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Respiratory Viruses of Children and Adults

– Welcome, everyone toWednesday Nite @ the Lab. I’m Tom Zinnen. I work here at the UW-Madison Biotechnology Center. I also work for the Division of Extension and Wisconsin 4-H, and on behalf of those folks and our other co-organizers, PBS Wisconsin, the Wisconsin Alumni Association, and the UW-Madison Science Alliance, thanks again for coming to Wednesday Nite @ the Lab. We do this every Wednesday night, 50 times a year. Tonight, it’s my pleasure to introduce to you Katie Schmit. She’s a physician in the Department of Pediatrics here. She was born in St. Charles, Illinois, which is right down Illinois 38 from Dixon, Illinois. She went to St. Charles North High School, and then came here to UW-Madison to study biochemistry. Then she went to St. George’s University to get her medical degree on the island of Grenada, then she did her clinical work in Brooklyn and lived in Bedford-Stuyvesant. Then she came here to UW-Madison to do her residency. She’s currently heredoing a fellowship in pediatric infectious disease, and she’s also doing a primary care research fellowship with the Department of Family Medicine. Tonight, she’s going to talk to us about something that’s near and dear to all of us who have ever had children, respiratory viruses of children and adults. The focus is on influenza. It’s gonna be interesting to see how the numbers stack up to this competing virus that we have going around right now. I think influenza may win. Please join me in welcoming Dr. Katie Schmit to Wednesday Nite @ the Lab. [audience applauding]

– All right. Thank you, Tom, for that introduction. Today, I’ll be discussing influenza, like Tom mentioned. I will focus on three key concepts that will help us follow influenza from the virus itself to the infection that it causes. So my goal is to help you guys enhance your knowledge about influenza you hear so much about, and the flu virus you hear so much about. I recognize that everyone in this room is starting from different backgrounds. There may be some virologists in the audience, but I’m trying to keep it quite basic with talking about key concepts about influenza that transfers over to different respiratory viruses. So before I get started, I have no financial disclosures. [audience chuckling] I will not be addressing any non-FDA medications during this talk.

So these are the three key concepts that I’ll be going through today to talk about in addressing influenza. So even though some of these are very specific and unique to influenza, overarching respiratory viruses, a lot of this is the same in regards to transmission and immunity, and within transmission, animal to human transmission as well as human to human transmission. So the first concept I’ll go over is viral properties that are unique to influenza, dealing with some surface antigens called hemagglutinin and neuraminidase, and then going to antigenic drift and shift, which reallyhelps us understand epidemics and pandemics and how they occur. Second concept I’ll go to is transmission. So this is focusing more on the human to human transmission that occurs with droplets transmission mainly, and then also discussing some of the environmental changes that allow influenza to replicate. The third concept that I’ll go through has to do with immunity. So not only population immunity, but I will talk about influenza vaccine overall. So I know I listed a whole bunch of things on that slide. Some things may be familiar to you, some things may be completely foreign, so I really don’t want you guys thinking like this at this point. I really want us to take this journey together and have a better understanding idea of some of these concepts that come through when we talk about influenza.

So my goal is to put you more in this realm. Being able to talk to family and friends about influenza, being more informed, yourself, about influenza and some other respiratory viruses. Realistically, I know that you may feel more like this after my talk, and that’s okay, but I’m hoping that we land more on this, where we just really understand the importance of hand washing and the key things with influenza and other respiratory viruses to reduce transmission overall. So before I go into those key concepts that I talked about, I’m gonna start with the burden of influenza. So this is important, and why I’m talking about influenza today has to do with the burden of disease that we see in the United States and throughout the world. So these statistics here, I’ll try not to bore you with a ton of statistics, but these statistics here are just from this influenza season. So starting from September to this is the most recent one on the CDC from February 22nd. These are the numbers that we’re dealing with. So when we talk about flu illnesses overall, we’re at 45 million flu illnesses in the United States. Okay.

So this isn’t world, this is in the United States, here. We’re talking about 500,000 influenza hospitalizations. So to put that in perspective, that’s about the size of Milwaukee. A little bit less than the size of Milwaukee, overall. So the entire city of Milwaukee would be hospitalized with influenza. In addition to that, when we look at flu deaths so far this season alone, we’re at 18,000 to 46,000 influenza deaths, which is quite a lot when we’re comparing it to some other things thatare going on at this time. Overall, the CDC tracks all of the leading causes of death, and in 2017, which is the most updated ones that they have, it is the eighth leading cause of death. So influenza and pneumonia combined are the eighth leading cause of death overall. So this is really important, and something I think a lot of us forget about, is how big of a burden this is. This is also from the CDC, the Center for Disease Control.

I’ll abbreviate it as the CDC going forward. This has to do with the median incidence of symptomatic influenza throughout the influenza years from 2010 to 2015 influenza seasons. So the seasons’ severity change quite a bit from moderate, to low, to high depending on certain types of viruses that are circulating that year, but overall, with all ages, this is the amount of people that have symptoms because of influenza. So 8. 3% of the total population has influenza symptoms throughout the influenza season. Then, when we look at specific age groups overall, we notice that the children less than five years of age have a higher percentage, and also adults age 50 to 64 also have a higher percentage. Again, every season it changes a little bit, there’s some certain seasons that it shifts, but really these are the ages that are affected the most. The deaths per year in the United States, it’s 12,000 to 61,000. Again, that changes depending on the circulating viruses and some of the other things I’ll talk about moving forward. But worldwide, there is 290,000 to 646,000 deaths per year.

The entire world. Okay, so that addresses just some of the burden, and why I think it’s important to talk about influenza, and why we should be educated about influenza overall. So now I’ll go into the viral properties I was talking about. So these are specific to influenza and help with influenza being virulent, and how it gets transmitted to others. So first, I’m gonna talk about the two surface proteins that are important, hemagglutinin and neuraminidase. So this is a depiction of the influenza virus that really graphically helps. So influenza virus is an RNA virus. This is important when we talk about some of the changes that the virus can have moving forward. So its genome, so the genetic makeup of this virus is RNA instead of DNA, which our genetic makeup is made of. So now, moving onto some surface proteins.

So the first one I wanna talk about is hemagglutinin, which is, really how you think about it is this the virus here, and how it sticks to cells, and how it’s glued to a cell is the protein called hemagglutinin. So this is the reason that the influenza viruses attaches to cells. Moving forward, it’s abbreviated as HA or H. I’ll come into influenza naming in a little bit. The second surface protein that you can see on this picture here is something called neuraminidase, which helps release the virus from the cell. So after the virus is attached, it gets engulfed into the cell, it makes new virus, and then prior to it getting out of the cell, it needs to be released by something. And this is what is releasing it, the neuraminidase. So you can think about the neuraminidase as a scissor, okay? So the hemagglutinin glues it to the cell, the neuraminidase cuts it off from the cell. Moving forward, this will be abbreviated as NA or N. And so, these are important when we talk about some of the naming of influenza viruses.

So if you guys have heard of influenza viruses named H1N1, H3N2, H2N2, those are why they’re named that way is based on these surface proteins. So the H refers to hemagglutinin, the N refers to neuraminidase. So now, we’ll go through the life cycle of influenza. So once it attaches to the epithelial cell of either humans or animals, what it does is that virus goes into the cell, over on the second portion here, and that is facilitated, the actual attachment like we talked about, is the hemagglutinin, goes into the cell, and then it releases its viral contents in that third stage, in the uncoating stage. Once its viral contents are in the human cell or animal cell, it then transfers its RNA material into the nucleus of that cell, and then what it does is it replicates it. So it makes more of itself, making more of these infectious viral particles that you can see within the cell, here. And then, once it’s ready, it goes to the cell’s surface and then it gets released, and that’s where the neuraminidase comes in and it helps with the process. So there are three different types of influenza, type A, type B, and type C. So first I’ll mention type C. Type C is not something we hear about very often, but it is a subtype of influenza.

It typically causes very mild respiratory illnesses in children. We don’t focus on it as much because it doesn’t lead to pandemics or epidemics, so it doesn’t lead to mass people having infections because of it, and the symptoms are quite mild so we don’t see deaths associated with it. This is the last time I’ll talk about type C, ’cause really, the importance of the influenza has to do with type A and B. So now, talking about type A, as I mentioned previously, type A is named by the H*N* or H#N# subtypes. When we look at different subtypes like I had mentioned, there are certain subtypes that infect different types of animals and different types of humans. So influenza A is quite unique because it can infect birds, can infect pigs, and it can infect humans. So this becomes important when we talk a little bit later about some of the pandemics that have happened in the past. And concern for pandemics happening in the future really has to do with multiple species being able to be infected with influenza A virus. Humans, at this time, have only been known to have H1N1, H2N2, and H3N2, so those are the most common ones that you’ll hear over and over again. They’re the most common ones that are covered in our vaccines as well.

Now, type B. So type B infects humans only, so it does not infect animals at all. There are two lineages of circulating influenza B for the past 20 years, and those are called Victoria and Yamagata. So I talked about the viral properties in regards to hemagglutinin and neuraminidase. Now, I will go on and change to talk about antigenic drift and antigenic shift. So these words sound very similar, and as a medical student, and learning all of this, they jumble up in your mind, so I’ll try and make them as different as possible as I can in using some analogies moving forward. But really, these are important to understand why we get outbreaks of influenza and why we get outbreaks between continents of influenza. So I’ll first start with antigenic drift. So this is a similar influenza virus that we saw before. Instead, it’s not opened, it’s actually closed.

So you have the hemagglutinin and the neuraminidase on the surface. So like I had mentioned previously, influenza is an RNA virus. With an RNA virus, that virus is at risk for having certain types of mutations. It doesn’t do a good job of proofreading through any of the viruses that it makes. It does not do a great job about it, and so it can have certain mutations. It can result in point mutations, which is just a minor mutation or a minor change that happens. So when this happens on those surface proteins, with hemagglutinin or neuraminidase, what you get is a virus that is closely related but not exactly the same as the initial virus. So as you can see here, the neuraminidase changed from this circular sort of flower structure over to these squares overall. So it’s somewhat similar, but definitely has changed. This can occur with influenza A and it can occur with influenza B as well.
This is what leads to seasonal epidemics. So you have your virus, it changes slightly, but people still have some immunity to it, then that’s when you get your changes and why the vaccine may not be the best fit or why certain people are getting sick because of it. So because it is closely related, like I had mentioned, there is some immunity and so people do have some cross-protection. So there is. . . Depending on how big the change is really depends on how much protection you have circulating. So we talked about the drift, minor change leads to seasonal epidemics, occurs with influenza A, and can occur with influenza B. Now, we’ll move onto antigenic shifts. So antigenic shifts, we’ll start with the same influenza virus, but now there’s a major change in the virus.

So it’s not just a small minor point mutation change, it’s a big change. So really, you’re completely changing what the virus looks like. So in this case, the hemagglutinin changes from that blue color to a yellow color and it’s a completely new virus. This occurs only with influenza A. And this is what leads to novel or new viruses that can cause pandemics. The other part of this that is important to know that, in order for these new viruses to cause pandemics, it has to be really distinct from any other previously circulating influenza viruses. So the immunity to this new virus has to be very low or none at all for it to actually cause a pandemic. So how exactly does this happen? How does an antigenic shift or those major changes happen? There’s two ways that have happened, and I’ll go over the history of some of this and some of the pandemics that we’ve had in the past, and which one fits into where. But as I talked about with influenza A on the previous slides, influenza A can infect animals and it can infect humans, so this is where the shifts become important. So I’ll start off and say I just made up these virus names.

They aren’t actual names, but we’ll start with the pig. So he has HpNp, the chicken has HcNc, the duck has HdNd, and then the human has HhNh. So what happens is these viruses normally circulate. Some of the animals may have symptoms, most of them don’t, so no one knows that they actually have these viruses. And then, somehow there’s a change in transmission and it goes from the animals to the human. Okay, so this is not like, let’s use for an example, the pig one, so HpNp, is not something that normally circulates in humans but somehow, someone was working closely with pigs or was exposed to the virus when working with pigs or eating pigs, and then the human gets the virus. This is something that’s called spillover, so it’s spilling over from the animal population into the human population. So you may see that word over and over again when people talk about outbreaks of respiratory viruses. In order for these viruses to go from the pig to the human and to actually infect the humans, there’s other things that need to happen in order for that virus to cause pandemics or to cause massive outbreaks of them. The virus itself needs to be able to survive and replicate in the human.

So it did a really good job about surviving and replicating in that pig, but now it’s in a completely different host with completely different receptors for things. And so that’s really important is if that virus can adapt or change to actually have that survival. Like I had mentioned previously, the human has to have no previous or very low immunity to this virus, otherwise their body would take over and get protected with antibodies. And then, in addition, in order for it to pass from one person to the next, you need to have the virus be able to be transmitted from humans to humans. So not only does it have to be a spillover event, there’s all these other factors that need to happen in order to cause pandemics. The pig is very unique in this situation because it has respiratory receptors for both the avian influenza, so the bird influenza, as well as the human influenza, so it really facilitates some of these interspecies transmissions. And where that becomes important is this second method of how antigenic shift can happen. It’s something called reassortment. So reassortment means, if we look in the middle here, that the pig was infected with multiple viruses, so from the human, from a previous pig, from a bird, and then within the genome of the pig, it recombines all of these genetic material and makes a new virus. Then that new virus can go and combined again with another virus, and then create another new virus, and then it can switch over to humans.

So this example here is what caused the 2009 outbreak with H1N1, referred to as swine flu, and so what happened in this situation is that there were two different swine species that were involved, so you have the Eurasian swine, which are located in Europe and Asia, you have your North American swine, which are located in North America, and then you have this previous combination with human and avian species. So overall, there were four different species involved with it that really produced this novel or new H1N1 virus. So this is called reassortment. The thing about reassortment is that it doesn’t always lead to pandemics. So reassortment can happen, we may not know that it’s happening, and as long as people are not getting sick or not dying from it, we still wouldn’t know. So a lot of this happens within animals and we are unaware of it. So this looks at the different pandemics throughout history. So we’ve had four total so far, the first one starting with the 1918 Spanish influenza. So what is predicted happened in that situation was that first method I had talked about. So all of these are big shifts that happened that causes the major mutations to cause a new virus and cause pandemics.
With the 1918 Spanish influenza, what happened is that there were birds that then transmitted their virus that humans had never seen before, to humans. And then, it caused a massive outbreak where 50 million people died with the 1918 Spanish influenza. Then, with the second outbreak in 1957, referred to as the Asian influenza, this involved that reassortment, so that second method I talked about where there is mixing of the genetic material to make these new viruses. But this involved an avian influenza strain as well as a human influenza strain to cause H2N2 pandemic. The third outbreak, here, is the 1968 Hong Kong influenza pandemic. And this one also had reassortment of the avian influenza and the human influenza that exchanged material, resulting in H3N2. The last pandemic, and the reason why it’s not on this particular article is that this article was written in 2005, and so the 2009 pandemic was not on that one, so we had previously talked about that, that was that quadruple reassortment with two different swines, an avian, and a human that then resulted in this new H1N1. For now, your next question, I assume, is gonna be, “Okay, well, what does this mean “and can we predict when the next pandemic is gonna happen?” There are a lot of experts that are trying to do that exact same thing, to try and predict what exactly is gonna happen and to try and come up with antiviral medications, to try and come up with vaccines that can actually protect against some of this. Overall, experts are really focusing on the avian influenza and their concern about the avian influenza actually causing the next pandemic. And the reason for this has to do with, there’s two current strains of avian influenza that have actually gone to humans at this point.

The first one is something called H5N1. So H5N1 started to become present in 1994 when they first noticed that there was a new strain in humans when someone got very sick, and they’ve been tracking it. It’s kind of spread throughout different continents. It’s been present in Europe, it’s been present in Asia, it’s been present in North America. The thing about this one is it causes very severe infection, and the case fatality rates are quite high. So the case vitality rates are 53%, which means 53% of the people that get this infection are dying from the infection. So for perspective-wise, the normal seasonal influenza, it varies a little bit by year, but it’s 0. 1%. Okay, coronavirus right now, the novel coronavirus COVID-19, is predicted to be about 3 to 4%. So when we’re talking about 53% case fatality rate, that is incredibly high.
The other interesting thing about this H5N1 is that the median age is very young at 20 years of age, which is something that has happened with previous pandemics, and I’ll go into that a little bit more when we talk about immunity moving forward, but it’s really hitting the younger populations with this type of virus. The thing about this virus, though, is that people that have been infected, they’ve been able to track that they’ve had exposure to ill poultry about one week prior to their onset. So really, the control of this virus has been monitoring poultry and mass killing of poultry when they demonstrate any symptoms. In addition to that, farmers are testing a lot of their chickens or poultry for this type of virus, and then will proceed to kill that whole area of chickens. The second one that also is concerning is something called H7N9, and this has caused outbreaks within China. The case fatality with this one, as well, is quite high at 30%. The median age is older, about 60 years of age. But the reason why this one is such a concern, in addition to the case fatality rates, is that it is resistant to Tamiflu. So Tamiflu is the main antiviral medication we use to treat and to use as prophylaxis for influenza, and a lot of the other viruses have not shown resistance to Tamiflu. That’s why it’s so routinely used, but this one in particular has shown resistance, which is really concerning when you don’t have a lot of other options to treat people with for their influenza.

And so the CDC and the WHO have actually labeled this virus as the highest potential for pandemic risk in the future. Luckily, this virus has incredibly poor human to human transmission. So people can get it from interactions with a poultry or a chicken that has this type of virus, but really, it’s not transmitting from one person to the next, so there’s no further spread that’s happening, which is really important. – Attendee: Is that true of H5N1 as well? – H5N1 has a lower human to human transmission. It’s not as much. There’s about 860 cases total from 2013 to 2018 that have been there, so it’s a pretty poor human to human transmission. But the concerning thing with these avian influenza is, like I talked about, if they go through any major antigenic shifts, that can increase their transmissibility or make their transmission from humans to humans better, then that’s where this gets really concerning. A lot of these patients end up in intensive care units, have very severe pulmonary problems, and then the high case fatality rates. So that’s why this is a very concerning area in regards to influenza. So I know I told you that these words sound the same and you may have heard me, and they kind of blur together when I talk about drift and shift, so I thought I would give you an example to take it home to try and really give you a better idea about remembering these.

So antigenic drift, imagine you’re on a lazy river, right? So you’re on the tube, you’re just drifting along, you’re drifting along, and then you get stuck on the side because there’s a big bunch of people that are coming by and you get pushed out of the way. So your tube goes in a little bit, shifts a little bit, but in the end, you end up in the same spot, right? So you have a little bit of a drift, but you still end up where you wanted to be. This happens with influenza A, and it happens with B, and this is what leads to your seasonal epidemics. So if you think about it, when you got stuck in that area, you’re close to the people that you’re around in that local environment. You can transmit that virus in that point, but then you go back to your normal lazy river once the crowding goes away. Antigenic shift, you can think about it as a gear shift. So as you shift the gear, you’re ending up in a different location, or you’re going in a different direction. So this is a major change from your endpoint that you initially had, or your starting point, I should say. And this occurs with influenza A and this is what leads to pandemics. All right, we talked about the viral properties, the surface antigens, the neuraminidase, the hemagglutinin.

We talked about the antigenic shift and antigenic drift. Now, we’ll go onto transmission. So I already previously talked about the animal to human transmission and why that’s important in regards to influenza, and now I’ll focus on the human to human transmission. So I’ll start with droplets. So let’s say you have your infected person that has influenza here, and they’re coughing, and they’re sneezing, and everything is going all over the place ’cause they try to control it, but as you know and you’ve seen in some of those videos, the snot goes everywhere, and it’s quite disturbing. And with that, they’re carrying influenza virus particles. So the influenza virus particles get into the air, and these are all different ways that infectious disease can be transmitted. So with influenza itself, it tends to be larger droplets. So instead of these smaller droplet nuclei that you can see here, they’re really larger droplets. So what that means is larger droplets can’t stay in the air for a long period of time, so you have to be quite close to a person in order to actually transmit influenza.

Some of the other things, like tuberculosis, which is airborne, so these tiny nuclei, they can stay in the air for a longer period of time and go further distances. So let’s put these two people in a bubble and let’s say, “Okay, what does that mean, really, “in real time?” The infected individual sneezes. How close does the susceptible individual need to be in order to actually transmit the virus? And a lot of studies have been done about this, and what they have found out is that it’s between three to six feet, so it has to be quite close. It’s not always super close, but it’s a pretty close contact within that three to six feet. The other areas that influenza has been shown, although they’re very lower on the list of being transmitted, is direct contact. So direct contact means that you have direct contact with that infectious particle, so if you’re sitting close to that person within that distance, and they sneeze, and then you grab their Kleenex, and now you have, I don’t know why you would grab their Kleenex but, [all chuckling] you, if it’s a family member, you don’t think about these things, so you grab their Kleenex, now you have influenza virus, potentially, on your hand, and then we touch our faces a lot, I don’t know if you guys have ever done the experiments about how many times you touch your face within a day or within a short period of time. It’s a lot. And so, what you would do is you have those infectious particles on your hand, you then touch your nose, you touch your mouth, you touch your eye, and then the virus particles are there. Again, this is a lower risk of transmission, but it’s still possible. Indirect contact is what we deal with a lot in the hospital, so indirect contact has to do with the person that’s infected sneezes on their hand, they touch an object, they walk away, you would come up, you touch that object within a shorter time frame, and you would then have influenza on your hand, and then touch your nose, or your eye, or your mouth in those situations.

So these are all important to understand, and a lot of studies have gone into this because of hospital situations and precautions that need to be preventing hospital outbreak. So I had to show one gross picture of, [audience chuckling] there’s a lot of ’em on the internet, but I had to show one gross picture of someone snotty. So now let’s go through, now that we talked about how you can get transmission, we have these infected people with influenza, they can transmit influenza virus anywhere from one day before their symptoms to seven days after their symptoms, okay? So the one day before the symptoms is something important to keep in mind, because they don’t know that they’re sick at that point, and so they can transmit it. The highest transmission rate is really three to four days after the symptom onset. So they cough or sneeze and a susceptible individual is within six feet of that. So then what happens? So once it gets coughed and sneeze, the susceptible individual then gets that viral particle in their nose, in their mouth, in their eyes, and then this happens. So this is a picture of influenza virus, and you have epithelial cells, which are right here. Epithelial cells are cells that line your respiratory tract, so all throughout from your nose to your pharynx, so your throat, and then into your respiratory system. So influenza, what it does is it attaches to these epithelial cells. So remember that glue I was talking about before? That’s where these become important.

So the hemagglutinin, or that glue, attaches to the sialic acid receptors that are present on epithelial cells. So once it attaches to those, then the virus can then enter into your system, and then replicate, and go through the life cycle that I talked about previously. So we have these people, the susceptible individual gets the virus, the virus attaches to the sialic acid, it goes into the cell, then about one to four days after being exposed to the virus, they develop symptoms. So the one to four days is when the virus enters, and then symptom onset, and so that’s referred to as your incubation period. So how long it takes for a person after they’ve been introduced with the virus to actually have symptoms. So relatively to some other viruses, this is quite short, and so people typically present with symptoms earlier on. So we talked about droplet, now we’ll go onto some of the environmental things that are important. So here is a picture of the world, and so what is important in this picture is that it’s a study that was done that looked at the peak month of influenza, so when influenza, during the season, their peak month is, and then how long it lasted for. So we’re very used to having a set period of influenza. It changes a little bit each year, but most of the time it’ll last from September to about March.

Some years it will last a little bit later depending on what’s circulating and what’s going on. With our peak time, around January or February in the United States. But other areas of the world don’t have that, or have different environments that have it peak at different times of the year. So when we look at some of these other places, this is when their influenza epidemics or pandemics peak, is that in the tropical environments, they are peaking around June or July, lasting about the same duration as our influenza season. But the interesting thing is over here in Asia, they have these semiannual peaks. So they have two peaks a year of influenza instead of having one peak like we do. That has to do with the environment. So influenza really likes colder temperatures and low humidity. So any time you alter that or change that, then influenza doesn’t do as well with circulating in the air. This is from 2013, so it would be interesting to see how this has changed, and what will change in the future with some of these climate changes and global warming, and what that will do for influenza, both the seasons, the duration of the seasons, and when they actually peak.

So now I’ll go onto immunity. So I’ll talk about population immunity and vaccines. So this is our third concept here. So we’ll start with this diagram here, and the importance of this diagram really has to do with immunity, and what the population immunity is doing, and how that relates to outbreaks or pandemics. So we’ll start all the way on the left here. So we have an introduction of a new virus. So influenza A, HxNx, which we’ve never seen before. Okay. So what happens after that’s introduction is that it leads to a pandemic. So you see your disease incidence here, so you get high disease rates, and then those will fall over time, and as those fall, you see this antibody, or the immunity to that virus, go up.
And then you get your next season, which there is some immunity, so some people have created these antibodies and can fight off these infections, and so, then you get lower amounts of incidence. And then as more of your population is exposed to this virus, you see that your antibodies go up, and then you see the rates of disease go down overall. So this middle range is where we see some of those drifts happen. So those are those minor changes that can affect and still cause disease, but really, people are protecting themselves with the antibodies they’ve had from the previous infection. So then what happens again is that, all the way on your right-hand side, there’s an introduction of a new virus. So now we’re introducing HyNy. So even though we had great immunity to HxNx, that really doesn’t help us for this new virus that comes. So with this new virus that it comes, you see a huge peak in your incidence rates of disease, causing another pandemic. And then, over time, what you see is the antibodies here go along and start to go up, and you see the same sorts of cycles happen over and over again. So this is what you see when you look at pandemics throughout history and that interpandemic era, where you’re seeing little spikes but they’re not as big.

It’s because the population has developed some immunity to it. I’m just gonna show this in a different way using our history to help follow along. So first I’ll start with the 1918 pandemic, or outbreak, the Spanish influenza that happened. So up top you have the circulating influenza viruses. Down below you have the timeline of pandemics or important things in influenza history. So in 1918, you see that H1N1 arises. It results in about 50 million deaths worldwide, then H1N1 continues to circulate throughout that time. So as you follow along the timeline, you have your 1918 pandemic, and then it circulates until about 1947. And then it has a slight drift that makes it a little bit different, but still protected. Then we get to 1957.

1957 is when we had our second outbreak, and that’s when you notice that H2N2 arises. So you have your big peak with no immunity previously, and then H2N2 circulates for a period of time. Then you have your 1968 outbreak, which you notice that H3N2 now arises. And then we get all the way to 2009, where we notice that there’s this novel H1N1, or the swine flu H1N1, that came up that resulted in 150,000 to 580,000 deaths in the world. What’s interesting about the 2009 outbreak is that it really affected people that were less than 24 years of age. And there was a lot of thought when this initially happened, like, “Why are all these adolescents or college students “that are healthy, for college students, “getting really sick and not doing well?” And what they noticed is that there actually was some similarity between the H1N1 that circulated here and the H1N1 that circulated here. That’s why this arrow is there. And so it seems like the older adults actually had partial immunity to the new H1N1 ’cause they had previously been exposed to a similar H1N1 that provided cross-protection or cross-immunity. So with these pandemics, you can see there’s certain age groups that get affected that aren’t the typical age group that you think of with the highest rates of incidence of influenza. So we talked about population immunity, we talked about antibodies circulating, now we’ll go onto influenza vaccine.

So we’ll start with our virus here. What some of you may have noticed on the previous slides is there are these areas that are called antigenic sites on this hemagglutinin, and these become important when we talk about influenza vaccine. So how does influenza vaccine work? What it does is your body is exposed to either a weakened or killed form of the disease, and then your body creates these antibodies, which are present here after being exposed to it, and then these antibodies, let’s say you got your flu shot, you developed your antibodies, and then you got exposed to influenza, unfortunately. And what happens is these antibodies go to these antigenic sites and actually clamp onto them. So we’re talking about these antibodies that were in your system go to the virus, the outer portion of the virus, and go on top of them. And so what that does, is our previous picture, is it blocks the virus actually being able to attach to those sites. So the virus is unable to attach the sites of the cells, and so they can’t enter into the cells, and then your body mops up this virus through other immune system cells, and is able to get rid of it so you don’t get sick. So that’s how the influenza virus actually works, is it really blocks this attachment part. So the influenza vaccine, we’ll talk about the 2019, 2020 one, these are the different viruses. You don’t have to read all of them, just know that there’s two influenza A viruses on there, and there’s two influenza B viruses on there.

All of the other stuff really is just really specific virology names and what specific virus they put into the influenza. But you can see here that the first one was an H1N1-like virus, the second was an H3N2, and then you have your Victoria and your Yamagata. The stars next to those first two ones is what changed from the previous year’s vaccines. So every year, at the end of the influenza season, a ton of experts get together and try to predict what they think is gonna be circulating the following year. And what they predicted for this year are these four. It’s still too early to know exactly how effective this is. There’s varying rates between the virus strains. It’s probably about 30 to 50% vaccine effectiveness this year, which is pretty typical of the influenza vaccine. But these first two are new ones this year. So the important thing to know and the important thing that I like to tell patients when we’re talking about influenza vaccine is you’re 50 times less likely to get sick from influenza compared to someone who doesn’t get the vaccine.

So I feel like this is an important concept that we don’t talk about very much. And, in addition, not only do you have 50% less likely, if you do get an influenza strain that’s not one of the ones listed, there is some cross-protection. So you can have less severe disease even if you get exposed to an influenza virus that isn’t covered by the vaccine that year. So now the vaccine impacts on influenza. So this is the most recent updated that the CDC has about what the actual vaccine is helping to prevent. So in the year of 2017 to 2018 in the United States alone, it prevented 5,700 deaths. It prevented 91,000 hospitalizations. Does anyone what this is, the picture of? Some stadium, it’s Lambeau. So Lambeau Field can hold about 81,000, so we’re protecting 10,000 more than what Lambeau Field can hold in hospitalizations. In addition, we protected 3.

2 million medical visits and 6. 2 million illnesses overall. So we protected over an entire state of Wisconsin population with illnesses with the vaccine. So that’s quite impressive of something that we can do and why a lot of medical providers really push for influenza vaccine. And this is just in the United States, it’s not worldwide. The rates are much higher when you look at the whole world. So we talked through these three concepts, which I think are important in influenza, and to help you understand some of the other things that can happen in other respiratory viruses that are important, why we see these pandemics or outbreaks. So with influenza, we talked about those viral properties that are important for the structure of influenza, how it gets into your cells, and then why it causes epidemics and pandemics. And then we talked about the transmission with droplets, and some other transmission that can happen as well as the environment and any climate changes that may affect that. And then the last concept had to do with immunity, which is important overall, about your population immunity, so overall, who’s being covered, and then also the vaccine itself.

So these are the important things to take away, and why pandemics happen is a change in each one of these concepts can really lead to a big outbreak of things. So viral properties, when we get new virus, or a novel virus, and then that virus is easily transmitted, and then the population has no previous immunity, that’s when we get really big outbreaks with viruses. So I’m gonna talk briefly about my specific research. I was just giving you a rundown about influenza. So my research really has to do with the impact of respiratory infections in children, and why I care about that, and why I think that that’s important is a lot of these numbers. So overall, $40 billion is spent per year on non-influenza respiratory infections in children. So those rates skyrocket when you actually include influenza into those accounts. It also accounts for greater than 45 million missed days of work and 22 million missed days of school because of kids being sick, parents needing to leave work, or parents themselves being sick, adults being sick. The other interesting thing is down here. So the $2 billion per year is spent on cold remedies.

So this is out-of-pocket money that we are spending on cold remedies, overall. So really where I found this gap in the respiratory infection research in children has to do with, we have clinical trials for some of these symptomatic treatments, we have clinical trials trying to use some of these antivirals in certain type of respiratory viral infections, but really, the measures that they use are not consistent between the trials, and they’re not validated. So they previously haven’t been shown to be valid in pediatric patients with acute respiratory infections. So what this means is that it’s really hard to compare clinical trials in children when they’re trying to see what helps improve their respiratory infections or helps to cure their respiratory infections. Then, it’s also challenging to interpret what this data means when they use measures that haven’t been validated or haven’t been researched previously. So Wisconsin Upper Respiratory Symptom Survey is something that was developed by Dr. Bruce Barrett, who is a part of the Department of Family Medicine and Community Health. He developed it in the 2000s and it was focusing on adults. So it’s an illness-specific quality of life instrument that was used to assess the negative impact of acute upper respiratory infections in adults. It’s been used in various different clinical trials, and really, what’s happened with it is it’s really exploded.

So 150 institutions around the world in 35 different countries use this survey to help with their clinical trials, their observational trials, and any pharmaceutical companies that have picked this up as well. It’s translated to multiple different languages to be used in these different countries. So what I am doing right now is taking that framework of the Wisconsin Upper Respiratory Symptom Survey and trying to validate it in pediatric patients. So it was validated and proven to work in adult patients, but as we all know, children are very different than adults in many different aspects. So what I’m trying to do is really assess their symptoms and their quality of life, and how that impacts their scores overall, and what that means with the overarching structure of the actual form. My goal is to use it in future clinical or observational trials focusing on children in an outpatient setting with acute respiratory infections. There is a lot of research being done about children that are hospitalized, children that have asthma, or infants with acute respiratory infections, but this part with the outpatient setting with acute respiratory infections, there hasn’t been as much research. So where I am now with things is I completed the administration to all the participants in my study. The analysis shows that it holds together quite well, and it’s valid and reliable, so now I’m thinking about where do I fit this in with different clinical trials and where do I go with this at this point? These are all of the people I would like to thank. So as you know, there’s a lot of people involved in a lot of this work.

With the WURSS Kids, these are all the people that have helped me get to where I am, and then my mentors as well. So I’m a part of two different departments at the University of Wisconsin, so I’d like to thank the University of Wisconsin Department of Pediatrics and the Department of Family Medicine and Community Health, and then the Wisconsin Survey Center helped to put together the WURSS Kid Symptom Survey that was used and validated. So thank you, guys, for listening and taking the time out of your night. [audience applauding]