyperinflations, flat diaphragm, things that most likely suggest maybe a COPD exacerbation, some lung trapping. If I had a patient who presented with a new onset chest pain well obviously patients who have an underlying history of CAD could they have an exacerbation of that could that be a supply demand mismatch could it be an MI in every scenario you're going to get ECG troponins make sure that you rule out a STEMI and in these patients you may see some ST changes you may see an increased troponin but that's again it goes along with the underlying condition that you're working up it's just that influenza can worsen in these kinds of scenarios if you see a patient who has JVD you see pulmonary and peripheral edema and they have an underlying history of CHF. Could this be an exacerbation? It definitely dang well could. You should get an echo along with already checking that chest X-ray and then getting a BMP to make sure that there's no cardiogenic pulmonary edema that's causing this. And I would be looking for maybe a reduced left ventricular ejection fraction and that BMP to be relatively high. All right. And so that's something that's relatively concerning. the muscle pain, dark urine. This can happen with influenza. It is myotropic in the sense that it can attack cardiac muscle and skeletal muscle. So if it caused like some rabdtomyis, that can lead to an acute kidney injury if some of that myoglobin gets lost into the kidney tubules. And so that's important to consider in any kind of patient with muscle pain that's new onet worse than usual and they got some dark urine, maybe go ahead and check a CK and see what's going on with that. And then on top of that, a UA with microscopy would find that they would have maybe findings of hematia. But when you actually check on the actual microscopy, they won't really have any kind of like blood. It's the myoglobin. And the BMP is going to tell you if they have an acute kidney injury based upon an elevated creatinine. And so that's kind of what we're looking for on these tests. Altered mental status is also kind of important in these patients, especially in a person who is very young, less than 19 years of age, and they have a viral infection and they were given aspirin, that can actually precipitate ry syndrome. And so, a patient who presents with a very significant acute onset of altered mental status after a viral infection with aspirin being given should concern you for ry syndrome. Often times, we check an ammonia level. We check some E LFTs and a coagulation panel because we're worried that they're an acute liver failure. and those ammonia levels will be high, their LFTs will be high. They'll show maybe elevated levels of their PTINR more so than their PTT, but this would concern me that they're in acute liver failure due to something like ry syndrome. And then lastly, if I had a patient who had influenza or sometimes on the exam they got the influenza vaccine, especially maybe more of like a live attenuated version, there is a theory that it could potentially create an immune reaction that antibodies will attack the myelin sheets on our peripheral nerves leading to demination that can cause ascending flaccid paralysis and maybe some atexia and that would concern you for something like gon beret syndrome. In this particular scenario, a lumbar puncture may show some type of like changes like an albinocytogic disassociation. So lots of protein with kind of a lower white blood cells which kind of helps you to think that this is not as much of a kind of a inflammatory reactions things like um like a viral menitis type of picture. This kind of presents more like in gon beret like this kind of scenario. But again this is really kind of going into the depths of it. I don't want you guys to think too much about this one. It's just trying to be thorough in the sense of exacerbations of underlying conditions or complications that are relatively rare can happen due to influenza. And that's what's good to take away from this. And again, with every single one of these, you have to treat the underlying complications. So, and every one of these, you treat the underlying diseases. We've talked about in multiple different lectures. For example, in this patient, you may need to do BiPAP and inhaled uh steroids or maybe an oral steroid. For this one, you have to treat them appropriately if they have an NST STEMI or a STEMI. In this patient, you may need to give them BiPAP. a ferocomide or kind of reduce their afterload or increase their actual inotropy. In this patient, you have to give them fluids. And this patient, you're going to hopefully kind of treat the underlying issues with the ammonia with things like lactolose and hopefully prevent them from bleeding by correcting their INR and giving their actual liver time to heal. And this one, you may have to do IVIG or Plex. And so it's all about treating the underlying disease and then you can also give antiviral agents because influenza probably exacerbated this in some type of way. All right, that's a lot to talk about when it comes to influenza, but what I really want you to understand is not just again the biggest things to take away from this so far is when we test for influenza, know why you're testing and who you're testing because again we know the patient population, but the reason we're testing them is it can actually guide management. We talked about some of the complications that can arise from exacerbations of underlying disease or rare complications that can

occur due to influenza or even sometimes influenza vaccines itself. But now we got to talk about this treatment part. So if you guys remember briefly influenza virus again it has a very specific structure called that hemoglutin which allows for it to attach to the P scialic acid on our epithelial cells. Then it under goes the endoccytosis mechanism to get into our cells. Then it under goes uncoding where ion channels on that endoome allow for protons to rush in. Then the M2 ion channels allow for it to rush into that virus and basically allow the virus to go into the state where it can just open up and release the RNA and some of the RNA polymerase into the cytoplasm. This negative sense singlestranded RNA then does what? It uses the RNA polymerase that's packaged into that virus to create mRNA and that has to put on that fivep prime cap to do that which then can be translated by ribosomes to make all the proteins that we need to make the virus right that's all those hemoglutin proteins that's the neurodase proteins the M2 ion channels making more of the RNA polymerase on top of that RNA dependent RNA polymerase also replicates the RNA converts it into complimentary RNA that we can use as a template strand to make multiple negative sense RNA strands, at least eight of them, to go into this one vesicle to make a new virus. When we assemble all of this together, that then allows for us to pop this virus off. But in order for us to pop that virus right off of the cell, we have to break a connection because what naturally happens to get into the cell also happens when the virus wants to exit the cell. And so that scialic acid wants to stick to the hemoglutin. So what do we do again? The nuramidase is a beautiful thing that then acts like a little scissors and cuts that connection between them and allows for the virus to butt off and then go and infect another cell and in the process it damages this cell. So we need drugs that can come in and actually help us to reduce the butdding of that new virus, reduce all of the replication processes to reduce the actual overall severity of the disease and the progression of it. So that's where things like nuramidase inhibitors are probably going to be your number one hitter. This is oceltavir. Ocelamavir is great because what it does is it inhibits nuramidase. If you inhibit this enzyme, can it go ahead and cut that connection now? No. So this thing stays stuck. You can't bud that virus off and allow for it to go spread and spread. The other drugs that come into mind is things like indoucleus inhibitors. This is like blox. Blox is great because it inhibits RNA polymerase. RNA polymerase is responsible for helping to f form that mRNA. It's also important for being able to undergo the replication processes. And so if I can't translate the proteins and I can't replicate the actual RNA, how am I going to make any new viruses and allow for that virus to butt off? The next one is the M2 ion channel blocker. This is a mantadine. We actually don't really use this drug anymore because funny enough the influenza this, you know, it's developed about a 99% resistance to it. So, we just don't use it. But the concept behind it is that it's blocking these M2 ion channels. So, again, if you think about that, boom, I'm going to block the M2 ion channels that protons can't come in. If they can't come in, can I uncote and release the viral RNA? No. And if I can't do that, I then can't go through all of my processes to help to make a new virus and to butt it off. But again, we found that we just don't use it anymore because of resistance. But I still want to include it because it is mentioned in a lot of different literature. So who do we give this to? I already talked about it. The reason why we only try to restrict testing to those who need it is because we have potentially a treatment process. It's those who have severe symptoms, right? they're presenting with any signs of respiratory symptoms or on top of that they're having to be hospitalized. Um, and those patients or they're high risk, those are the ones that we really want to give this drug to. So complicated, meaning they're having signs of respiratory distress, they're having to be hospitalized for their influenza means that they could really benefit from this. And those who are high risk, they could end up with a severe infection. being having to be hospitalized. they should get this to reduce exacerbations of their underlying disease and reduce the progression to having a complicated influenza. And then again the last one is those who are not complicated. Their symptoms they came on within at least less than 2 days or 48 hour time frame. And if I give this I can maybe reduce the symptom timeline by about like a day or so. And so again in theory that could be beneficial. So that is why I want you guys to understand that. So again putting it all together when you have a patient who is presently positive for influenza you ask yourself the question is it uncomplicated or complicated if it's uncomplicated and their symptom onset was less than 48 hours what do you do okay that one I can give them oelmavir or blox because it may reduce their symptom timeline by about a day or so if the answer to that is no then the question is it complicated ated influenza. Are they a high-risk population? So a COPD or um they have CAD, they have immunosuppressed, they're pregnant, they're very young, they're very old, they're very sick, they're having to be hospitalized. In that scenario, give them ocelm or bloxave. If it's not, the next thing is you just have to treat them supportively. So that's the thing in that scenario, there's just nothing else that I could do if we kind of follow this algorithmic flow. That's the way I want you guys to think about these things systematically. Now again paying homage that we mentioned all of these drugs but amantadine is just really not given anymore because the influenza's develop such an insane resistance to it we just don't use it anymore. There's one other concept I want you to understand. If you think about this, what if we could just block the virus from even attaching to any kind of epithelial cell? We could reduce this whole downstream effect pretty significantly and reduce any damage in general from influenza. That's where vaccines come into play. And I just kind of want to introduce them because you think about these are basically antibodies. They're IGG antibodies that are directed against these proteins. And if they go and bind on to it, you basically block the virus from attaching. And if it can't attach, you can't replicate, you can't butt off

you can't cause any damage. That's a beautiful thing. And that's where I want us to now move into talking about vaccines. There's a couple different types of vaccines that we should utilize. Well, the most common one that you probably see across the board whenever you go to your primary care physician, you go to a clinic is the inactivated influenza vaccine. It's that intramuscular injection that you get. The goal of this is to be able to generate an immune response. And so what they do is they inject in the viral antigens probably like the hemoglutins, the nuramidases that basically will be reviewed as foreign to our immune system. But the goal is to develop a memory to it. So to develop memory B cells, so if we're ever exposed to it, we'll have that little B cell receptor that will recognize them. We can mount an immune response and we're good to go. The other thing is that for some of those memory B cells particularly, we need a actor B cell that actually turns into a plasma cell and then pumps out antibodies so that we have those antibodies if we're ever exposed to those antigens in the future. Boom. We can neutralize them. We can activate the immune system via optinization, the whole concept, right? And so that's the goal. And so that's what these kind of vaccines do. This is just an example of one of them. Now, this is probably the most common one that we give to any patient who is greater than or equal to 6 months um of age. That's why when you think about this, anybody who is technically less than 5 years old, they're at high risk. They're a kind of a high-risisk patient, but they get even higher risk the lower you go. Particularly less than 2 years of age, you're especially at high risk. But anybody who's like less than six months, they're very high risk because they don't have a very standard immune system. And on top of that, we can't vaccinate them. And so that's really important to get these vaccines in them as soon as you can. But it's really important to also remember that this is your standard dose. As a person gets older or they become higher risk, you need a higher dose. And so other alternatives, especially as the patient becomes greater than or equal to 65 years of age, they're very high risk. So we give high dose sometimes four times the standard dose or we give an adgivant version where basically you give it maybe a protein to bind onto it that makes it amunogenic and you get a more profound immune response. And so these are alternatives. It's still the same vaccine. It's just the dose or the adgivant that you add into it is what's different from any other person who gets this from 6 months of age or equal up to 65 years of age. Once they're above that range or equal to that range, they need a high dose, four times the standard or an adgivant version. All right. Now, another type of vaccine is a live attenuated vaccine, but this is an intraasal spray. This one's very, very interesting, but there's only specific patient populations that we can give this to. So, the concept behind this is that you spray a live virus, but it's very weakened or attenuated. When it gets into the respiratory system, you mount an immune response. One of those things is to generate memory B cells. So if you're ever exposed to that, it has the B cell receptor to be able to trigger an immune reaction immediately. On top of that, we want aector B cells to become plasma cells and produce antibodies against it if we ever become exposed to it in the future. So these cerological antibodies are flowing around. So if it ever gets there, you have the immune uh kind of like system capable of neutralizing and fighting off that virus. But it adds another two layers to it. The other concept here is that the virus actually does trigger your plasma cells to produce IgA antibodies that then can go into the mucosal lining so that if you're ever exposed to it, it can neutralize it before it actually causes damage. That is really cool. And on top of that, this virus is a live virus. It's very weak. So, it's not going to produce that same profound effect that an influenza would. However, it can get into the epithelial cells, cause them to express a piece of that antigen on their MHC1 complex, and then CD8 cytotoxic tea cells will then be exposed to it. They'll then no longer be naive. You'll actually start developing memory CD8 T cells that whenever you're exposed to this in the future and they do infect that cell, they can get to it. So the difference between the live attenuated versus an activated or even recominant which we'll talk about in a second is you get mucosal immunity and you get cytotoxic tea cell immunity. That's the benefit. The downside of this is that when you give a live virus anybody who has an imunompromised system should not be getting this. So if they're very young, if they're very old, and on top of that, probably anybody who has an imunompromised immune system, you should not be giving this to. So we say anybody who is within that 2 to 49 year old range, they're okay. All right? But we cannot give it to them if they're pregnant because they have an impaired te- cell immunity. We cannot give it if they're immuno compromised. And also they have COPD and asthma. The concept behind this is whatever the additives is that is placed into this it actually or even the actual virus itself it may cause a bronco spasm that could put them into a exacerbation. So it's not necessarily the imunompromised component. It's just the risk of that drug causing a bronco spasm. But again, we avoid it in those who are pregnant, immuno compromised and we stay away from older individuals just because they may not be able to take even though it's a weakened virus that live virus could actually cause some problems. So we stay away from that in those patient populations. So really young, really old or imunompromised and again bronospastic risk. The next one is the recombinant influenza vaccine. This is just the same thing here. It's an injection and it does the same kind of concept. You inject the viral antigens, they basically generate a memory immune response, which is you generate memory B cells, you generate actor B cells that become plasma cells, they produce antibodies. It's the exact same concept. So what's the difference from this one to this one? Well, in this one, the FDA really particularly says that you should only give this to anyone who is greater than or equal to 18 years of age. But when you actually look at the concept of how these are made and overall efficacy, you would prefer something like this. The concept here is that the inactivated vaccine, we actually use like egg, like certain types of eggs, egg cells to really use that virus to replicate that. Um, so it uses the egg cells to replicate, replicate the actual virus. Problem is that when you replicate these viruses, usually what happens is you only need the antigens. And so you'll process it and you'll go through this very specific stage where you'll kind of separate out and get only the components that you need, which is those viral antigens. Here's the big thing, though. You see these like little squiggly lines? This may happen because of mutations that occur with inside of that egg cell. It's at very high risk for particular mutations. Those mutations can lead to small little changes in the structure of the hemoglutin or the neurodedise from the way it was originally. Look how this one looks. Look how these look. They're slightly different. And because of that, the antibodies that you generate may be slightly less effective. That's why sometimes certain types of flu vaccines may have a 30 40% efficacy because of this concept. That's why the recombinant influenza vaccine, we actually take this virus and we actually separate out the genetic material. Once we've done that, we actually use like insect cells and use that as the machinery to generate and make more RNA. And then from there, we use that to say, okay, we got the RNA. Let's make our viral proteins. And since this doesn't have any risk of mutations, the proteins here that we make look exactly like the proteins on the virus that we started with. That's the current circulating strain of that year. Because of that, there is no mutations. And a much higher efficacy, a 100% genetic match against the current circulating strain. That's what makes this one a little bit more effective. But obviously, we're limited based upon the age range that we would give this. But otherwise very effective vaccine. All right, that covers all of these components of vaccination. But I have one last thing to add. What about the patient who maybe they did get the vaccine, but they got it really like let's say they just got the vaccine like a couple days ago and then they're in a nursing home or they're in a particular area of like um close contact community where there's an outbreak, right? Or the patient didn't get the vaccine and they have high risk. they, you know, they need something that's going to get them through this at that time frame. any patient who is high risk and I think the best example is like a nursing home whenever there's an outbreak of the flu any high-risisk patient so again greater than equal to 65 they're imunocmpromised they're pregnant they have coorbidities and they haven't been vaccinated they got vaccinated less than two weeks ago they don't have the immunity they don't have those antibodies memory cells to fight off the virus effectively and if that happens and they have a confirmed close contact influenza exposure. So there's a person in the actual nursing home that has been sick, you need to give them ocelavir. It's again there is certain types of things that we don't often recommend it for, but the best example that you may see on an exam is a nursing home. They have an outbreak of influenza. The person has had close contact. They didn't get vaccinated or they got vaccinated less than two weeks ago and most of the patients in that nursing home are already high risk. based upon age for the most part and coorbidities they should get oeltemir. All right. Oftent times you're giving it to the patient before they even have the symptoms or have the infection. That's why we call this a cheop prophylaxis. It's almost like a preexposure if you will. But again not routinely recommended according to uptodate but something that you may see on the exam. All right let's put all of this together now. So again big thing to think about here is ask yourself the question is the patient pregnant amino compromised do they have COPD asthma if that is the case I cannot give them this live attenuated influenza vaccine that's pretty much as straightforward I'm putting them at high risk right they could potentially end up with an influenza infection they could end up with some issues bronco spasm so in that scenario I'm not giving this one so I'm left with these two well when I determine between these two it really just comes down to age so is there a significant age restriction well this one definitely does. This one, not so much. The only thing it has to be is they got to be greater than 6 months um old. That's really it. So, I'd want to give this one. Which dose do I give? Well, it just really depends. Are they between this and 65? Okay. Well, okay, it's greater than 6 months, but are they greater than equal to 65? If it's no, oh, then that's the standard dose. If they are, then I have to give the high dose or the adgiant version. If again they have a significant age restriction which is I can only give this if they're 18 years or up well then in that case what am I going to give the recumbent influenza vaccine. If I have the patient who is not pregnant not immuno compromised or they do not have COPD asthma that's probably the patient I would find to have benefit from the live attenuated vaccine. All right so that puts everything together for you guys for understanding the prevention. So, with this video, we talked about a lot of stuff, man. We talked about the pathophys, clinical manifestations, the worst case scenarios, how to diagnose them, how to treat them, and how to potentially

prevent it. I hope that you guys like this video. Hope you learned a lot. And uh, man, I love you guys. I thank you guys. And as always, until next time.