This Podcast Will Kill You - Ep 123 Hand, Foot, and Mouth (and Butt?) Disease

Episode Date: August 22, 2023

Hand, foot, and mouth disease (HFMD). The dreaded scourge of daycares, kindergartens, even occasionally college campuses, and the topic of this week’s episode. From the multiple viruses that cause HFMD to the wide array of symptoms (bye bye, fingernails), from the relatively recent discovery of this disease to the ancient origins of all viruses (deep time, y’all), from the changing nature of outbreaks to the development of potential vaccines (fingers crossed) - in this episode we’re going way beyond the basics of hand, foot, and mouth disease. Whether or not you’ve had the pleasure of being up close and personal with this disease, this episode is sure to leave you slightly horrified/mildly impressed by the infectiousness, longevity, resilience, and deep roots of the HFMD viruses. See omnystudio.com/listener for privacy information.

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Terms and Conditions Apply. Visit blueapron.com slash terms for more information. Welcome to Dirty Rush, the truth about sorority life, the good, the bad, and the sisterhood. With your host, me, Gia Judice, Daisy Kent, and Jennifer Fessler. The reality of Greek life has been a mystery for those outside the sorority circles until now. Is it really a supportive sisterhood that's simply misunderstood? or is there something more scandalous having on campuses across the country? Let's get dirty.

Listen to Dirty Rush on the IHeart Radio app, Apple Podcasts, or wherever you get your podcasts. Then she says, have you seen a photo of my son? And I'm like, who is this person? Welcome to the Boys and Girls podcast. Arranged Marriage is basically a reality show and you're auditioning for your soulmate. And who's judging? Only your entire family? I sacrificed myself to this ancient tradition, hoping to find a lot of.

mind love the right way. And instead, I found chaos, comedy, and a lot of cringe. Listen to boys and girls on the Iheart radio app, Apple Podcasts, or wherever you get your podcast. On a Saturday in the late summer of 2018, 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 hand foot 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 2 a.m., 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 102, so I loaded myself with NyQuil 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 hand foot and 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 and 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 11 weeks.

That's almost three months, a fiscal quarter. 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 11 weeks after my initial infection. And in the meantime, I was not going to be swapping spit with anyone. I went to the lake with my girlfriends around then, and I vividly remember 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 from 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 11-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 to. And I also hope that more people become aware of just how long an infected person remains contagious. My gosh. I, yeah, that sounds awful. You know, like, I know about hand, foot, and 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. And also how awful it is to just have your skin sloughing off. 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.

Sorry you had to relive it on the podcast, but we all appreciate it. Hi, I'm Aaron Welsh. And I'm Aaron Alman Updike. And this is, this podcast will kill you. And today we're talking about hand, foot, 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. Same. No idea.

Mom. Can you text me? Tell me. Yeah. But it seems like it's everywhere. Maybe it's just like. because that's the age that we're at where you just hear about, you know. Everyone's toddlers 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 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. Oh, okay. Erin, what is in out of 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 lime juice and some tonic water. So refreshing. We'll post the full recipe for that quarantini as well as our non-alcoholic placebo-rida on our website. This Podcast Will Kill You.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.com. Must I go through the spiel. There's lots of good stuff. There's transcripts and there's bookshop.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. Well, 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. Dinner shows up every night, whether you're prepared for it or not. And with Blue Apron, you won't need to panic order takeout again. Blue Apron meals are designed by chefs and arrive with pre-portioned ingredients so there's no meal planning and no extra grocery trip. There, assemble and bake meals take about five minutes of hands-on prep. Just spread the pre-chopped ingredients

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Get 50% off your first two orders plus free shipping with code this podcast 50. Terms and conditions apply. Visit blueapron.com slash terms for more information. Anyone who works long hours knows the routine. wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keefe's working hands hand cream is such a relief. It's a concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands caused by constant hand washing and harsh conditions. Working hands creates a protective layer on the skin that locks in moisture.

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This season on Dear Chelsea with me, Chelsea Handler, we've got some incredible guests like Kumail Nanjiani. Let's start with your cat. How is she? She is not with us. Okay, great, great, great way to start. So this is a great beginning and hopefully you'll be able to, I don't know, maybe you will cry. Amanda Seifred. Life is so short.

If you feel something like that, you have that. fire in you for this experience. It's not for a guy. It's for the experience of being in love and like, it's bigger than a guy. Elizabeth Olson. I love swimming naked so much. And I know you love taking pictures of yourself naked. I love to be naked. I just want to be in my brown underwear all the time. Ross Matthews. You know what kids always say to me. Are you a boy or girl? Oh my God. That's so funny. I know. So I'm always like, hi. I try to butcher it up for kids, you know, so they're not confused. Yeah, but you're butching it up is basically like an angry woman. Right. No, I turn it to be Arthur.

Listen to these episodes of Dear Chelsea on the Iheart Radio app, Apple Podcasts, or wherever you get your podcasts. Hand, foot 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, hand foot. 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 serotypes and subtypes of enteroviruses. And by a lot, I mean over 90 or over 100. And a lot of these are viruses that people have probably heard of because they cause disease in humans. These include Coxacky viruses, polio viruses, enteroviruses. enteroviruses, echo viruses. And enteroviruses actually also include rhinoviruses, like the cause of common colds. I learned about that. But also, what's an echo virus? 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.

Echo viruses cause other viral illnesses. That's all I got. That's all I've got. 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 pear echoviruses as well. There's a whole bunch. 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 serotypes that used to be always called, say, Cuxacki virus A, one, two, three, four, five, blah, blah, blah, blah.

And Cuxacki 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 it, old papers and then new papers and I was just trying to reconcile, like, what are they talking about? I know. 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 today.

Wonderful. Hand foot and mouth is most commonly caused by a few of these human enteroviruses, specifically ones in enterovirus group A. These ones have names, Coxacki virus A16, and human enderobirus. enterovirus 71, although there are a few others as well, including Coxsacki virus A6, which we'll talk about, and A10, A8, and a few others. All of these that cause hand, foot, and mouth tend to be in this enterovirus group A species. But there are B group species that cause, or Coxacki Group B, that cause hand foot and mouth occasionally. It's off 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 hand foot and 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. 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 hand, foot 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. But for some reason, I feel like this hand, foot 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 Yeah. Maybe you'll tell us, Erin. And also how we make those distinctions. I think it's really valid.

Today, I'm going to focus on Coxsacki virus A16, Enterovirus 71, and a little bit about Coxacky Virus A6, because those are the three that I found the most information about, as we'll see. 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 polio virus episode. Polio virus, 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 hand, foot, 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 antiraviruses, including those that cause hand, foot, and mouth.

And importantly, fecal oral, as with poliovirus. 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 hearty little beasts. You have to admire them. But 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, star, 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 master's 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 0.1%. Exactly. 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 hearty.

Yeah. That's great. The incubation period, so the time between when you get exposed to when symptoms develop, for most enteriviruses, including the ones that cause. hand, foot, and mouth disease, is generally between three and five days. And as we'll see, and as you heard in our first hand, hand, hand, foot, and mouth disease usually lasts between a week and 10 days. But you can continue shedding virus, especially in your stool, but also even in your throat secretion, so in your saliva, for weeks at a time. It's gnarly.

And these are incredibly contagious viruses. So if we look at studies that have tried to estimate the R 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 vary based on population. They vary based on virus subtype.

So for antivirus 71, it's estimated usually closer to five. And then for Coxacky virus A16, it's like an average of two and half or so. So yes. And then also if you look specifically in like household transmission, in some studies, household transmission is like 52% of households are going to get infected and other studies as high as 85%, especially for kids under six. So it's incredibly infectious, really easy to spread around. But what actually are the symptoms? Like what is, like what is hand, foot and mouth disease. For the most part,

hand foot 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 fearmonger too much in this episode because the whole group of enterovirus We're talking about over 90 different viruses. A lot of them have the potential to cause severe disease. But the vast majority of cases of what we call hand, foot and 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 10 and 70% of people become symptomatic,

which is like a huge range. But for example, with polio virus, about 75% of people are asymptomatic, and only 25% 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 till the end? 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 antiraviruses, you can potentially shed virus before you realize that you're symptomatic. Say before your fever starts. Spoilers. Aha. 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 hand-foot-and-mouth disease multiple times in your life. Yay, woo-hoo. But it's very likely that there is some degree of cross-protection among different, say, Coxsacki virus strains and

enterovirus, numbered enterovirus strains, because adults are much less likely to have symptomatic hand-foot-and-mouth disease, and it's thought that that's very likely due to previous exposure. The most susceptible people for hand-foot-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 they're just, mutate. Yeah. Mutation happy and yeah. Yeah. It's fun. Good stuff. Okay, so let's talk about what this looks like, shall we?

Yeah, we're finally there. So most cases of hand, foot, and mouth happen in little kids. That's the stereotype for a reason. Mostly kids under age five. 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 knew you were going to 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?

HFMB. I don't think we just keep adding body parts to it. And fingernail disease. Well, yeah, we'll get there. 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 on to the genitals as well. One thing that's interesting and kind of specific about hand, foot and 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. Cephalus can. I think that's probably one of the main ones that we've covered on this podcast.

Rickettsia or Rocky Mountain Spotted Fever can. Right. Yeah. Rat bite fever can. We haven't done that. There's a number of other pathogens, but it's kind of. 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 hand foot 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 butt 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 sores in that area, you're also having a lot of generalized inflammation because that infection is there in your throat essentially. Yeah. Okay. Yeah. So adults and older kids certainly can get hand, foot, and mouth like you heard in our first hand, 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 a 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 hand, foot, and mouth can be caused by any of the pathogens that I mentioned that cause hand foot and mouth disease. Coxacki virus A16 is probably one of the most common causes of uncomplicated hand foot and mouth. Enterovirus 71 is the other most common cause of hand foot and mouth. But enterovirus 71 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 enterovirus 71, it's often a viral meningitis 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 enterovirus 71, 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 edema 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 anterior virus 71 infections. This virus can also affect the spinal cord and cause an acute flaccid

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 flaccid paralysis. I want to stress that these are not common manifestations of Nterovirus 71 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 perspective, though, in some of the larger antivirus outbreaks that we've seen, for example, in Malaysia in the late 90s, there was over 2,600 cases of hand foot and mouth disease that were reported, and 34 deaths. So a very small number

comparatively, but still a number. In Taiwan, in the late 90s, an estimated 1.5 million people were infected with hand, foot and mouth disease, 405 admitted to the hospital with some type of neurologic complications, and 78 children died in that big outbreak. Jeez. Yeah. And then in 2008 in mainland China, just under 500,000 cases and 126 deaths in children were reported due to hand, foot and mouth disease. And the vast majority of those cases were likely or confirmed to be enter a virus 71,

which is really common in Asia, but is present around the world. How, like for a typical outbreak or like a suspected outbreak of hand, foot and mouth, how often is virus testing done to know which strain it is? It's a really good question. And it's going to vary so much by place that I don't have a great answer to that. Okay. Yeah. Here in the U.S., the vast majority of people who get hand foot 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 enteriviruses that can cause hand, foot and mouth are pretty widespread and becoming more so because of globalization. So how likely is it that if you repeatedly get hand foot and mouth or you get hand foot and mouth multiple times, how likely is it that those are, you know, Coxsacky virus A16 and then A6 or just a mutated version of A16? Oh, I think that's an impossible question to answer. It's a 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 hand, foot and mouth disease, any of them can cause severe infection or can cause severe infection or can cause. mild infection. It's just that some of them have been shown so far to be more likely to cause a severe infection than others. So enterovirus 71 is more likely to cause neurologic manifestations if there are going to be neurologic manifestations. Coxsacky virus A16 more likely to just cause uncomplicated regular run-of-the-mill hand, foot and mouth. And then there is Coxackie A-6. This is yet another strain of Coxacivirus, which really recently has been found to cause hand-foot-and-mouthed disease, like 2008 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 1960. I thought that's Entero Virus 71. A-5. Oh, I don't even talk about A-5. 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 Coxsacchi virus A6 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 Coxsackey 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 across the entire arms, especially in areas that you tend to get eczema. So like in your elbow folds and things like that, this is called eczema coxacium.

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 hand-foot-and-mouth disease rash is not itchy. It also can cause what's called a delayed onocomadesis, 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 off. And toenails? Townails 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 or months after you get the infected, that nail just falls off. It'll grow back. And, and this one is really horrible image, palmo planter disquamation, aka the skin of your hands and feet just sluff off. The same way that we might see in a fungal infection or in like a maceration 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 slough alone is enough to just, ugh. It's bad. Yeah. And this is not only in adults. Coxacivirus A6 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 for enterovirus 71. 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 hand foot and 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, et cetera, no matter how we get exposed, whether it's fecal or respiratory. So, yeah, yes. Yeah. Yeah.

Any more questions? I mean, treatment, I assume, is supportive if necessary. Exactly. Like you said, hydrate, chill. Watch TV. Yeah, we don't have any specific antivirals 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 hand, foot, and 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 complications, right? Yeah.

But they all share this sort of clinical picture of fever, 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 and 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, when it's like more like along the lines of like a salmonella Xero-type, 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 Coxsackie Group B doing in there, you know, whatever?

That's just enter a virus group B. Yeah, but what's to do it in there? How is it different? Why is there A? Why is there B? So, yeah. But Aaron, where did these things come from? Why do they do this to us?

Or maybe not that part. It's a philosophical question. Is it? I don't know. It could be. Yeah. Let's figure out how we got from there to hear. right after this break.

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This season on Dear Chelsea with me, Chelsea Handler, we've got some incredible guests like Kumail Nangiani. Let's start with your cat. How is she? She is not with us in. Okay, great, great, great way to start. So this is a great beginning, and hopefully you'll be able to. to, I don't know, maybe you will cry. Amanda Seifred.

Life is so short. If you feel something like that, you have that fire in you for this experience, it's not for a guy. It's for the experience of being in love and like, it's bigger than a guy. Elizabeth Olson. I love swimming naked so much. And I know you love taking pictures of yourself naked. Yes.

I love to be naked. I just want to be in my brown underwear all the time. Ross Matthews. You know what kids always say to me? Are you a boy or a girl? Oh, my God. All the time. I love it.

So I'm always like, hi. I try to butcher it up for kids, you know, so they're not confused. Yeah, but you're butching it up is basically like Doris Day. Right? No, I turn into Be Arthur. Listen to these episodes of Dear Chelsea on the Iheart Radio app, Apple Podcasts, or wherever you get your podcasts. Hi, I'm Danielle Robeye, host of Bookmarked, the podcast by Reese's Book Club.

And this week on Bookmarked, we're basically hosting the Ultimate Girls' Night. Reese Witherspoon, Jennifer Garner, Judy Greer, Rita Wilson, and Gauri Rice, and author Laura Dave. These are the women behind season two of the Apple TV series, The Last Thing He Told Me. We're talking about turning a book into a hit show and what it really takes to bring a story to life. The most important metric for me is do I want to share this book with somebody? That's what creates community, and that's the main thesis of our book club and why we started it, It was just to connect people together. Listen to the bookmarked by Rees's Book Club podcast on the Iheart Radio app, Apple Podcasts, or wherever you get your podcasts.

Hand, foot 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 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 we'll likely learn about in the current events section, the nature of some hand, foot, and 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 Coxackey 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 of

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.

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 hand, foot, and mouth disease. Okay. In 1957, 1958, and 1959, outbreaks of a highly infectious disease seemingly never before described were reported in New Zealand, Canada, and England, respectively. 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. And the 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 60 cases occurred in the Toronto one and 83 in the in the Birmingham, England outbreak, again, including all or predominantly children.

If we had to give, like, medals out for each of these outbreaks and what they contributed, it would go like this. 1957 New Zealand, the first recognized outbreak of hand, foot and mouth, though only, like, in retrospect, was it recognized as hand, foot and mouth? Because they didn't test for the virus at the time. 1958, Toronto, first time that Coxsacki virus A-16 was found in samples from people who were infected, showing that this was a viral infection caused by an antarovirus. And 1959, Birmingham, the first time the name Hand, Foot, and Mouth was used to describe this disease.

So kind of like, boom, boom, boom. Here we go. We've got it. So the 19th, it's the mid-20th century. Virology is like just cruising. Well, really getting a good 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 hand foot and 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 sense. Yeah. But as it always happens, once hand foot and 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 1959, there was an outbreak of Coxsackie A-16 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 hand, foot and 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 1960 discovery that a different virus, Coxsacky Virus A5, there's my shout out, was responsible for a small outbreak, changed it from the hand, foot and mouth virus to the hand, foot and mouth viruses, with, you know, 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 1959 outbreak in California. Over the decades since the

discovery of hand, foot and 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. Yeah. 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 hand, foot, and mouth disease season in certain regions. Oh, yeah. I mean, because 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. Yeah. 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. That's pretty cool. 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 head, 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 hand foot 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 hand foot 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 hand, foot, and mouth disease come from? We can say that enteroviruses are an ancient group and there are RNA viruses, so it's easy to underestimate the time scale of viral evolution, and they recombined

with each other, so it's also difficult to trace evolutionary relationships. There's not very much specific research that I could find on interoviruses. 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 hand, hand, foot, and mouth disease, or the name Coxsacky virus come from? We know the answer to the first, the 1959 outbreak. And the second is that Coxacki viruses were named after a small village on the Hudson River south of Albany, where two children lived from whom Coxsacki viruses were first extracted or isolated in 1948 by Gilbert Daldorf, a director in the New York State Department of Health. So there's a town called Coxacky in 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. Oh, 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 predate 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 paleoverology? Because I kind of want to. Do it.

What is paleoverology? 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, bacteriophages. And that makes sense, given that identifying those 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 cell's machinery to make more virus. They turn into like viral production factories. Viruses can be characterized by what type of genetic material they have.

Like we've talked a lot about RNA viruses. 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 Karl Zimmer tries. In his book, Planet of Viruses, he writes that, quote, there are 100 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 42 million light years. It is in fact too much to comprehend. You can't.

We need one of those grains of rice videos. Yes. You know? I do know. What? And that's just the ocean. That's just the ocean. Yeah, that's not even...

All of the biomass on land. Planet Earth. Wow. Oh, my goodness. Okay. Mm-hmm. Since the discovery of the tobacco mosaic vial, in the late 1890s, 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 possible for a virus, and these viruses can be infected by a virus.

A virophage. 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 virophages, 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 kind of the same reason, right? Yeah. 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 fossils, 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 ourselves, 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 endogenization. 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 8% of our human genome is comprised of sequences of viral origin.

So we are all virus. We are all virus. But we're 8% virus. Isn't that amazing? Like we're just hanging out, live in 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?

So these sequences are called human endogenous retroviruses. But side note, apparently it's not just retroviruses that can become endogenized. That's just my own little like, eh-oh. Well, actually. Yeah. While most of this 8% 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. Sincitin.

So, uh-huh. We talked about that. 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. So yes, I not only that, but Sincitin 1 and Sincitin 2 may play a role in preeclampsia and even some preliminary hypotheses on the development of other conditions unrelated to pregnancy. Other human endogenous retroviruses may affect our immune system and have been linked to various autoimmune diseases and ALS, among other things.

You know, I feel very kind of. conflicted about this, Erin. Why is that? Because I feel like on the one hand, this is the most incredible information. Like, it's so my brain can't handle it. It's incredible. And then on the other hand, I'm like, that makes sense. Because, I mean, especially because, like, yeah, they're a virus.

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 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 sort of the turning off was selected for. It was like, we're going to do better if we don't do whatever this virus is instructing us to do.

Yeah. 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 paleoverology, 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 like go back to grad school kind of and research. search 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 wave? 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 like a little bit of extra reading. And so

there do seem to be, there's a growing database where people have identified endogenous 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 it to be like, where's my endogenous 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. Just send us info so we can read more about it. Thanks. Yeah. So I promise you that this will definitely not be like I'm going to stop talking about endogenous 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 endogenous retroviruses, maybe in an episode on preeclampsia, 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. How do we determine the functions that they have or don't have? I mean, just also like trying to tease apart regulatory functions of things. I love it. 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 going to 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, maybe. 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-stranded RNA viruses, like the antaroviruses that cause hand-foot and 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 predate, 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? I what? They just beep up around. I can't, I just can't get over it. So, So some scientists think that viruses could have emerged from a similar process. Right. 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 that it needed to cut and paste itself into another cell's genome and make more of itself.

And voila, voila, virus. Okay, okay. And there are viruses that have actually formed. this way or 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. Hepatitis D was the first thing that I thought of because it's like it's not a

virus that affects 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 hyperdependent. Yeah. Hyper periscite. Yeah. So very cool. 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 eukaria, which helps to explain the existence of bacterial viruses, bacteriophages from bacterial genomes, eukaryotic viruses from eukaryotic genomes, and archaeo-viruses from archaeal 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 2000, scientists discovered giant DNA viruses. The first of these to be described, Mimi virus, because it mimics microbes, is bigger than anyone thought viruses could be. So you know how 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. Right. These would get filtered out. Some of these viruses are bigger than bacteria. What? Yeah,

than some bacteria. Bacteria range and size, whatever. But it's so cool. And this giant virus, this mimmy virus 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 proofreading abilities, those mistake-ridden large genome viruses would die out. Right? So 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 replication compared to other viruses, some scientists have speculated that these giant viruses evolved from more complex ancestors losing their free living ability. So I like to think of it as like,

Like this giant virus started out as a free living independent being, just happy being itself, going through eons, chilling. And then it met a cell and was like, oh, hey, you're 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. 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, m. Yeah, or maybe not. Because their genomes don't show the same degradation that obligately intracellular bacteria like rickettsia and chlamydia do. 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.

Right. And it's possible that 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. Yeah. 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 stepwise. 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 will 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? 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 hand foot and 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 2023-ish. Don't sound so disappointed.

No, I'm excited. It's going to be great. Okay, good. Right after this break. At this point, all of these modern viruses enteroviruses that cause hand foot and mouth disease have been seen pretty much across the globe in my reading at least Coxacivirus A6 is perhaps the newest one to be spreading and making headlines

about it with epidemics that started like I mentioned in 2008 in Europe spread throughout Asia and made their way across the Atlantic to the U.S. Antirovirus 71 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, hand foot and 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 spread, that it's really common for hand-foot and 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 enterovirus 71 infections. So we have some numbers and we can really see that.

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 Aaron Math, but just guessing, it's almost certain that there are hundreds of thousands, if not millions of cases of hand, foot and 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 rise? Yeah. Like Coxacivirus A6. I don't know. I was waiting. I was like, she's got the answers. I don't. ever have answers, Aaron, but it's fun to think about. Is it because it's out competing the other

Coxsackey 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? Mm-hmm. Another thing that's interesting just about the general epidemiology of hand-foot-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 in epidemics tend to happen. That may not be that surprising to anyone who listened to our polio virus 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 interesting. 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 chickenpox, 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 have herd immunity, you would need to have well over 80% of people no longer susceptible. so immune to the infection. Wow. That's a lot. Right. It's a lot. It's not as high as for something like measles.

No. 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 hand, foot, and mouth disease, if we look at the case fatality. rate of all cases from all causes of hand, foot and mouth disease that are uncomplicated, the case fatality rate is incredibly low between 0.06 and 0.1%, which is very low. Yeah. When it comes to more complicated cases that have neurologic involvement, the mortality rate

can be between 10 and 25%, which is significantly higher. Mm-hmm. So I think that right now, in terms of current research, there's a lot of interest, understandably, in these more severe subtypes. Not only in what is causing this increased virulence with, say, enterovirus 71 and Coxsacky A6, 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. Okay. The vaccine that only exists against enterovirus 71, 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 saw said that it's estimated to have 90% percent. to 97% 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, and mouth and butt disease. And fingernail and toe nail. And fingernail. Yeah. We did it. We did. I mean, this was, I really loved that deep dive, Aaron. 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 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 hand, foot, and mouth disease, there are several great papers. One is by Richardson and Liebowitz from 1965. 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 Dersinska at all from 2015, 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 71 specifically. So for more on that, you can check a paper in the Lancet Neurology

called Clinical Futures, Diagnosis, and Management of Enterovirus 71. I 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. I want to check that one out. Yeah, it's pretty cool. Not a lot of the path of physiology, but just lists of all the different ones. It's still 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.com under the episodes tab. Thank you to Libby again for sharing your first-hand account. Like, oh, thank you. Yeah. Thank you to Bloodmobile for providing the music for this episode and all of our episodes. Thank you to Leanna Scolachi 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. Yeah, I hope 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 your mouth. Really do. Really.

And the changing pad. Scrum it. Everywhere. Welcome to Dirty Rush. The truth about sorority life. The good, the bad, and the sisterhood. With your host, me, Gia Judice, Daisy Kent, and Jennifer Fessler. The reality of Greek life has been a mystery for those outside the sorority circles until now.

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