Ep 111 RSV: What’s syncytial anyway?

were born early. They needed some help with breathing and maintaining their own temperatures, but all were discharged from NICKYU two weeks later. We had a lot of visits from community nurses to check on their health. They checked their weight and for any signs of infection. I was told a number of times to watch out for a virus called RSB, as it was a risk this time of year, especially for very young babies, and especially for those with

a sibling who was attending nursery or school. I understood that we tipped a few of these risk boxes, but I wasn't concerned. I thought would be okay. When Lenny was five weeks old and not yet the weight of most newborn babies, he seemed more sniffly than usual. He was drinking his milk more slowly, and he had been sick a couple of times. I thought he had a cold. I thought he would get better in a few days. One morning, we woke up and I went through the

usual morning routine. Lenny seemed like he was okay, but he still had a cold. So I left him till last so I could feed the others and spend a bit more time with him. But as I picked him up to feed him, I thought he looked pale. He seemed maybe a bit colder than usual. I felt panic. I was worried. I still couldn't drive, having only had a sea section weeks ago, so I phoned my husband and he came home and took us to the hospital. By the time we got there, and after only a

ten minute drive, Lenny had gotten much worse. In fact, he was rushed straight through to reesos and what felt like tens of staff rushed into the room to help him. He had become so sick so quickly that they thought he could have sepsis. He was tested for a number of illnesses, and the swabs later came back positive for RSB. By this time, Lenny had been admitted to the High dependency unit. He had been put on a seapap machine to help with his breathing. It was later switched to

BiPAP and he narrowly avoided being intubated. After he stabilized, he needed support with nutrition and hydration and was given a cocktail of drugs. The other two triplets were admitted to Award over night for observations, but were discharged the next day. We were advised to keep Isabelle and Teddy away from the hospital so they wouldn't pick up any infections. It was a heartbreaking logistical nightmare caring for our three apparently well children on our critically ill baby all at once.

Lennie spent five nights in hospital, which was amazing considering how ill he was when he'd got there. He recovered as quickly as he had got sick, and I felt so positive and thankful to take him home. Little did I know that we were only midnightmare at this point. Less than a week later, isabel seemed to not be drinking her milk very well. After what had happened with Lennie, we had learned to watch out for signs that babies were struggling to breathe and Isabel was exhibiting a number

of red flags. She was sucking in a little around her rib so that we could see the slight outline of her rib cage, and there was a little recession in the front of her neck too. It suggested she was struggling to breathe. I took her to hospital. I was concerned, but not really worried, as she seemed nowhere near as sick as Lennie had been. But while she was being examined she had napnia and it was clear that she was starting to struggle significantly with her breathing.

She was admitted to the high dependency unit where Lenny had been and given oxygen support. All night long, the machines beaped endlessly and the nurse would rush over to do what she could. The following day, Isabel deteriorated. Her tiny body struggled to breathe so much that now her entire rib cage would be visible at points. Despite all the support, her oxygen levels were too low and she went from seepap to BiPAP and then was moved to

PICU and intubated. The procedure was a struggle because she was so small, and she was left with a bloody nose and a collapse lung. She was so sick that I asked the doctors as much as I could bear to if I was going to lose her, and no one could give me the reassurance they wanted. Slowly she became stable on the ventilator, which she didn't improve as

the days passed. We sat beside her bedside and the nurses took so many samples of blood from her feet to check her blood gases that her feet looked like pin cushions. Anula after canula came out and it became harder for the doctors to find places to fit new ones. Her body convulsed as it couldn't expel the mucus from her lungs, and the nurses would rush to suction it

through the endotracheal tube. It hadn't made sense to me why Isabel was so much sicker than Lennie, but it transpired that Isabel had had RSV and she'd developed bronchiolitis like a brother, but she developed a complication pneumonia. Thanks to the amazing care she received at the Royal Manchester Children's Hospital, Isabel recovered and she came home in time

for Christmas with her brothers and her big sister. On our last day in Picu, I remember a doctor telling me to be careful for the rest of the winter and for next winter two and she was right. Isabel was admitted to hospital with bronchiolitis the following winter, but as a much stronger one year old, and it was not so scary this time around. She needed some help

with breathing and new Trician, but she was okay. As she started to feel better, she even began to enjoy all the attention from the lovely staff as they came into her room. Each one who came in looked right at her and said hello. And after she was discharged, I was putting her to bed one night and she stood up and she looked at me and she said her first word hello. I will be forever thankful to the incredible medical and nursing staff. You saved my babies.

also really great because we get to talk about them all.

This year we saw a really early start to the RSV season, and I will not be surprised if it ends up having a pretty long tail as well, so we might end up seeing cases well into the spring. But we'll get into all of that later. First, what

the heck is RSV. Yeah, obviously it's a virus, it's in the name, but specifically it's a virus in the family Numoviridae, which includes viruses in the genus metaanumavirus, which is another common cause of human respiratory infections like common cold type infections, and then RSV, which is in the genus orthoneumovirus. So these are RNA viruses. They have an

envelope much like influenza. They have a non segmented genome, unlike our friend influenza, which remember has multiple little chunks of RNA uh huh, And just really off the bat, I want to emphasize how incredibly important of a virus RSV is. It is one of, if not the single, leading cause of acute lower respiratory tract infections and hospitalizations, especially in kids underage five globally.

news and you can't avoid it. And I know that part of that is because we're just seeing a really unusual number of cases, But is there anything else to that? Like, why do I feel like people have only started hearing about RSV now?

any other particular respiratory infection. So when a kid or a grown adult or an older person got infected with a respiratory virus, it was like influenza or something else, and that was kind of the only distinction that was made. So part of it might just be that we're doing better diagnostics so we can understand just how important this individual virus is. I think that might be a big part of it.

and potentially spreading germs that way tend to have much higher RSV transmission, whereas in tropical latitudes it tends to be the rainy season, which is obviously a lot more humid, that tends to see higher transmission. So it's the seasonality aspect is really interesting. In general, the incubation period for RSV that I've seen most commonly reported is between four and six days, could be a little less, could be

a little more. And then let's talk about the symptoms. Yeah, and for this, I'm kind of almost going to tell another little first hand account here because I remember very vividly when my kid got his first RSV infection, and I remember what the doctor explained to us, and I just think it was such a good explanation of the course of RSV that I'm going to tell it to you now. So when my kid got RSV, he was

probably three months old. He was definitely under four months because he only had one dose of Protestis vaccine and I was convinced that it was Protestant. Oh god, it wasn't protests. I made him test for it. But anyways, I remember that he definitely had a fever, but it came down with a little bit of til and all.

He didn't seem all that miserable at first, but then he was just coughing so much, just coughing, coughing, coughing his brains out, and he was so snotty, like an epic amount of snot And intermittently I started hearing him wheeze, And of course I was in med school at the time, so I would listen to him with my stethoscope, and I was like, he's wheezing. That seems bad, Like we should at this point, we should go to the doctor.

What do I do? I need a real doctor. So I brought him to see his doctor, and his doctor said, this is almost certainly RSV. It was like November peak. Here we go RSV season. At the time. The doctor said, he's not wheezy at this moment, but I believe you that he was wheezing at home, because he will probably continue to wheeze intermittently. He's been sick now for two or three days, So here's what's going to happen over

the next two or three days. So like days four to six of illness, he's either going to start to get better or he's going to get worse. And if he gets worse, here's what you'll see. He'll start breathing fast, a lot faster than usual. It'll look like he's working

hard to breathe. What you'll see are retractions, which mean that if you take off his clothes, you'll be able to see his ribs where his belly pulls in underneath his ribs when he tries to breathe, Oh my god, or in the little v of his neck right above his chest, you can see it kind of sucking in as he takes in a breath. Those are called retractions. If that starts to happen, you'll take him to the emergency room and they will do care for him. And those are the two ways that this disease is going

to go. And that's what the doctor told me. And it sounds terrifying, yeah, and it is terrifying, but I will say that it was one of the most reassuring things to know. Here's what to look out for, here's the things that are going to happen, and here's the kind of two ways that it's going to go, and what to do in both scenarios.

And in kids, especially babies, they're not good at coughing yet. They just don't have the muscles and they don't have the reflex to get up gunk when they cough, so they don't produce a lot when they're coughing. And then they either get better over time or they get worse. And it's often that days four to six or so is when they might start to get worse. So this

is a long disease that we're talking about. That's a long time to be watching a kid like a hawk and wondering kind of which way it's going to go.

Usually RSV, even in adults, is a pretty snotty type of cold. So you might have quite a lot of congestion in very very little babies, like under six weeks old, or very tiny babies that are very premature, they can actually have such little reserve when it comes to their respiratory system that they can present a little bit differently. Sometimes they might just look kind of lethargic, like they just don't really look like themselves. They have no energy.

Sometimes they might just have apnea, which is when they just stop breathing entirely for a spell, which is terrifying. Now in elderly adults over age sixty five, or in adults or children with underlying lung conditions like COPD or asthma, cystic fibrosis, things like that, you can also have a more severe infection that can lead to something like a pneumonia, a viral pneumonia, which we've talked a lot about on this podcast. So then the question you ask, the question

of who does this happen to? And before I get to that, what I want to talk about is what is actually happening in our airways? And I think once we understand that, we can understand who is at highest risk for severe infection. Okay, so what actually happens when we get infected with this virus as a respiratory virus RSV is initially and primarily infecting the epithelial cells of our respiratory tract. I feel like we talk about these cells all the time.

never been exposed before, you have no immunity whatsoever. That means infections in the very young, as well as in the very old, or the immunal compromised. So those are the three biggest groups that we're going to see more likelihood that you'll have a severe RSV infection because it's making its way down into your lungs. But the other part of it is that with RSV, I keep saying there's a lot of snot right, there's a lot of mucus.

That's largely because we see a huge amount of immune response, especially in the form of neutrophills, which are one of our white blood cells that often are the first to kind of rise up to try and fight off a virus that tend to infiltrate into spaces with an RSV infection.

So if this virus is infecting the small airways of our lungs are bronchioles, which are the kind of smallest of the branches of our lungs, then you're going to have a lot of white blood cells, these neutrophills, as well as fluid and gunk that's getting in to your lungs itself, and fluid in gunk is never good in our lungs for anyone, but for tiny babies, especially premature

tiny babies. They also have tiny airways. So these tiny airways are even more susceptible to obstruction, and that obstruction is what causes the primary disorder that we see in severe RSV, which is called bronchiolitis. So bronchiolitis is this obstruction. It's the plugging up of the tiny ends of our airways, the small bronchi and what are called the terminal bronchioles. This happens because of swelling, because of mucus, because our own cells are getting left off and all these immune

cells are coming in. These then get plugged up and eventually collapse, and that is what also causes that wheezing sound that I mentioned that you can hear if you listen to a kid with bronchiolitis's lungs. All this gunk makes it so that it's really hard to breathe out the air that makes it into our lungs, so it's

obstructing the flow. I know, it's awful, and I just want to contrast this to the other most common lower respiratory disease that we usually talk about on this podcast, and that is pneumonia.

be a pneumonia. In tiny kids, those airways are so small that they get plugged up before it even makes it down to the alveoli.

Prematurity is one of them. So being born at before thirty seven weeks, those kids are almost twice as likely to be hospitalized than kids who are born at term, kids who are born premature who also have what's called chronic lung disease of prematurity, or it used to be called broncho pulmonary dysplasia. It's a whole other episode. But those kids are about fourteen times more likely to need

hospitalization with RSV infection. And for those kids with chronic lung disease, the risk is also higher throughout infancy till about age two instead of just the first six months. And kids born with congenital heart disease also have a much higher risk of being hospitalized, about three times as high as kids with no other risk factors. And then, like I mentioned, kids who have various immune deficiencies or

underlying lung conditions. Gotcha, But because this is such a prevalent virus, when you look at absolute numbers, the majority of kids that get hospitalized are often otherwise healthy and don't have any underlying risk factors, which just goes to show you how incredibly prevalent this virus is. Like every kid is getting infected. Erin what is sensitia? I don't know, Yeah, I feel like I should know.

which usually means high flow oxygen. And if a kid is really really sick or just really small and doesn't have the reserves to be able to keep fighting to breathe, then it's mechanical ventilation, which means intubation and a breathing machine, which has its whole own host of possible complications. Yeah, but that's really all that we have. There was an anti viral that was tried but hasn't been shown to

be effective. Lots of people want to think that broncho dilators like we use for asthma, so like albuterol, think albuterol inhalers. They have no real benefit in RSV baranchiolitis. Same thing with steroids. So it's really all just this supportive care, which is scary when you think about places that don't have access to high levels of oxygen at high flow or mechanical ventilation or hospitalization in general.

to do that. On an individual level, whether a kid has RSV bronchiolitis or bronchiolitis caused by any other respiratory virus, which is possible. RSV is not the only thing that causes this same phenomenon of the plugging up of the small airways, the same way that influence is not the

only thing that causes viral pneumonia. Right, So on an individual level, it really doesn't change management all that much to test or to not test, and tests can be expensive, they can be hard to get, so it might not

be worth it to test an individual person for RSV. Okay, So there's not an easy answer there, but it is it's an interesting kind of you know, public health versus individual health versus like does it change a a doctor's or someone's management of a person who comes in with these symptoms?

of prematurity. This is amazing, right, Yeah, this is something that has good evidence can reduce severe disease and reduce hospitalization in these really high risk kids and babies. But because there's always butts, it is incredibly expensive. One estimate that I saw from I believe it was the UK, was like five thousand pounds per dose. Oh my gosh, I know, And I didn't see numbers on how expensive

it is in the US. It's cumbersome. Yeah, More it's cumbersome because it is an injection like a vaccine, and it has to be given once a month, oh usually for five months during that RSV season, and it's imperfect. It doesn't prevent against infection necessarily, but it does reduce the risk of hospitalization. So because of all these limitations, I actually have no idea what the actual availability and

access of this is, not just across the globe. I imagine the access across the globe is non existent in a lot of places, especially if you think about not just low and middle income countries that might not have access to an expensive drug, but also tropical latitudes where there isn't as well defined of a season of RSV.

can't diagnose asthma until four or five years old. Okay, but as of right now, we do not have a clear sense of whether kids who are genetically predisposed to the development of asthma something about them makes them more susceptible to RSV or severe RSV infection, or is there something about RSV infection severe RSV infection that either precipitates or maybe even expedites the development in asthma in kids who are predisposed.

the other way. But it's still a really muddy picture, so we still don't know for sure.

and perhaps a little bit more transmissible. But from what I found, we don't have great data on strain differences when it comes to disease severity or things like that. And I think it's probably because of how much we've just underestimated RSV in general. I don't know how often even if we're test for RSV, we're testing for strains of RSV.

But that's not going to be all of the history section because that would be a pretty lousy podcast episode if I ended it there. So let's get into it a little bit, starting with how we first learned about the virus. In October of nineteen fifty five, at the Walter Reed Army Institute of Research in Silver Spring, Maryland, a group of twenty quote unquote normal chimpanzees around fifteen to twenty months old began showing signs of a respiratory disease.

Runny nose, sneezing, coughing, the usual, And at first it was just a handful of the chimpanzees, but within a few days nearly all of them had gotten sick. As listeners of this podcast are well aware, an outbreak of an apparently contagious disease in a population of lab animals sets off some pretty loud warning bells, and so the researchers at the institute were very eager to find what pathogen might be responsible. They took some throat swabs from the animals and ran a bunch of tests on it.

I'm not going to bore you with the details, but ultimately what they found was not a familiar old measles or polio or or cocksacky virus, but a new thing entirely, a virus they named the chimpanzee Caariza agent not RSTY the link.

They all produced antibodies against the pathogen. Researchers Morris, Blount, and Savage published the account of this first observed epizootic of the chimpanzee Caariza agent in nineteen fifty six, and in it they didn't really hint at answering or even acknowledging the question of, like, how scared we need to be about this new pathogen. It seems to be able to infect both chimpanzees and humans. It's a really contagious respiratory, you know, a scary thing. But they didn't really talk

about it. But in their very last sentence they did suggest that this agent may be a lot more widespread than just in chimpanzees. At the Walter Reed Institute quote. However, a number of human beings, particularly adolescents and young adults, have antibodies in their SIRA directed against the Kariza agent, suggesting that these individuals have experienced infection with the new

agent or one closely related to it. Very shortly after this paper was published, two more came out that showed that this virus may be a significant cause of respiratory infections, especially in certain age groups. And the authors of these studies basically what they did was they set out to test what pathogens they could potentially find or isolate from infants with severe lower respiratory illness. Okay, and they wanted

to see, Okay, what's this illness being caused by. Are there any new viruses or bacterial species that we need to worry about? And so on? And it just so happens that one of the viruses they isolated from these

sick infants was indistinguishable from the chimpanzee cariza agent. Interesting, and the more people looked, the more they found that this virus, which was assumed to be new, may not be new at all and may actually be responsible for an incredible number of lower respiratory tract infections, particularly among infants and young children. Although already adults were also seen to have antibodies against the virus and to get sick themselves.

Suggesting that reinfection was not just possible, but potentially common. And these authors also suggested in these papers that given the fact that chimpanzees are not the sole host nor were likely to be the reservoir species of this virus, and they are actually got it from humans, perhaps chimpanzee

caariza agent was not the most fitting name. With its ability to produce sensicial changes in tissue cultures, which we now know what that means, and its manifestation as a respiratory infection, maybe it should be called something along the lines of respiratory sensicial virus. Definitely not like our most I don't know, captivating story of how something got its name, but I like it. Not but I like it.

For instance, as early as nineteen fifty eight nineteen fifty nine or so, physicians noticed that the virus could cause illness with a huge range of severity, from in apparent infection to fatal bronchiolitis. They noticed that the age group with the highest infection rates and severest symptoms was infants, who also may have the highest rates of viral shedding.

They noticed that even though some infections may be mild or they all still seemed to involve the lower respiratory tract, and that infections, at least in North America followed this seasonal trend, which is the one that you described aaron infections rising in November December, peaking in January February, and

falling to low levels by April. Over the next decades, into the nineteen seventies and the nineteen eighties, RSV became a very familiar name during the winter months, one of the usual suspects when somebody brought their infant or child into the doctor's office for acute respiratory symptoms and also

a huge cause of hospitalizations for young children. For instance, studies from the nineteen eighties reported that during that decade and estimated one hundred thousand children were hospitalized for RSV each year in the US, costing three hundred million dollars annually. Who So, how did this virus become so prevalent in such a short amount of time. Maybe it didn't, Yeah, probably didn't. I think more likely it was there all along.

I've tried to look into the evolutionary origins of RSV and earlier suspected outbreaks in human history, but I didn't really have much luck. And to me, honestly that that makes sense, right, Like, in terms of its relationship with humans throughout history, RSV does cause a super distinct infection. Many other viruses can cause illness that looks a lot like RSV, And so it's kind of hard to look back retrospectively as we know and go was that RSV

was that influenza? Like? What could that have been?

tool to determine what was making you sick. It's unclear. I did wonder. I tried to look into this, but I didn't really see anything. I wondered whether there was a connection between the rise in daycare, if there was a rise in daycare during that time that also led to a rise in infections. But I didn't really find any papers that had investigated that. So it's just going to remain my little personal question.

rainy months for thousands of years. On the evolutionary side of things, like I said, there's not really much info that I could find about where specifically RSV came from and when it was estimated to have first infected humans. So I decided to broaden my search a bit to see if there had been any research on the evolutionary origins of the subfamily that RSV is part of, Numoviina,

or the family paramixa Virida. The subfamily Numovina contains viruses that are very similar to human RSV, including murnumovirus, canine pneumovirus, bovine RSV, ovine RSV, and caprine RSV, and the paramix of Virida has some very familiar names measles, mumps, distemper, Newcastle disease. I found a paper from twenty twelve that

I actually read for our mumps episode as well. I was like, this sounds familiar, and then I searched in my folders, and in that paper, the authors tested bat and rodent species for paramix viruses, and they found a bunch of novel viruses in bats that seemed to be relatives of RSV in humans. This doesn't mean that RSV came from bats, just that this bat RSV like virus and human RSV and bovine RSV all share a common ancestor.

It does to me present the possibility that human RSV and other human pneumaviruses or paramixaviruses originally spilled over from a mammal species, whether that was bat or cow or rat or something entirely different. Interestingly, just a little asterisk human RSV is more closely related to bovine RSV than

to these bat or mouse RSV like viruses. Ooh yeah, I wish I had more details for you, and also for myself, because I'm really curious to know more about the evolutionary origins of this virus, but sadly I don't have that information. If any of you out there listening has a paper or just has some info with some details, please send it our way. I'd love to read it.

RSV infections. Vaccination, like you mentioned aaron, was one route that was explored early on and continues to be explored. But like you said, we don't have a vaccine for RSV, and I know you're going to talk a lot more about why that is, and also where we stand with

some of the vaccines in development today. There's also ribevierin a synthetic nucleoside imglobulent therapy, other experimental therapies like RNA interference therapy and so on, which I'm sure you'll talk more about some of these potential horizons for RSV treatment. In terms of the history of RSV specifically, that's really all that I have to offer. It was first recognized relatively recently as an important respiratory infection in young children.

Its role in infecting older people and people who are immunocompromise has been observed. More recently, We've learned a lot about the year to year dynamics of the virus and its circulating strains. But don't worry. I'm not just going to stop here and leave you with this like super duper record short history section, especially for the season premiere,

like I can't do that. Instead, I'm going to do a mini deep dive on a topic related to not just RSV, but many other respiratory viruses and respiratory diseases. It's a life saving therapy that you hope to never need, but are grateful for when it's there a device whose history goes back further than I ever imagined, and one that frequently dominated headlines, especially during the first couple months of the COVID pandemic. I'm talking about the mechanical ventilator.

are severe, sometimes that includes a mechanical ventilator. So I started thinking about where this amazing technology came from and how our understanding of the risks of lung injury and how breathing works has led to improvements in artificial ventilation.

Our story starts in the mid sixteenth century with the anatomist Andreas Vesalius, whose name we may or may not have mentioned on the podcast before I can't remember, but whose anatomical illustrations I'm pretty certain we've posted on our social media.

In his fifteen forty three anatomy treatise De Humanicorporus, Visilius described what we would today recognize as positive pressure ventilation. Quote, but that life may be restored to the animal, and opening must be attempted in the trunk of the trachea, into which a tube of reed or cane should be put. You will then blow into this so that the lung may rise again and take air. How interesting isn't that? Like? Fascinated that? Yeah? Of course this wasn't Visalias just hypothesizing

about how you could perform artificial respiration. He actually experimented on animals to show this. Yeah.

bit of you know, see something on that yeah. In one of his many scientific ventures, Hook set his sights on testing Galen's hypothesis that the act of breathing was

necessary for circulation. He took a dog, made a bunch of cuts in this poor dog's chest wall and pleura, and then used bellows like the things you used to blow air into a fireplace, to create a constant flow of air into the lungs, and observed what happened when he stopped wow quote this as in pumping air into the airway using bellows being continued for a pretty while, the dog lay still as before, his eyes beating very regularly.

But upon ceasing this blast then suffering the lungs to fall and lie still, the dog would immediately fall into dying convulsive fits, but be as soon revived again by renewing the fullness of his lungs with a constant blast of fresh air. End quote. With this gruesome experiment, Hook showed that it was indeed airflow into the lungs that

was necessary for circulation and thus life. Another one hundred plus years would pass before scientists learned what oxygen was and recognized its importance and respiration, which is a whole separate and cool story that I would love to tell someday. But an unfortunate consequence of this discovery of oxygen was that mouth to mouth resuscitation, which had been developed by that time, it fell out of use because people believed that the air you would be exhaling into someone else's

lungs during mouth to mouth would not contain oxygen. Yeah, it would be depleted. How interesting? Yeah, huh. The next big advancement in artificial ventilation happened about one hundred years after then, when scientists began playing around with negative pressure ventilation. I'm going to pause here to explain briefly how negative pressure and positive pressure ventilation works, and the difference between them.

When you breathe, your diaphragm contracts, which expands your chest cavity and allows you to fill your lungs with air, specifically your alveoli, which is where oxygen is exchanged for carbon dioxide in your blood. When you exhale, your diaphragm relaxes and you exhale that carbon dioxide along with a

mixture of other gases, including oxygen. This normal lung function can be disrupted by a number of things, including respiratory infections such as RSV as you described aarin, and in severe cases, someone may need the assistance of a ventilator to make their lungs work and take in the oxygen they need. So how do these ventilators work. There are two general strategies, at least like how they're grouped historically.

For artificial ventilation. There's negative pressure ventilation, which was the first to be developed and widely applied starting in the early nineteen hundreds, but isn't really in use anymore. And there's positive pressure ventilation, which is what the ventilators we see today use. Negative pressure ventilation works like this. Basically, you seal someone's body from the neck down or at the very least leaving just their mouth and nose open,

into an enclosed air tight room or box. Then you suck out all the air from that space, creating negative pressure. This causes the chest cavity to expand with air, allows your lungs to draw in that air, and then you would pump air back into the room or box, so bringing the pressure back up, and that would lead to exhalation. This is how an iron lung works.

the whole breathing process from inhalation to exhalation. And this is what we see in hospitals today, these big specialized machines that were the topic of much concern and discussion during COVID peaks, when hospitals began to run out of them, for instance, and many places didn't have them for instance.

plunger annually. Yeah. Jones advertised his ventilator as the cure for an impressive number of conditions such as paralysis, neuralgia, asthma, bronchitis, dyspepsia, and deafness. Deafness, Yeah, I don't, I don't understand, but it was the eighteen sixties, like anything goo. An early version of what would later be known as an iron lung was developed in the eighteen seventies with the intention of placing these along the scent to resuscitate people who

had drowned. Oh yeah, kind of an interesting little thought there. But the real iron lung, the one that was so integral during the first half of the twentieth century during polio outbreaks, it's the iron lung that you're picturing right now in your head. That was developed by Philip Drinker and Lewis Shaw at the Harvard School of Public Health in the late nineteen twenties. Drinker got the idea after treating people with paralytic forms of respiratory failure, especially from polio.

So he thought, if only I could develop some sort of machine that would maintain ventilation support, you know, just for a little bit of time without having to tend to it, you know, have it be automatically administered, just until their lungs heal enough so that they can breathe on their own, just until they get better. And he first tested his iron lung on cats and then found success, and then he tested it on himself and then other volunteers.

But the first patient to use Drinker's iron lung was an eight year old girl who was having trouble breathing due to a polio infection. Her breathing was getting weaker and weaker, her lips were turning blue, and just at the point when her doctor thought she wouldn't be able to recover, they decided to try the iron lung. Almost immediately after being placed in the device, she recovered consciousness and asked for ice cream, which I love. I thought that was so sweet.

but they did leave a lot to be desired. If you picture one of these things, your body has to be sealed off from it, and that makes it impossible for healthcare workers to tend to any other part of your body that's inside this iron lung, for instance, not to mention the discomfort that you would feel not being able to move or like just be trapped in this

you know machine. And so to deal with this lack of access to the body, they thought, let's just build a whole negative pressure room where you can hold multiple patients in like bunk beds, and you have their heads just like sticking out of the wall, and then like a nurse or a doctor could go into that room and then tend to the patient's bodies. Interesting. Yeah, that obviously not the most logistically sound solution. Difficult, Yeah, the

need for an alternative solution. Two iron lungs became very apparent during the polio epidemic of the nineteen fifties, where cases were so high that hospitals ran out of iron lungs. And you can look up these photos of hospital wards with rows upon rows of the machines. When there was an iron lung shortage, some hospitals resorted to performing tracheostomies and then manually ventilating patients, which was previously only something

done in an emergency or while operating. I want to read you a description of the situation from a hospital in Copenhagen in nineteen fifty quote. During several weeks, we had forty to seventy patients in our hospital requiring continuous or intermittent bag ventilation. To do this, we have employed about two hundred medical students daily. Oh my gosh, yeah daily.

I read one paper that put the total number of students providing manual ventilation at fifteen hundred and the total number of hours at one hundred and sixty five thousand.

catch on and one doesn't marketing. Yeah, but even the person who developed the iron lung also was working on a positive pressure ventilation device. Interesting, so it's yeah, yeah, this, this polio epidemic during the nineteen fifties really showed that like, hey, we should maybe not do that anymore and turn towards positive pressure ventilation.

replace respiratory muscles or respiratory function. But over the next decades, especially with declining rates of polio, thanks to the vaccine. They began to be used to correct the levels of oxygen that someone was getting, which was possible due to a greater under standing of the different gases in our blood and how to measure them and monitor continuously and then make tiny adjustments here and there, and so all of this was done in sort of like you know,

gradual fashion. We've come a very long way since those early ventilators, not just the iron lung but the first positive pressure ventilators that came on the scene, and we've come a long way both in terms of technological improvements in these ventilators as well as strategies of use like full support to partial support, because there are, like I mentioned, there are risks and negative health consequences to using these ventilators, and so that's been really crucial over the past few years.

But we're still we're still learning very very much. As the COVID pandemic has made painfully clear. The ventilators that we currently use are expensive, they require highly trained individuals, They are not as bulky as iron lungs, but are still bulky and not very mobile, and we really need cheaper, more transportable, and easier to use ventilators to increase access to these life saving devices, and this seems to be

a pretty exciting and active area of research. I didn't do very much digging into like where we stand today, because that's more of your thing. But I did come across one paper that described a soft implantable robotic ventilator which helps diaphragm function, so that could be kind of cool. Hopefully we'll see some improvements or cool new approaches to

ventilation in the future. But the future is outside of my jurisdiction for this podcast, as is the present, really, so I'll hand it over to you, Aaron, to tell me where we stand with this virus today and just how unusual twenty twenty two to twenty twenty three was in terms of case numbers.

use these estimates as like general numbers. But the estimated total annual global burden of RSV in children under age five, because this is the group that we look at the most significantly, is almost thirty four million episodes of a Q lower respiratory illness. So that's not even close to everyone who's affected, but these are the kids who are getting quite sick lower respiratory tract infections.

doctor with RSV. Wow, anywhere from about fifty eight or sixty to eighty thousand hospitalizations every year, and an additional sixty to one hundred and twenty thousand hospitalizations for adults over age sixty five Yhi is so much higher than I realized.

changed a lot of things. We talked about that in our influenza episode at the end of last season, and I'm sure we'll talk about it in future respiratory episodes as well. And the truth of it is, I don't think we fully understand how much it's going to change

and how lasting this change is going to be. But for the year and a half, two years where we were really quite locked down, so like twenty twenty twenty twenty one, we saw significantly less RSV, especially in young kids, than we had seen previously, like a lot less, a lot less hospitalizations, and just a lot less doctor's visits in general for RSV and other respiratory Infections twenty twenty two.

What we saw was really early RSV starting at the end of summer and reaching peaks even into October and November, like what are normally peak numbers. We're recording this right now, full disclosure in December of twenty twenty two, and this will be released at the end of January. I don't

know what's going to happen. I don't have a crystal ball, but I won't be surprised if this infection has either another peak or has a very very long tail right where we see a lot more infections just persisting for longer, more hospitalizations for longer because there's a large cohort of kids who might be being exposed to RSV for the first time later in their life because this is the first time they've been around other kids.

far as you know, phase three clinical trials. But so far it's just been very difficult to develop a vaccine that has a good balance of immunogenicity, so actually stimulating enough of an immune response to be protective, especially in the kids who are the most vulnerable, right the youngest of kids age zero to six months or up to a year, who are going to be infected for the first time, who we know are at highest risk of severe infection, stimulating enough of an immune response to provide

protection while also being safe and not causing any adverse effects. There was a vaccine candidate back in the nineteen sixties that was an inactivated version of an RSV virus that was inactivated with formuline that ended up causing significantly worse

disease in that vulnerable population in young infants. It caused what was called an enhanced respiratory disease after a first vaccination in kids who had never been exposed to RSV before, and that is terrible and horrific, and because of that, it really set things back a ways because it's going to of course, make people a lot more cautious when it comes to future vaccines and clinical trials, especially for

that population who is so vulnerable to begin with. And longtime listeners of this podcast will know and remember from many of our episodes just how rigorous safety standards are when it comes to vaccines and their testing and implementation, which over the years, especially since the nineteen sixties, has only become more rigorous, right, which is a good thing, but it also means that it takes a lot longer to develop these vaccines. That's kind of the long and

short answer of why we still don't have one. There are dozens of vaccine candidates, and what I think is really interesting is that not only are there candidates of various vaccine platforms that are understudy, like everything from live attenuated vaccines to whole inactivated or killed vaccines, to component vaccines or protein vaccines to bah bah bah blah mRNA and RNA like yeah, nucleic acid based vaccines like the covid ones. So there's people doing research on like every

different vaccine type that you can imagine. But there's also different populations that people are trying to target for protection, which is really interesting in the context of RSV. So first, we know that older adults are also at really high risk, So there's people working on vaccines that are going to target older adults to just boost their immunity or something

like that. There's also an effort to target just older kids in general, because older kids, especially after six to twelve months, that's when we tend to start to use, usually at twelve months live attenuated vaccines. But then there's these really vulnerable tiny infants, and we don't have vaccines for them right now, and we had really bad experience with the vaccines we tried to develop in nineteen sixty So another potential way to protect those youngest babies who

are most vulnerable is maternal vaccination. So vaccination during pregnancy the way that we do for protessis YEP, and so there's also groups that are working on developing maternal vaccines that produce enough immunity that can be passed through the placenta and potentially through breast milk as well to provide

protection to these youngest of infants. So cool. Plus, as I mentioned, there is already a monoclonal antibody that is in use, and there is work on additional monoclonal antibodies or other ways to give monoclonal antibodies that might be more cost effective, et cetera. And even though, like you mentioned Aaron, we get reinfected with this virus all the time, right, which makes you think, like, how can you develop a vaccine for something that we just get reinfected with all the time? Flu?

And so because of that, there is this theoretical we should be able to develop a vaccine that's at least protective against severe disease and hospitalization.

with vaccine candidates and vaccine research. And we'll post all of our sources from this episode and every one of our five other seasons worth of episode on our website this podcast will Kill You dot Com under the episodes tab.