On a Saturday in the late summer of twenty eighteen, I went to visit two of my best friends to have dinner and play with their little ones, who were about two and four years old at the time. My friend is a teacher and had recently gone back to school in preparation for the coming fall semester, so her kids had just started going back to daycare after a
summer home with mom. My friends told me that there had been an outbreak of handfoot, and mouth disease at their daycare, and both of the little ones had gotten sick. They said it was super contagious for kids, but not to worry, as it doesn't really affect adults. I saw a couple of little red bumps near their ankles, but thought nothing of playing with the tots or kissing them
good night as usual. The following Wednesday, around two am, I sat straight up in bed, shaking with violent chills and experiencing what might have been the worst sore throat of my life. I checked my temp and had a fever around a one hundred and two, so I loaded myself with niq will and stayed home sick from work for the.
Next two days.
By that Friday, I was starting to feel a little better and I returned to work, but that day the blister started. They were mostly painless, just empty bubbles of skin on my hands and feet that would rise to the surface and then tear off in chunks. At that point, I was pretty sure that I had a case of handfoot in mouth. Remembering that the disease was very contagious for kids, I did my best to be conscientious and avoid my coworkers with children at home at the team
meeting that morning. As the days went by, my sore throat eased and I was feeling like my normal self, but the bubbly blisters on the palms of my hands and soles of my feet kept coming. A little after a month after initially feeling sick, I shared a kombucha with my mom, really thinking nothing of it as I had felt fine for weeks at that point. Three days later, however, she was hit with a terrible sore throat, in fever, and then blisters. I had given her hand foot and
mouth five whole weeks after I first got sick. I was shocked, so I did a quick google and discovered that once infected, a person can be contagious for up to eleven weeks. That's almost three months a fiscal quarter. I was floored, and after that I got serious about making sure I didn't get anyone else sick. I remember putting a reminder in my phone for a date in late October that would have been around eleven weeks after my initial infection, and in the me time, I was
not going to be swapping spit with anyone. I went to the lake with my girlfriends around then, and I vividly remembered that I had taken a piece of duct tape and covered the label of a jar of salsa and scrawled the word infected on it in sharpie so that I could double dip safely. One of my girlfriends remarked that she felt like if she didn't catch hand, foot and mouth for me, that we must not be that good of friends. But thankfully I didn't get anyone
else sick. The blisters did stop around that eleven week mark, and the course of disease was pretty similar for my mom. I think most people, especially parents, are at least vaguely aware of the disease, but I hope that more people come to realize that adults can get sick too, And I also hope that more people become aware of just how long an infected person remains contagious.
Oh my gosh, I yeah, that sounds awful, you know, Like I know about hand foot in mouth because I have a lot of friends who have had it or their kids have had it.
But I guess I just like didn't really it never really registered how long it can last and how long you're infectious. Yeah, so how awful it is to just have your skin sloughing off?
Like it doesn't sound fun. Let's say that.
That is the understatement of the century for sure.
Thank you so much, Libby for being willing to share that story with us.
Yes, yeah, oh sorry you had to relive it on the podcast, but we all appreciate it.
Hi.
I'm Aaron Welsh.
And I'm Erin Almond Updyke and.
This is this podcast Will Kill You.
And today we're talking about handfoot and mouth.
Yeah, and we've gotten so many requests for this one.
I mean, it is so common.
It is, and I don't think I even realized how common it was.
Do you know if you had it as a kid.
You know, I was thinking about asking my mom because I have no recollection of it.
Yeah, yeah, the same no idea, mom, Mom, can you text me time?
He knows.
Yeah, but it seems like it's everywhere. Maybe it's just like because that's the age we're at, where you just hear about you.
Know, everyone's toddler's bringing it home from daycare exactly.
Yeah, but there's a lot to unpack about this episode.
I'm excited to dive.
In me too.
But first, it's quarantine any time it is, So what are we drinking this week?
We're drinking out of the mouths of babes? Get it? I do get it? Yeah, you get it if you don't listeners, it's because it can be transmitted by respiratory droplets and it's mostly little kids. Okay, what is in the mouths of babes?
I didn't expect this one to crack me up as much as it did, Like we were talking about it all day.
Why is it so funny now?
You know?
Because it's the moment it is. It's a pretty delicious drink. It is gin and cherry juice and some lime juice and some tonic.
Water, so refreshing. We'll post it's the full recipe for that quarantine as well. As our non alcoholic plusy Brita on our website, This podcast will Kill You dot com and our social media Do you follow us there? You should follow us there?
You should follow us there?
On our website This podcast will Kill You dot com? Must I go through the spiel? There's lots of good stuff. There's transcripts, and there's bookshop dot org and our goodreads list and merch and music by Bloodmobile and resources or the citations for all of our episodes.
What do I normally say? References? You know, there's lots of stuff there. Check it out. It's a great time.
It is. It is Wow with that. Shall we get into the biology of this disease?
Let's do it, short and sweet intro.
I'm loving it.
Let's dive in right after this break.
Handfoot and mouth disease not to be confused with hoof and mouth or foot and mouth, which is something different that affects animals.
It is.
The naming is confusing.
Yeah, I don't know. I didn't do it, but anyways, handfoot and mouth disease is an extremely common viral infection of humans. It's caused by any one of a number of different viruses in the group enterovirus, which I think the only other enterovirus that we've covered so far is poliovirus. If I'm remembering correctly.
I think that's right.
Yeah, So, as usual, viruses are going to get a little confusing in this episode, but we'll do our best.
So.
Enteroviruses are a group of single stranded, non enveloped RNA viruses that are all in the family Picornaviridae. And this includes a lot of different zero types and subtypes of enteroviruses. And by a lot, I mean over ninety or over one hundred and a lot of these are viruses that people have probably heard of because they cause disease in humans.
These include COCKSACKI viruses, polioviruses, enteroviruses, echoviruses, and enteroviruses actually also include rhinoviruses like the cause of common colds.
I learned about that, but also what's an echovirus? Because I kept seeing that and I was like, this must be of public health importance in some regard, But I just don't know what.
Echoviruses cause other viral illnesses.
That's that's that's cause illnesses.
Yeah, there's like a whole bunch of different types of illnesses that all of these enteroviruses can cause, including echoviruses and ones called par echo or pair echoviruses as well. There's a whole bunch there's it's too much, and the organization and like subtyping system has changed in recent years.
So now all of the human enteroviruses in the genus enterovirus are four major species A through D. Within each of these A through D, there are a bunch of different zero types that used to be always called say, Koksaki virus A one, two, three, four, five blah blah blah blah blah, and Cooksaki virus B blah blah blah. They used to have a bunch of different names, and now they've all been grouped within these A through D species.
Yeah, that was interesting because when I was looking at old papers and then new papers, and I was just trying to reconcile, like what are they talking about?
How are these things related? You know, it's hard.
Well, the good news is that we don't have to talk about every single enterovirus in the world's wonderful, wonderful handfoot and mouth is most commonly caused by a few of these human enteroviruses, specifically ones in enterovirus group A. These ones have names Koksaki virus A sixteen and human enterovirus seventy one, although there are a few others as well, including Koksaki virus A six which we'll talk about, and
A ten, A eight, and a few others. All of these that cause handfoot in mouth tend to be in this enterovirus group A species.
But there are B group species that cause or cocksacke Group B that cause handfoot in mouth occasionally soft some papers.
Probably yes, not to an extent that I'm going to talk about them in any great detail. But as we'll see, what handfoot in mouth disease really is is kind of a presentation of a generalized viral illness. And so that's why you can have a variety of different virus subtypes, call them subspecies, call them serotypes, what have you, that are all slightly different. Some of them are more virulent than others, so they might have a tendency to cause
more severe disease. Some of them might be less virulent than others so cause a less severe disease. But overall, there is a group of these viruses that cause very similar signs and symptoms, and that group of signs and symptoms is what we call handfoot and mouth disease.
Does that make sense?
Yeah, it's interesting because you know, I think that a lot of the time we think about one disease, one pathogen, but we've also covered many that don't follow that rule.
Right.
For some reason, I feel like this handfoot and mouth in particular, because there's such variation in those signs and symptoms associated with different viruses that I.
Was like, why are we calling this all the same thing?
I think that that's a really valid point, honestly, Like how we define these different viruses to begin with, and then how we define the clinical syndrome that we call a disease. It's really interesting to think about, like how which came first and yesh, maybe you'll tell us sered and also how we make those distinctions. I think it's
really valid. Today, I'm going to focus on Coxsacki virus A sixteen, enterovirus seventy one, and a little bit about Koksaki virus A six because those are the three that I found the most information about as well. Say, but first, let's keep it a little bit more general, shall we Love that enteroviruses as a group are transmitted in a
number of different ways. Think back to our poliovirus episode. Poliovirus, by the way, is enterovirus group C, so not very closely related to all these a group enteroviruses, but kind of closely related. So enteroviruses are transmitted by direct contact with things containing the virus, like secretions. The blisters that we'll get to talking about with handfoot and mouth disease are full of virus, so direct contact with these blisters
or that fluid can transmit the disease. Respiratory droplets are a huge source of transmission for a lot of different enteroviruses, including those that cause handfoot in mouth and importantly fecal oral as with polioviivirus, And this is especially an important way of transmission for kids and between family groups. And because interoviruses are really hardy little viruses environmentally stable, they can also be transmitted via fomites so infected surfaces as well.
I mean, they're hardy little beasts.
You have to admire them.
You can also be horrified, Yeah, of course by them too.
How long are we talking?
I knew you were going to ask that I have like star starsar how long, I don't know as usual, but I can tell you these are very environmentally stable viruses. They can be recovered from water sources, including ocean water. HI did my masters on some of that. They're resistant to freezing, they're resistant to most alcohol based hand sanitizers that we use. They're resistant to a lot of cleansers. Yep.
So they are the point one percent.
Exactly because they're because they're non enveloped viruses. They have evolved to withstand the acidity of our stomach and be transmitted fecal oral so they are very hardy. Yeah, it's great. The incubation period, so the time between when you get exposed to when symptoms develop for most enterra viruses, including the ones that cause handfoot and mouth disease, is generally
between three and five days. And as we'll see, and as you heard in our first hand account, the whole course of handfoot and mouth disease usually lasts between a week and ten days. But you can continue shedding virus, especially in your stool, but also even in your throat secretions, so in your saliva, for weeks at a time. It's gnarly,
and these are incredibly contigued viruses. So if we look at studies that have tried to estimate they are not which listeners likely remember, is the reproductive number, the average number of new cases that become infected by a single index case like how many people get sick from one sick person. The estimates range between two and five, which varies by virus subtype, but anything over one means you have like exponential growth and outbreak potential.
And these studies did they look like within different populations, because I would imagine daycares would be on the higher end of that exactly.
So these very based on population, they vary based on virus subtypes. So for enterovirus seventy one, it's estimated usually closer to five, and then for Coxsacki virus A sixteen, it's like an average of two and a half or so. So yes, and then also if you look specifically in like household transmission, in some studies, household transmission is like fifty two percent of households are going to get infected, and other studies as high as eighty five percent, especially
for kids under six. So it's incredibly infectious, really easy to spread around. But what actually are the symptoms like what is handfoot and mouth disease. For the most part, handfoot and mouth disease is considered a relatively benign, self limited disease, as we heard in our first hand account. That doesn't mean it's not miserable to have, but it
does tend to be self limited and not very severe. However, I am going to get into some of what the potential complications are because it's always important to talk about these complications because they're real and they do exist even when they're incredibly rare, and because it's also fascinating from a virology perspective, how something can cause such a mild
illness and such a severe illness with the same virus. Yeah, So I don't want to fear monger too much in this episode because the whole group of enteroviruses we're talking about over ninety different viruses. A lot of them have the potential to cause severe disease, but the vast majority of cases of what we call handfoot in mouth are relatively low virulence. Pathogens or for whatever reason, are causing self limited disease in the vast majority of people that
they infect. In fact, many people who become infected are asymptomatic entirely and are just happily shedding virus to everyone else without getting sick at all.
What do we know what proportion of those are asymptomatic.
It's a great question. It does depend a lot on the virus and also what age group we're talking about. Much more common in adults to be asymptomatic compared to kids. Estimates range between ten and seventy percent of people become symptomatic,
which is like a huge range. But for example, with poliovirus, about seventy five percent of people are asymptomatic and only twenty five percent of people show symptoms of polio, so it's likely on the low end of people who show any symptoms whatsoever after exposure.
Okay, I have a couple of like, immunity questions and infectiousness questions.
Should I hold those?
Meant, you can ask them now if you like, before we get into the symptoms.
Okay, about the infectiousness, you said that you can shed virus for weeks and weeks after first showing symptoms. Are you infectious only once you start showing symptoms?
Great question. I believe, like with many enteroviruses, you can potentially shed virus before you realize that you're symptomatics, say, before your fever starts.
Spoilers, ah, And then this, I think this actually is really sort of jumping ahead.
But in terms of.
Reinfection or immunity, is there any sort of cross serotype or cross species immunity? And I guess maybe not enough because there's no vaccine.
Spoilers, I don't.
Know, a few spoilers, jumping ahead just a little. But in general, because we are talking about a whole bunch of different viruses, you can certainly get infected and have handfoot and mouth disease multiple times in your life, yay wohoo. But it's very likely that there is some degree of cross protection among different say COCKSACKI virus strains and enterovirus numbered enterovirus strains. Because a, adults are much less likely to have symptomatic handfoot and mouth disease, and it's not
that that's very likely due to previous exposure. The most susceptible people for handfoot and mouth disease, both severe disease and just symptomatic disease in general are little kids, especially under age five, especially under age two. Really, So yeah, so there's likely some degree, but certainly not enough that we have like the potential for one vaccine for all of it.
Right well, and also like the fact that these are RNA viruses that.
Right, they're just take yeah, mutation happy.
And yeah, it's fun, good stuff. Okay, So let's talk about what this looks like, shall we?
Yeah, very finally there.
So, most cases of handfoot and mouth happen in little kids, that's the stereotype for a reason, mostly kids underage five and and so this illness starts as many childhood illnesses do, and that is with a fever. Likely this goes hand in hand with some general malaise. The kid is probably feeling pretty crappy, and they probably have a sore throat. They're probably eating or drinking a lot less than usual
because of that sore throat. And because we're talking about little kids, a lot of these kids are pre verbal, they might not be able to tell you that something is wrong, So that eating and drinking a little bit less and maybe being crankier than usual might be the first signs that something is wrong. Since they can't tell you my throat hurts, then it'll start with the rash. And this rash happens in three major places, the hands,
the feet, and the butt. I'm gonna say that, actually, yeah, a lot of people call this hand, foot, mouth, and butt disease.
Can we like shorten the disease name somehow?
Please?
We'll make you to keep adding body parts to it. And fingernail disease part of the end.
But those are the main places where we tend to see this rash. It can be across the whole arms and legs, It can go onto the genitals as well. One thing that's interesting and kind of specific about handfoot, in mouth is that on the hands and feet, this rash is often found on the palms and souls. Specifically, this is a place that not a lot of other viruses or pathogens cause a rash. And I know you're going to ask, because you've asked in previous episodes, And no, I still don't know why.
What are the other ones? I was hoping you weren't going to quiz me because I don't know?
Syphilis? Can? I think that's probably one of the main ones that we've covered on this podcast, ricketsia or Rocky Mountain spotted fever, and yeah, rat bite fever. Can. We haven't done that there's a number of other pathogens, but it's kind of a relatively short list. Okay, so it makes people who are trying to figure out what's going on clue in that, oh, this might be handfoot and
mouth disease. The rash itself usually starts as little red spots, flat, little red spots that progress into blisters that are filled with fluid. And again this fluid is full of virus. The ones on the hands and feet and but usually don't itch, They usually don't hurt that bad. But the ones that are in the mouth can be quite sore and like I said, can make it so that you don't want to eat or drink a lot, or little kids might have a lot of drooling just because of how uncomfortable they are.
Why is it that the ones in the mouth, and like, why does your throat hurt?
So because you're not just having like soores in that area, you're also having a lot of generalized inflammation because that infection is there in your throat essentially.
Yeah, yeah, okay, yeah.
So adults and older kids certainly can get hand foot in mouth like you heard in our first hand account, but it's more common in little kids, likely because of both exposure. The list of things that small children will not lick is much shorter than the list of things that they will put in their mouth, and like I mentioned, because of cross protection that you get from prior exposure. As we grow up, so by the time you're grown up, you've been exposed. Now most of the time. That is
how this infection goes. It'll run its course. Kids and adults need symptomatic treatment, popsicles, rest, hydration, that sort of thing, and then people tend to recover over a pretty long course of seven to ten days. But that's not where we're going to end. That uncomplicated form of handfoot in mouth can be caused by any of the pathogens that I mentioned that cause handfoot and mouth disease. Coxsacky virus A sixteen is probably one of the most common causes
of uncomplicated handfoot in mouth. Enterovirus seventy one is the other most common cause of handfoot in mouth, but enterovirus seventy one can also cause a much more severe infection. All of these can, but enterovirus is more likely to cause a more severe infection, and one of the main ways that does this is by invading the central nervous system. Many viruses, including our friend polio, which again is related to these viruses, can invade our central nervous system and
cause a number of different severe neurologic manifestations. In the case of entiovirus seventy one, it's often a viral mentaingitis or encephalitis, So infection and inflammation of the brain or meninges the lining of the central nervous system, So this instead of just looking like a fever and sore throat and feeling sick, would look like a fever, stiff neck, headache, potentially loss of consciousness or behavioral change. These are very
typical viral meningitis symptoms and they're very serious. In the case of entervirus seventy one, if it invades the nervous system, it tends to cause a brain stem encephalitis specifically, so our brain stem is the bottom part of our brain that controls a lot of our basic functions like breathing and our heart being able to function properly. So when you have inflammation of this part of our brain, what we can see is then issues in the way that
our heart and lungs are able to actually function. So this can lead to a lot of a debas or swelling and fluid in the lungs because they're not working the way that they're supposed to neurologically, and that actually can lead to death in severe neurologic terovirus seventy one infections, this virus can also affect the spinal cord and cause an acute flacid paralysis, which really looks a lot like poliomyelitis.
So this is an infection and inflammation of the sheath around our nerves that then cause our nerves to our muscles to not be able to function and a flacid paralysis. I want to stress that these are not common manifestations of enterovirus seventy one of hand foot and mouth disease, but they are really important because these are potentially deadly infections and in some cases can result in lifelong complications
from a severe neurologic infection. To put some numbers into pive though, in some of the larger enterovirus outbreaks that we've seen, for example, in Malaysia in the late nineties, there was over two thy six hundred cases of handfoot in mouth disease that were reported and thirty four deaths, so a very small number comparatively, but still a number.
In Taiwan in the late nineties and estimated one point five million people were infected with handfoot in mouth disease, four hundred and five admitted to the hospital with some type of neurologic complications, and seventy eight children died in that big outbreak.
Geez.
Yeah. And then in two thousand and eight in Madeland China, just under five hundred thousand cases and one hundred and twenty six deaths in children were reported due to handfoot in mouth disease, and the vast majority of those cases were likely or confirmed to be enterovirus seventy one, which is really common in Asia but is present around the world.
How like, for a typical outbreak, or like a suspected outbreak of handfoot in mouth, how often is virus testing done to know which strain it is.
It's a really good question. It's going to vary so much by place that I don't have a great answer to that. Yeah. Here in the US, the vast majority of people who get handfoot and mouth disease probably never even go to a doctor, so we might not even know that they had it. If they do go to a doctor, it's probably not the emergency room, so they probably don't even have the capacity to do that viral testing.
Maybe they do, maybe they don't, but if they're not that sick, then they're likely to not get testing anyways.
So it's really very likely that it's only the severe cases, the ones who are very sick, who have these maybe neurologic signs or signs of just a more severe infection, that end up in emergency rooms that end up getting testing, and that testing would probably need like multiple rounds of testing to be able to determine exactly which strain of an enterovirus or which species of an enterovirus we're dealing with.
Right, Yeah, And so it's possible.
Is it possible, I'll rephrase that, to have multiple circulating viruses that are the cause or contributing to the outbreak at the same time?
For sure? Yeah? Yeah, yeah, because these all pretty much exist across the globe. There's of course geographic variation in what's most common, but all of these enteroviruses that can cause handfoot in mouth are pretty widespread and becoming more so because of globalization.
So how likely is it that if you repeatedly get hand foot in mouth or you get hand foot in mouth multiple times? How likely is it that those are, you know, Cocksacki virus A sixteen and then a six or just a mutated version of A sixteen.
I think that's an impossible question to answer for fun one though. I'm not even done though, because there's one more specific virus that I want to shout out. And when I'm shouting out these specific ones, do know that any and all of these viruses that cause the disease or the clinical syndrome that we call handfoot in mouth disease, Any of them can cause severe infection or can cause mild infection. It's just that some of them are have been shown so far to be more likely to cause
a severe infection than others. So enterovirus seventy one is more likely to cause neurologic manifestations if there are going to be neurologic manifestations. Cocksacki virus A sixteen more like to just cause uncomplicated, regular run of the mill handfoot in mouth. And then there is cocksacky A six This is yet another strain of Koksaki virus which really recently has been found to cause handfoot in mouth disease, like
two thousand and eight was the first big outbreak. Correct me historically if I'm wrong.
I thought, hold on, I'm looking at my notes, but I swear I have a paper from nineteen sixty.
I thought that's entrovirus seventy one.
A five.
Oh, I don't even talk about A five.
Yeah, I mean I mentioned it briefly, but that's it.
Must have come and gone. It had its time or not.
Who knows, I guess well.
In any case, this particular virus seems to be more likely to cause both severe disease in the form of severe skin manifestations and more likely to cause symptoms and severe disease in adults. So remember, most of the time, adults don't end up getting symptoms even if they become infected and are shedding these various viruses, but Koksaki virus
A six seems to be an exception. This virus has been making its way across the globe and is now present pretty much worldwide, and cases associated with this particular virus have caused extensive cutaneous or skin variants, some of
which were not previously seen in Koksaki virus infections. So these include things like very very large blisters like deep blistering eruptions, they include much more extensive involvement of the skin, so not just hands, feet, but but across the entire arms, especially in areas that you tend to get eggzema, so like in your elbow folds and things like that. This
is called egzima cocksackium. It has also been shown to cause these lesions that look like very very thick blisters, kind of crustier looking than a normal blister, not quite a fluid filled situation, but a really widespread, very itchy rash, which normally a handfoot in mouth disease rash is not itchy. It also can cause what's called a delayed on a comadsis if I'm saying that correctly, aka, your nails fall off.
It sounds like a much lovelier way of saying, and then your fingernails fall off.
Your fingernails fall and toenails.
Toenails potentially too. This happens from a rest of the nail matrix growth plate, so it stops your nails growing for a little while, and then a few weeks months after you get the infected, that nail just falls off. It'll go back and this one is really horrible. Image palm o planter desquamation, aka the skin of your hands and feet just fluff off, the same way that we might see in a fungal infection or in like a masderation if a foot has been in like a wet
boot for too many days. Sorry your face, Oh yeah, yeah, I mean just the word sluff alone is enough to just it's bad. Yeah, And this is not only in adults. Cocksacuars A six has been found to cause these more severe skin manifestations in both kids and adults. Why great question, me, I don't know. Presumably it's something about the difference in these virulence factors, but we don't know the specific ones, and the same is true true for enterovirus seventy one.
With all of these, it's also very likely that host factors are playing a role as well, whether that's differences in the way that we respond, for example, in our T cell response to these various viruses, that certain individuals might be more likely to have a severe case than other individuals, But again we don't know what those host factors are either, right, But in general, all of the variety of viruses that can cause handfoot in mouth disease.
While they vary here and there, some being more virulent, some less, so in general, these are all human specific viruses that have a pretty wide tropism. That is, they can infect a pretty wide range of cell types, and that is how they can end up causing disease across this wide spectrum our skin as well as our nervous system, giving us fevers, etc. No matter how we get exposed, whether it's fecal, oral, or respiratory. So yeah, yeah, any more questions.
I mean, treatment I assume is supportive if necessary, like you said, hydrate chill.
Yeah, we don't have any specific intivirals at this point, but especially in the case of severe infections or neurologic manifestations, hospitalization with just supportive care is kind of the only thing that's available. Right, But that is handfoot in mouth. You know.
It's funny because I thought I would be very feeling very strongly about needing there to be multiple names, but it seems pretty consistent. I mean there's like degrees, Yes, there's degrees. I think that that's a good way of looking at there's degrees and then there's implications, right, Yeah, but they all share this sort of clinical picture of fever,
feeling crappy, this rash that's pretty specific. Usually there's throat involvement, lesions in the mouth, and then there's complications therein there's this can invade further and cause what a lot of viruses can cause in terms of neurologic manifestations, or it can cause really bad skin rashes that might look a little bit different and make it harder to diagnose, but at the end of the day, are still hand foot
in mouth disease. I do think that, And again I am not a virus genetics expert by any means, but the fact that they're all named different viruses I think makes them seem like they are more distant from each other than in actuality. Right, So it's like more like along the lines of like a salmonella exactly, stererotype, the numbered serotype or whatever precisely.
So now you can think of these all as variants of human enterovirus group A, right, right, and then you think, oh, okay, that kind of makes sense. But we also don't fully understand why why this one and not that one?
Right, And there are more viruses that cause it, which just adds a little bit more flavor to the whole thing, and like, what's cocksacky group B doing in there?
You know, well, that's just enterovirus group B. So yeah, but.
How is it different?
Why is there A?
Why is there B?
So?
Yeah, but Aaron, where did these things come from? Why did they do this to us?
Or maybe not that fart philosophical question. I don't know, it could be.
Yeah, let's let's le's figure out how we got from there to hear?
Right after this break.
Handfoot and mouth disease, what have we gotten ourselves into? I mean, and I say this because you know, just like we talked about the biology of this disease is it's a teeny tiny bit more complicated than this one microbe, one disease model that we're used to hearing about, that
we're used to learning about. And because of this, the way this disease can manifest is sometimes like it depends, it depends, like you said, on the host, It depends on the type of virus, It depends on the age of the individual, like it depends on lots of different things, and as will likely learn about in the current events section, the nature of some hand foot in mouth disease outbreaks has been changing in kind of major ways with some epidemics,
like you talked about Aaron, involving never before seen case
numbers or these new symptoms fingernails or mortality rates. And it's interesting to see if in the future, you know, as we gain more resolution on the role that these different viruses play in disease manifestation, like maybe we will get some sort of like separating out of names, kind of in the way that the naming or classification of kokshaki viruses has been revised confusingly, but it's not all NonStop complications and well yes, but also no, we're going
to get a little mid episode break here because the history of hand foot and mouth disease is fortunately, like pretty darn straightforward, so much so in fact, that it's not even going to take up this whole history section.
Ooh yeah.
So this gives me a chance to explore something that I've been wanting to on this podcast for a very long time.
Oh my gosh, I'm so excited.
I have no idea, ida, and I'm going to keep you in suspense on what exactly that something is. And first we're going to talk about the history of handfoot and.
Mouth disease Okay.
In nineteen fifty seven, nineteen fifty eight and nineteen fifty nine, outbreaks of a highly infectious disease seemingly never before described were reported in New Zealand, Canada, and England, respect The disease seemed to affect primarily children and was very mild, with many parents not even feeling like they needed to call a doctor. So a lot of the cases in some of these outbreaks were only like the case numbers only went up after the fact, after the outbreak was over.
When they started to like survey the community, parents were like, oh yeah, but like you know, my kid was fine. Popsicles, popsicles delicious. Infections involved lesions in the mouth and on the hands and the feet, and sometimes rashes on other parts of the body. Sometimes there was a fever, but
in general recovery was rapid and complete. While only eight children were involved in the earliest New Zealand outbreak, or at least discussed in this paper, a total of sixty cases occurred in the Toronto one and eighty three in the Birmingham, England outbreak, again including all or predominantly children.
If we had to give.
Like metals out for each of these outbreaks and what they contributed it would go like this. Nineteen fifty seven, New Zealand the first recognized outbreak of handfoot in mouth, though only like in retrospect was it recognized as handfoot and mouth because they didn't test for the virus at the time. Nineteen fifty eight Toronto, first time that Cocksacki virus A sixteen was found in samples from people who were infected, showing that this was a viral infection caused
by an enterovirus. And nineteen fifty nine Birmingham the first time the name handfoot in mouth was used to describe this disease. So kind of like boom boom boom, here we go done. So the nineteen it's the mid twentieth century virology is like just cruising. We'll really getting on
at start. But yeah, pretty cool stuff. But even at the time that these early outbreaks were reported, none of the researchers involved thought that, like, this must be the first time that humans have been infected with this disease. They just figured that previous cases or outbreaks had probably been chalked up to foot and mouth disease or some
other viral infection. The timing of the discovery of handfoot in mouth disease seems likely to be a combination of this is a very mild illness that has flown under the radar. This looks like something that has already been described and so didn't really encourage a closer look.
And we only just now.
Have the molecular tools to be able to identify and classify viruses.
Yeah, ding, ding makes it makes sense.
Yeah, But as it always happens, once handfoot in mouth disease was a known entity, a reported entity, it began popping up all.
Over the world, like seriously global.
The same year of that Birmingham outbreak in nineteen fifty nine, there was an outbreak of cocksacky A sixteen described in California, and in the years that followed, Hawaii, Arizona, Japan, China, Vietnam, Malaysia, Australia, Thailand, Spain, Sweden, Bulgaria, Brazil, Kenya, basically everywhere, like within I don't know how many years exactly, but everywhere was reporting outbreaks of handfoot in mouth disease.
As the distribution of this disease spread and as the case numbers climbed, researchers quickly realized that this was not the mild, mannered, predictable virus that they had assumed at
the beginning. For one, the nineteen sixty discovery that a different virus, cocksacky virus A five there's my shout out, was responsible for a small outbreak changed it from the handfoot and mouth virus to the hand foot and mouth viruses, with more to be added to that over the following decades, and the mild nature of this disease was called into question with the report that two infants had died during
the nineteen fifty nine out in California. Over the decades since the discovery of handfoot in mouth disease, it continues to surprise US Epidemics involving hundreds of thousands or even you talked about one that was over a million people have occurred, Like those are huge numbers. Strange outbreaks quote unquote strange. I'll call them atypical. Strange is not a very scientific word.
I suppose.
That target teenagers or older adults rather than young children have also happened, like I read about one at a university I think Loyola maybe. Anyway, new virus serotypes have been linked to more virulent forms of the disease. Viral recombination has also thrown a wrench in the predictability of this disease. Researchers are investigating the potential effect of climate change on shifting or expanding handfoot in mouth disease season in certain redis.
Oh yeah, I mean.
Because like, like you talked about how the environment can play a big role in how long it can survive, not survive, but how long it can stay viable on surfaces.
I saw one paper that was investigating how long they can live and accumulate in clams. Oh boy, which was actually something that my lab was studying. Like it's terrifying.
Actually, yeah, yeah, it really. I think like as I was reading, it started to feel more and more like a tip of the Iceberg situation with foot and mouth disease.
Yeah.
And I know that you're going to talk about where we go from here, vaccines, changing epidemiology of outbreaks, research on prevention, whatever else there is to talk about in terms of the current and future world of handfoot and mouth disease. But I still need to talk about where this came from.
Yeah.
Of course, now that we've learned about the many players involved or possibly involved in handfoot and mouth disease. You could understand why that might be a little bit of a tricky question to answer. If you interpret that question as where does this group of viruses that cause handfoot
and mouth disease come from? We can say that enteroviruses are an ancient group, and there are ana viruses, so it's easy to underestimate the time scale of viral evolution, and they recombine with each other, so it's also difficult to trace evolutionary relationships. There's not very much specific research that I could find on terraviruses, so I don't know where, when,
how those sorts of steps, unfortunately. But you could also interpret that question where does this thing come from as where does the name handfoot and mouth disease or the
name cocksacky virus come from. We know the answer to the first the nineteen fifty nine outbreak, and the second is that Koksaki viruses were named after a small village on the Hudson River south of Albany, where two children lived from whom Koksacki viruses were first extracted or isolated in nineteen forty eight by Gilbert Dohldorf, a director in the New York State Department of Health. So there's a town called Koksaki.
Oh New York.
Yeah, how funny, right?
Or a village?
I don't know the difference. But for the rest of this history section, I am choosing a third interpretation of your question. Ooh okay, not where does this disease or where do the viruses that cause it come from? But where do viruses come from?
Stop it?
What do we think the very first viruses looked like acted like? Did they pre date cells? Or did they come from cells? How do we even begin to form hypotheses around the origins of viruses? Should I go back to grad school to get a degree in paleovirology because I kind of want to do it? What is paleovirology? We'll get there.
I love it.
I was very.
Excited to get to go down this rabbit hole, which I have.
Never gotten to go down.
Yeah.
I feel like we've talked about it. Yeah, now's our moment.
Now's the moment.
I was going to say that everyone listening to this podcast is no doubt familiar with viruses, but then I remembered the last few years, and so instead I will say that, no doubt everyone in the world is familiar with viruses. The vast majority of the viruses that we are familiar with are pathogenic, either to humans or to humans and other animals, or to animals, or to plants,
or to bacteria bacteria phases. And that makes sense given that identifying those you know more deadly, those super harmful viruses is top of the priority list. But the world of viruses is much much larger than just those pathogenic ones, and being harmful to humans or the animals that we have or wildlife is by no means a requirement. Probably
nobody needs this definition, but just in case. A virus is simply a teeny tiny or in other words, sub microscopic infectious agent made up of genetic information wrapped in a protein coat. Viruses are not considered living organisms because they rely on living cells to multiply, which they do by invading a cell and hijacking the cells machinery to make more viruses they turn into like viral production factory.
Viruses can be characterized by what type of genetic material they have, Like we've talked a lot about RNA viruses, and we've talked about DNA viruses and also how they replicate in infected cells. The number and diversity of viruses on this planet is beyond imagination. It's just too big
for us to even try to imagine. But Carl's immergize in his book Planet of Viruses, he writes that, quote, there are one hundred billion times more viruses in the oceans than the grains of sand on all the world's beaches. If you lined up all the viruses in the oceans end to end, they would stretch out forty two million light years.
It is, in fact, too much to comprehend.
You can't.
We need we need one of those grains of rice videos.
Yeah, you know, I do know.
What.
And that's just the ocean.
That's just the ocean. Yeah, that's not even all.
The biomass on.
Earth. Wow, Oh my goodness.
Since the discovery of the tobacco mosaic virus in the late eighteen nineties, which was the first to be described, I know I've mentioned that at least once or twice or three or four times on the podcast, scientists have classified and named a few thousand species, but there are likely billions, trillions, even more viruses out there waiting to be discovered. Like virus species, viruses are found on every corner of the earth, infecting every cell you can think of.
There are even giant viruses with genomes larger than scientists ever thought for a virus, and these viruses can be infected by a virus a viral phage. That's like one of my favorite fun facts. Blows my mind. Research is in its infancy for sure when it comes to these giant viruses and their viral phages. And really research is
in its infancy when it comes to viruses period. Although we may have observed and written about viral infections for thousands of years, we only made the connection between disease and infectious agent relatively recently. We are in a thrilling
and sometimes terrifying time for virology research. Thrilling for how often it seems like there is a discovery made that completely upends what we thought we knew about viruses or the borders around what it means to be a virus, and terrifying for the same reason right the insidious long term effects of a viral infection, the increasing number of links made between viral infections and autoimmune conditions and cancers or other conditions, The sheer unpredictability of viruses even when
we can predict certain things about them, they still continue to surprise us, surprise us in sometimes not so pleasant ways. Right, we are learning about the world of viruses at an unprecedented rate, and it has given us profound insight into slash spurred debate on what it means to be alive, the surprising ways that evolution can work, the blurred line
between help and harm, even what it means to be human. Because, as you can probably imagine, viruses like bacteria and other pathogens don't really turn into fall at least in the traditional sense. A select few can leave behind traces of infection in their host skeleton, like remnants of smallpox virus in the teeth of vikings, but even those are somewhat limited in how long they can last without degrading past
the point of recognition. But there is another way that ancient viruses can be detected and studied millions of years post infection, and that is through our genome.
I'm so excited.
We've talked about retroviruses on the podcast before, and the way that these viruses work is that when they infect our cells, they end up inserting their genetic material into our cells DNA, so that our cells end up replicating that genetic material and then producing a whole lot more of those viruses. But what's super cool about this is that if one of these viruses ends up infecting a germ cell like egg or sperm, that viral DNA can
be inherited and then inherited and then inherited. What this process I know right, is called indogenization, and it has happened over and over and over again in our species history, in many, many species history, all species history, some more than others. That's also very interesting. And it's estimated that up to eight percent of our human genome is comprised of sequences of viral origin.
So we are all virus, we are all virus.
We are eight percent virus. Isn't that amazing?
Like we're just hanging out living life. Well, we've got this huge amount of viral DNA in our.
Genomes and it's like just being there.
Well is it?
Is?
It? Is it?
These sequences are called human indogenous retroviruses. But side note, apparently it's not just retroviruses that can become indogenized. That's just my own little like.
Especially.
Yeah, while most of this eight percent is inactive, as in it's just like doesn't code for anything, It just chills there. Some parts do still have an impact from regulating when certain genes turn off or turn on, or even say coding for proteins that are crucial for placental development.
What uh huh.
Yep sincyitan soh uh huh.
We talked about that.
We talked about this. Yeah, like it has played a tremendous role in placental development and many other aspects.
And that gene, that sequence, that protein is from a virus.
M h.
What so yes, I not only that, but since cyiton one and since cyiton two may play a role in pre eclampsia and even some preliminary hypotheses on the development of other conditions unrelated to pregnancy. Other human hodogenous retroviruses may affect our immune system and have been linked to various autoimmune diseases and als, among other things.
You know, I feel very conflicted about this, Aaron. Is that because I feel like, on the one hand, this is the most incredible information, like it's so my brain can't hand it's incredible. And then on the other hand, I'm like that makes sense because I mean especially because like, yeah, there are viruses that that you know still today that make their way into our DNA. We've talked about some
like of the hepatitis viruses that do that. HIV can do that, and so of course it makes sense that that viruses have been doing this forever, and I mean, evolution is so random that of course if that happens and there's some benefit to it, then it's going to become a part of you. Like, but so it's so logical and so mind blowing at the same.
Time, I think that what really blows my mind too is that some of these are still having an effect, whereas like, for the most part, these viral genetic sequences have been like turned off because they were probably so that's sort of the turn off was selected for It was like, OK, we're going to do better if we don't do whatever those virus is instructing us to do. But the fact that there are many out there that do still play a role, and it's like, I think
it's also really probably challenging. Like this field of this is paleovirology involves studying ancient viruses as well as the impact that these endogenous retroviruses and other extinct viruses have had on the evolution of their hosts. And it sounds like an incredibly cool field of research, which is why I want to go back to grad school kind of and research it, but we'll just end up reading papers
about it instead. But it also seems really challenging, like how do we know what is a viral like an endogenous retrovirus versus not?
That's my question.
How do we know?
How do you what's the tag? Do they have a little sign that they waive?
So I think that there are, and also like this is now I am like way out of my depth because I'm like, Okay, this is not what I prepared for, but I did do it like a little bit of extra reading, and so there do seem to be there's a growing database where people have identified indigenous retroviruses, and then you can look for similarities across other species that
have these sort of genetic sequences. Okay, and I think that there might You're right that there might be like little tags or something that indicates like this looks like a viral sequence. Okay, But there's a program I think that you can also, like a bioinformatic program that you can run genomes through to be like where's my indogenous retrovirus.
Oh wow, Yeah, so I don't really know much about like at all about the mechanics, and so if that was completely wrong, which it very well could be, I'm very sorry.
Please correct me.
Send an email, yeah, just send us infots so we can read more about it.
Yeah.
So I promise you that this will definitely not be like I'm gonna stop talking about indigenous retroviruses here, but it will not be the last time on the podcast that we go into them, because I do want to take us further down the rabbit hole, like as deep as it can go with indogenous retroviruses, maybe in an episode on pre eclampsia, Like that seems like it would be really I mean, that's on.
Our short list of episodes to do for sure.
So and then we can get sort of up close and personal with like what does this gene do? There are other genes that seem to be involved as well, like how do we determine the functions that they have or don't have? I mean, just also like trying to tease a part regulatory functions.
Of I love things.
I love it, very cool, love it, okay, love it, kind of scared of it.
Seems overwhelming.
That's life, okay. But today, for the rest of this history section, I want to take you even further back. By comparing endogenous retroviruses across different animal species, like who has what? How different are those sequences? We can learn a lot about the evolutionary relationships among those animals, and we can also learn a lot about the evolutionary history of those viruses. How closely do they resemble viruses or viral genes that are around today. How long ago do
we think they were incorporated into the host genome? What purpose do we think this viral gene held for the virus, like it had to have done something, it had to have benefited it in some way.
What was it doing?
These endogenous retroviruses, often referred to as molecular fossils, can give us valuable insight into what viruses may have looked like or how they acted millions of years in the past, even hundreds of millions of years. But millions is not billions, and if we want to explore the possible origins of viruses, we're gonna need to go back billions. So let's get into some of the hypotheses on the origin of viruses. All of these hypotheses have to try to reconcile these
two kind of paradoxical statements about viruses. Number one, viruses infect organisms across the three domains of life, the archaea, the bacteria, and the eukaria, and some viruses, even though they infect super distantly related hosts, share some of the same proteins or some very similar proteins, and this suggests to scientists that viruses emerged really early on, like before these domains split from one another, possibly before cells existed.
Number two, This is the conflicting contradictory statement. Viruses infect organisms period like they have to infect cells in order to replicate, So viruses both needed cells to exist and had to exist before cells to display the diversity they have.
So how do we explain this?
Yeah, yeah, well, traditionally three different scenarios are proposed, and I'm going to try to go through each of these, but in not too much detail because I'm not a virologist by any means. And I'll also try to mention a few of the hybrid hypotheses that have been proposed more recently. And my goal with this is not to convince you of any one hypothesis or even give you what you need to draw your own conclusions. This is an area of active research where there doesn't seem to
be any strong consensus. So my goal here is just to introduce some of these ideas and kind of get you to think about how cool and incredible and weird viruses are, and to think about a time that you may not think about that often.
Deep time, baby. Okay.
The three hypotheses are virus first, escape, and reduction. Okay, let's start with the virus first hypothesis, which is more or less exactly what it sounds like. Under this hypothesis, viruses came before cells. They emerged from a soup of RNA molecules and had proteins to help them replicate once cells assembled. Later on, these sort of proto viruses evolved
to infect them. There's wide agreement among biologists that RNA molecules existed before DNA, and that they were the first replicating molecules, in which case today's single stran did RNA viruses, like the anenteroviruses that cause handfoot in mouth disease, are
representatives of the descendants of these ancient ancient viruses. Okay, Another thing in the support column for this hypothesis is that in a huge number of viral genomes there are genetic sequences that aren't found in cells, which might suggest that viruses came before cells rather than deriving from cells, because otherwise, where.
Did these genetic sequences come from?
Right?
There are a couple of problems with this virus first idea. One is that there is no gene or coding sequences found in all viruses, and another is just the mechanics of it, like how can a virus replicate without a cell? How can it get that protective protein shell that capsid around its genetic material to find its next host and replicate more. The next hypothesis can help answer that, the
escape or sometimes called vagrancy hypothesis. Under this hypothesis, cells predated viruses and viruses actually derived from cells.
How do they do this?
Well?
In the genomes of our cells, there are these super cool things called retro transposons, which are genetic elements that move around the genome, cutting and pasting genetic code.
Like how ah, what oh I just beat up around?
I can't I just can't get over it.
Who.
So, some scientists think that viruses could have emerged from a similar process where a mobile genetic element got wrapped up in a nice little protein coat and escaped the cell, like in a little vesicle or something, along with the tools it needed to cut and paste itself into another cell's genome and make more of itself and voila virus.
Okay, okay, okay.
And there are viruses that have actually formed this way or are thought to have formed this way through gene escape, one of which is the human hepatitis delta virus, which can only infect humans and requires the hepatitis B virus to replicate, and it probably came from human genetic material hepatitis delta virus.
Oh that's so interesting because when you were talking about the viruses that infect other viruses, hepatitized d was the first thing that I thought of, because it's like, it's not a virus that infects other viruses, but it's a virus that requires another virus to already exist in the cell for it to be able to infect that cell.
It's like hyper dependent, yeah, hyperterocyte. Yeah, so very cool, right, And with this scenario, these so called pickpocketing or gene robbing viruses could have been formed from escaped genes from each of the domains Bacteria, Archaea, and Eukarya, which helps to explain the existence of bacterial viruses, bacteriophases from bacterial genomes,
eukaryotic viruses from eukaryotic genomes, and archaeoviruses from archaeo genomes. Okay, but if this were the case, we shouldn't find viral genes or genes of viral origin because they would have all come from these cells.
Yet we do.
So. Here enters the third hypothesis, or the reduction hypothesis. This idea was revived when in the early two thousands, scientists discovered giant DNA viruses. The first of these to be described Mimi virus because it mimics micro is bigger than anyone thought viruses could be. So, you know how, like on the podcast when we talk about the history of the discovery of viruses, we talk about how they were called filterable transmissible agents because you filter all the
bacteria out and yet there's still something there. These would get filtered out. Some of these viruses are bigger than bacteria. What, yeah, than some bacteria. Bacteria range in size whatever, But it's
so cool, and this giant virus than this. Mimivirus has also an incredibly large genome, which goes against this conventional idea that viruses have small genomes and they're restricted to having small genomes because the larger the genome, the more likely that mistakes are made in replication, and since they don't have proof reading abilities, those mistake written, large genome
viruses would die out right. So if you're like imagining typing, trying to copy a paragraph, the longer the paragraph is, the more likely you are to make mistakes. And let's say that you can't proofread your mistakes.
Right.
Yeah, but these giant viruses still exist, and they not only have these big genomes, but they also appear to have genes or forms of genes that may have coded for protein synthesis or may have been involved in protein synthesis.
It's wild, it's wild. Also, they have very low mutation rates, which is really cool because you would think larger the genome even though it's DNA, but still, and because of how much they resemble cells and rely less on hosts for a replication compared to other viruses, some scientists have speculated that these giant viruses evolved from more complex and
esters losing their free living ability. So I like to think of it as like, this giant virus started out as a free living, independent being, just happy being itself, going through eons chillin', and then it meticell and was like, oh hey, you me me you, maybe we could like form a partnership work together. And over time that virus grew to be more and more dependent on its partner.
It stopped working on itself and didn't care about living freely and eventually turned into a Parasite's that's the story in my head.
I really love it.
And so it's even been proposed. I think it's pretty controversial, but it has been proposed that these giant viruses are the descendants of an extinct fourth domain of life.
Oh mg, yeah, or.
Maybe not, because their genomes don't show the same degradation that obligately intracellular bacteria like Ricketsia and chlamydia, and so it's possible some scientists think that they evolved from smaller DNA viruses through genome expansion wild wild. So at this point, though, these giant viruses don't really seem to hold the complete
answer for viral origins. Did viruses come before cells? Did they escape from modern cells about four billion years ago, which is when the last universal common ancestor was thought to have originated, or did they derive from more complex ancestors now extinct. These three hypotheses have been revised, championed, abandoned, revisited,
and will probably continue to be debated forever. They do seem to be mutually exclusive in their traditional forms, yet none explains the origin of viruses in a completely satisfactory way,
and it's possible, but no single hypothesis ever will. Some people have proposed hybrids of these scenarios, like viruses evolving from ancient cells which later gave rise to modern cells, which is why we see genes or elements that are unique to viruses yet are not found in these more modern domains, or protoviruses that could replicate themselves came first, and then ancient cells emerged, and they stole protective proteins from those cells, So it's sort of like step wise,
or that there were multiple origins of viruses, especially separately for RNA and DNA viruses. At this point, it mostly seems like a philosophical question, albeit one that we'll keep changing the more that we learn about the viruses around us as well as those within us in our genomes. And I know that I probably gave you a lot more than you bargained for when you asked, where did this thing come from?
Hah?
But hopefully you found this little foray into viral origins fun or at least somewhat interesting. And now I'm going to turn it over to you to bring us out of deep time into what's going on with handfoot in mouth disease today.
Oh my gosh, Aaron, I want to stay in deep time and just ponder.
Let's do that. Let's have a deep time hour, can we?
That sounds great? Okay, But right now we'll take a quick break and then I'll bring us back to twenty twenty three. Ish.
Don't sound so disappointed.
I know, I'm excited. It's gonna be great. Okay, good right after this break. At this point, all of these modern viruses and taroviruses that cause handfoot in mouth disease have been seen pretty much across the globe in my reading, at least, Koksaki virus A six is perhaps the newest one to be spreading and making headlines about it. With epidemics that started, like I mentioned, in two thousand and eight in Europe, spread throughout Asia and made their way
across the Atlantic to the US. Enterovirus seventy one is also globally distributed, but seems to cause the largest and most severe epidemics in Asia for reasons we don't really understand, because it's not limited to Asia, certainly, but across all of its range, especially in temperate regions, handfoot in mouth tends to be a seasonal disease. It usually occurs in summer as well as having smaller peaks in spring and fall, and across the globe, infections are by far most common
in kids under five years old. It's also probably not that surprising, both given how infectious this is and just the ways that it's spread, that it's really common for handfoot in mouth disease to cause outbreaks. Whether those outbreaks are small or incredibly large just depends on the certain set of circumstances surrounding it. But what that means is that we don't have great numbers on global prevalence. Yeah, it's also not a reportable disease for most of the globe.
A lot of Asia does actually report, especially ento ravirus seventy one infections. So we have some numbers and we can really see those seasonal trends, and from there we can see that there are tens to hundreds of thousands of reported cases during these peak seasons, depending on the
country that we look at. So if we extrapolate that data using not quite air and math, but just guessing, it's almost certain that there are hundreds of thousands, if not millions, of cases of hand foot in mouth across the globe every year. This is a very common infection. Yeah, So then the question is why does it seem like perhaps some subtypes, especially those that maybe cause more severe infection, are on the right eye, like Koksaki virus A six. I don't know.
I was waiting.
I was like, oh, I don't ever have an answer there, but it's fun to think about. Is it because it's out competing the other Cooksaki viruses because it's a more virulent infection somehow? Is it just that most of us haven't yet been exposed, so there's a lot more susceptible individuals in the population. Is it some combination thereof Probably, but it's important that we try and get a handle on this, especially as we're looking at these viruses that seem to be causing more severe illness.
Right.
Another thing that's interesting just about the general epidemiology of handfoot, and mouth disease is that in addition to seasonal variation, there also tends to be these cyclical epidemics where every two to five years, larger outbreaks and epidemics tend to happen.
That may not be that surprising to anyone who listened to our poliovirus episode recently, because that used to happen with poliovirus as well, and it's likely related to just the how many kids have been born and how many susceptible young babies you now have in a population that have never been exposed to any of these viruses.
Yeah, it's it's interesting, Like I wonder what the susceptible population requirements are, you know, in order to be sustained. I feel like we talked about this in different episodes, and like our measles episode, compared to other things like chicken pox, you don't really need to have a certain you know, threshold of individuals to maintain infection.
Well, one of the at least one paper that I read, I remember seeing that they estimated that to heard immunity, you would need to have well over eighty percent of people no longer susceptible, so immune to the infection.
Wow, it's a lot, right, it's a lot.
It's not as high as for something like measles, but it's also that much more complicated because there are so many different viruses that can cause this. So yeah, so
there's definitely a lot of variation within that. The good news is that even though we talked about the severe complications of handfoot and mouth disease, if we look at the case fatality rate of all cases from all causes of handfoot and mouth disease that are uncomplicated, the case fatality rate is incredibly low, between point zero six and
point one percent, which is very low. When it comes to more complicated cases that have neurologic involvement, the mortality rate can be between ten twenty five percent, which is
significantly higher. So I think that right now, in terms of current research, there is a lot of interest, understandably in these more severe subtypes, not only in what is causing this increased virulence with say enterovirus seventy one and cocksacky A six, but also what are the drivers of this seemingly increase in outbreaks that we've been seeing year after year. There's also, of course a lot of work
to be done on vaccines which do exist. There are at least three that have existed, at least one that is licensed, but they've only ever been licensed in China. The vaccine that exists only exists against enterovirus seventy one, which again is more common across Asia, so it's licensed in China. It does seem that it's quite effective. The study that I I saw said that it's estimated to have ninety to ninety seven percent efficacy even over a
couple of years, which is pretty incredible. But other than that, I don't know a ton about it, and I don't know the likelihood that it would be licensed anywhere else. But there's certainly a lot of research to be done. As always as always, and that is hand, foot in mouth and butt disease.
And fingernail and to fingernail.
Yeah, we did.
It, we did. I mean this was I really loved that deep dive. Arin. I'm just not going to stop thinking about viruses in my body.
Well, I'm glad and if for anyone out there who wants to maybe read more and because there's idea so much more out there than what I even touched on at all.
So go to our sources.
And I'm going to shout out a few right now. If you want to learn more about the history of handfoot and mouth disease, there are several great papers. One is by Richardson and Leibovitz from nineteen sixty five. And if you want to learn more about the origin of viruses like where to even begin, there are many different sources. One is by Drzinska at All from twenty fifteen called Viruses and Cells Intertwined Since the Dawn of Evolution.
There's just a lot.
There are a lot of sources for this one, I can imagine. For the biology, there was a few papers that were really nice overviews and a lot of papers that I had on enterovirus seventy one specifically, So for more on that, you can check a paper in the Lancet Neurology called Clinical Features, Diagnosis and Management of Entrovirus
A new one. Really loved that one, and I used the American Academy of Pediatrics red Book, which had information on all of the different enteroviruses, and I even threw in a fun paper about all of the skin rashes that involve palms and souls, just for.
Fun to check that one out.
Yeah, it's pretty cool, pretty cool. Not a lot of the path of physiology, but just less of all the different.
Ones and it's so interesting.
You can find the list of all of our sources because there's many more from this episode and all of our episodes on our website This podcast will Kill You dot com under the episodes tap.
Thank you to Libby again for sharing your first hand account like oh oh, thank you yeah.
Thank you to Bloodmobile for providing the music for this episode and all of our episodes.
Thank you to Leana Scolacci for our amazing audio mixing. Thank you, we love it. You're the best.
Thank you to the Exactly Right Network.
And thank you to you listeners.
For anyone out there who requested this, we hope that you got your questions answered.
I hope you so yeah felt validated. I don't know, yeah yeah that too. And a special shout out to our patrons as always, thank you so much. Your support means everything to us.
It really does. Well.
Until next time, wash your hands
You filthy animals, and your feet and you really do really and the changing pad scrum it everywhere,