This Podcast Will Kill You - Ep 90 Human African Trypanosomiasis: A lot to unpack

Episode Date: February 8, 2022

Here on the podcast, we’re no strangers to multi-host parasites with complicated life cycles, intricate ecologies and dense human histories. But human African trypanosomiasis (HAT) might require the most unpacking yet. In this episode, we do a deep dive into the tsetse fly-transmitted HAT, whose other name, sleeping sickness, doesn’t quite capture just how deadly this parasitic infection can be. First, we ask how these two trypanosomes cause the signs and symptoms they do, especially the strange sleep disruptions that gave this neglected tropical disease one of its names. Then, after a brief detour discussing the fascinating ability of tsetse flies to give live birth, we explore the many political and ecological factors that set the stage for the devastating HAT epidemics of the early 20th century. We wrap up the episode with a look at the current global status of HAT, and with new, effective, and easy-to-administer drugs on the scene along with a downward trend in cases, we’re certainly hopeful for the future elimination of this disease. See omnystudio.com/listener for privacy information.

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all the time, even when it was hot. Just taking a bath was an ordeal. I didn't know what was wrong. All the tests came out negative. I went to Flemetro and Musi in 1992. They performed a spinal tap and the result was negative. I continued to suffer. My bones ached terribly. I was extremely cold. I had fever but would never sweat. I was losing weight. I arrived here in Bandoondu in 1999 in a very precarious state of health. I went to a health center where they performed another spinal tap. The result was still negative. I went to Fometro in 2010. again the spinal tap. It seemed there was no solution to my problem. I could hardly stand up. I was nearly paralyzed, constant back pain, constantly sleeping in my bed. When I would go to prayer,

I couldn't follow the preacher. I would just fall into a slumber. I insisted on getting the right tests. Maybe I had sleeping sickness. They just kept telling me I was fine. I went to the hospital and still no diagnosis. Here at the general hospital, the test was negative, just malaria. I was totally confused. In the meantime, my health deteriorated. In 2010, in January, they brought me to Vanga. I was practically in agony. It was there, finally, that I discovered I had sleeping sickness. I was transferred back here to Bandundu for treatment. I knew nothing of all of this since I was unconscious. They started me on the treatment, although I had no idea what had been prescribed. I was crying all the time. I had to be carried and fed like a child. I was a complete disaster.

I didn't think I'd ever walk again. But the treatment was effective. When I regained consciousness, I was discharged from the hospital. I started to walk again. I was so thrilled. My eldest sibling died from sleeping sickness in 1980 in Mushi. In the city where I live, a friend of mine contracted the disease. She suffered complications.

She had been treated with the shots. In the end, she died. The patients that were treated with the new treatment were healed. But most of those that were treated with the shots had enormous difficulties. Some are paralyzed for life. I was among the first patients to be treated with the new products. My opinion is that we have to keep using the new products.

They are good and don't harm the patients. I was paralyzed. And thanks to the new treatment, I can walk again. Wow. I honestly don't even know what to say. Yeah, same. There is so much to unpack, I feel like, in this story. just the horror of this disease and in many times the horror of the treatment itself too,

as I'm sure we'll talk about. But yeah. So that was from a video titled A Life Saved by NECT, Yvette's story of sleeping sickness from the Drugs for Neglected Diseases Initiative. Hi, I'm Aaron Welsh. And I'm Aaron Allman Updike. And this is, this podcast will kill you. Welcome. Today we're talking about sleeping sickness, aka human African tropanasomyasis.

Yeah. Yeah. This is a, like the exact type of disease that really got me interested in disease and medicine and public health and global health and all of the things because it's, yeah. Yeah. It's a lot. It's a lot. It's a really complex disease system. It's a really complex disease history. And I, you know, I think I now say this every time, but I was surprised by how much I absolutely had no idea about. Same. The biology was so much more complex. I mean, I knew that the kind of ecology was complex, but I had no idea about the complexity of the biology, like in humans. even. And I know nothing still about the history. I can take some guesses. Yeah, sadly. It's going to be a big episode. Yeah. But I think it'll be a very interesting one. Yeah, I think so too. I'm excited about it. Yeah. But before we get into too much detail, Erin, it is

quarantini time. It is. Aaron, what are we drinking this week? We're drinking the nightmare. We are. I think a pretty appropriate name for this disease because this disease truly does seem like a nightmare. And it is in many ways a nightmare. So. Yep. What's in the nightmare, Aaron? Great question. In the nightmare is lavender simple syrup, camomile tea, whiskey, and a little bit of lemon juice.

Dish. Yeah, it's not a nightmare to drink. We'll post the full recipe for that quarantini. and our non-alcoholic placebo rida on our website, this podcast will kill you.com and all of our social media channels. We will. Other business includes our website, which has lots and lots of things. I promised myself last time that I was going to do a post-it note of all of the things on our website, and now I am so mad at myself for not following through.

All right. Well, it comes to me anyway. Our website, you can find sources for where we get all of the info for each of our episodes. You can find transcripts. You can find links to Bloodmobiles Music now on Spotify. You can find links to our Goodreads book list and our bookshop. org affiliate account. You can find our Patreon and some sweet, sweet merch.

Yes. Oh, real quick. I did remember one piece of business that we should cover. we have gotten a number of emails about our C-DIF episode in which I didn't include the update that Clostridium difficile has been reclassified several years ago, I think, around 2016, to the species Clostridioidioidis difficile. C-diff is still C-diff, but it's a different C. Yes.

Yeah. All right. Let's talk about sleeping sickness now. Let's, let's do it. Okay. 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

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Sleeping sickness or human African tropenosomiasis, which, like, I might at some point just call tropanosomiasis or H-A-T because it's shorter. it is caused by a tripanosome. We've talked about those once before. In the same genus as that which causes Shagas disease. In this case, it is a different species, and in fact, it is two different subspecies. So today we're going to be talking about tripanasoma brucei-rudesiancy and tripanosoma-brusii-gamiancy.

I might just say gambiancy and rhodesiancy. because that's short. I do the same. It's a lot easier, yeah. Sometimes you even just see like TBG or TBR. I don't know. So, tripanasomes, as a recap, are unicellular eukaryotes. They are shaped kind of like little, if you look at them on a microscope slide, like little commas or maybe little bananas.

I don't know. They have a little flagellum that they use to swim around. Okay. T. Broussiye, all the species, because I didn't mention this, but there is yet another subspecies, tripanasoma bruceae, which causes a disease in cattle called Nagana, I believe is how you pronounce it. So, tripanosoma brucei is transmitted by yet another new vector species that we have never touched on in this podcast. It is the blood-feeding Sitsy fly. Sitsi fly, setsy fly.

We've had discussions about this pronunciation, and we've looked up many videos. And I think it's one of those that different people are going to pronounce differently. Yeah. All right. So that's Sitsy flies. Sizi flies, I'm really excited to talk about these. But I promise I'm not going to geek out quite as hard as like we did during the Typhus episode with Lice. Yeah, we did pretty hard.

Yeah. It's not going to be quite. as hard. But specifically that Sisi flies in the genus Glossina is who we're talking about today. I want to geek out just a little bit. These flies are fascinating. They are viviparous. Which means they give live birth. They give birth to live little larval young. I had no idea that that was a thing in insects until this. But I've never taken an entomology class, so what can I say? I have a PhD in entomology, and I learned something new. So these female flies deposit their larva into the soil directly.

They have eggs that they actually hold internally until they develop into, I believe, third in-star larvae. They deposit those larvae into the soil where they burrow in, they then pupate and emerge as adult flies? It's so fascinating because, like, first of all, I really want to know, has this happened, has this evolved in other species of insects? And, like, what are the, like, what are the evolutionary pressures or pathways for this thing to be like, I'm going to spend all of my time and energy on, I mean, they're relatively long-lived for flies. And so maybe that's part of it. But I just, like, I just want to know so much more about. viviparous insects.

I know. And I, like, specifically didn't deep dive on them. But, like, you, we so could. Yeah, we really could. Because there is, there's a lot, there's a lot there to unpack. But we're just going to leave it at, aren't these flies so cool? Let's deep dive another time. Another important part about these flies is that both male and female flies

blood feed as adults. And so here is how human African tripanosomyasis becomes a problem. When these flies feed on a human host or an animal host, they pick up this parasite, this tripanosome in the blood meal. These parasites enter the digestive tract of the fly. There they differentiate, they replicate, they burst out of the digestive tract, travel through the. the fly's body, enter into the salivary glands. In the salivary glands, they differentiate again into the infective form of tripanosome, continue to replicate, and then when that fly takes its next blood meal, their salivary glands are full of infective stages of this parasite that they can inject under their host's skin. Okay, interesting. Is this the way it is for all tripanosomes transmitted

by Setsu flies? As far as I know, yes. And this process, we have actually seen this process before. This is actually not a very uncommon way of vector transmission. Something like dengue fever is very similar, right? Where the virus has to enter the GI tract, make its way out of the GI tract, through the body and into the salivary glands. Importantly, this is very different than the other tripanosome we've talked about, which is Shagas disease, which is transmitted just through the feces, so that parasite just travels kind of straight through the gut of the kissing bug. Right. Here, this parasite not only has to migrate through the gut, through the gut wall, through the body,

into the salivary glands, but during this process, it also differentiates multiple times and changes forms in a very complex way. And this whole process actually takes these tripanosomes about three to five weeks, which is a really long time. Yeah, that's a really long time. Yeah, that's a very long time. And like you mentioned, Aaron, this fly is very long lived. From what I read, its lifespan is at least two to three months. And they blood feed every three days or so.

likely largely because of this complexity, not only the complexity of the life cycle of this fly, but also the complexity of the maturation process of these parasites within the fly, it's actually found that for the most part, the prevalence of tripanosomes in flies is actually very, very low, like 0.1% of flies in any given study area tend to be infected. That's bizarre. It is. So what's going on? I don't have a good answer for that.

So because you would think that like flies are so long lived, parasites seem to be in them for weeks at a time. But I think what it is is that a lot of those parasites, even if a fly is picking up parasites, they don't necessarily make it all the way to an infective infection in the fly. Okay. So at any point in time, it's 1% of flies that are infected with infectious stage parasites. It's 0.1%. 0.1%. Yeah.

Yeah. Okay. Okay. And as far as I found, at least, this is not a parasite that's vertically transmitted. So even though these female flies have their young that develop in their bodies, they're not passing those parasites onto their offspring. Yeah. Okay. Gotcha.

So there's a lot more to unpack there. I am sure because this is a very interesting and complicated genus of bug. But that's where I'm going to leave it. And let's get back to the life cycle of the parasite. So the parasite is now in the salivary glands. The fly takes another blood meal and in so doing, through their little proboscis, deposits a whole bunch of parasite underneath our skin. Those parasites enter our lymphatic system and our bloodstream.

And from there, they're able to replicate. they differentiate again in us as well, and they travel to various organs and establish an infection. It gets even more interesting, Aaron. The biology of this parasite, there's so much here. I'm not going to do every aspect of it justice, but I do hope that I at least give a teaser of all of the different interesting parts of this parasite. That's my kind of goal here, okay? I'm down.

So our human immune system, when we see this, these parasites is actually primed to recognize these parasites. And we do. Our immune system does. We actually even have a protein in our bloodstream that's usually really good at eliminating other tripanosomes that's called tripanosomelytic factor. Did you know that we had that? No. I have, yeah. Okay. Keep going. So if we get infected with most other species of tripanosome, not the two that we've talked about that caused disease in humans here, we're able to fend off that infection, like a lot of other animal tripanosomes. But tripanasoma brusii, subspecies, rhodesiency, and gambiancy, specifically have resistance

factors that render this particular protein that we have not useful. So my mind is blown because this is filling in so much of the evolution part that I researched. and I was like, but what does that mean about this and the history? So this means that we are like we can witness this as an arms race kind of a thing. Right. Yeah. Oh, my God, that is so cool. It gets even cooler, okay?

Tripanosomes have on their cell surface a lot of different proteins that our body uses to identify and recognize them as non-self, right? Antigens, essentially, that we make antibodies against to remove them from our bodies. And we're really good at that. But the tripanosomes that cause human African tropanosomyasis, T. Brousiae, rhodesiancy, and Gambiancy, from now on, those are the only two that I'm going to talk about. Okay. They have hundreds, maybe a couple of thousand variants of these proteins. And they express them one at a time and they constantly switch them up. So by the time our body manages to make antibodies against one of these glycoproteins, that one

barely even exists anymore and they've changed to a new one. Here's the way that I think about this. These tripanosomes are me when I was like 16 sneaking into a movie. Are you with me here? Into an R-rated movie. No, I wasn't that risque, Erin. It was probably PG-13. You were 16 sneaking into a PG-13 movie?

Let me tell you, let me finish my analogy. It's going to make more sense. It's flawed from the start, but fine. No, no, no. I'm talking about like movie hopping. Like you're trying to go to more than one movie without paying. Oh, my gosh. Okay.

Okay. I see. Right. Okay. So this is what's happening. The tripanasomes are sneaking into movies. And the security guards see them. They get on their walkie-talkie and they're like, we've spotted the culprit.

They're wearing a pink jacket. That's a very flamboying. jacket. So by the time the security guards get into the theater, that tripanosome changed their pink jacket out for a green one. And the security guards are like, hmm, there's no pink jacket here. Wait, who's that in the green? They look suspicious. And then that person slips into a different theater. And by the time the guards get to the next theater, they've changed their jacket again for like a cheetah print one. And the gods are like, look, there's no one here in pink or green. We're just going to give up. We're going to go get popcorn. It's like that. But,

But at the same time as this, the tripanosome is replicating, unlike me in a movie theater. Or you can think of it as like letting a bunch of their friends in with different color jackets. It sounds totally overwhelming. I know. Before you know it, our immune system literally just can't keep up. So we'll probably manage to kick out some of them that we're still wearing pink or green jackets, but the rest of them managed to escape our security cards. And that is how tripanosoma brucii, rudiziency, Gambian.

can establish an infection in our bodies. Okay. That is very interesting and that I feel like has a lot of implications for vaccines and therapies. Sure does, Erin. Sure does. Oh, boy. Okay. Yeah.

Yeah. It makes the vaccines very difficult, if not nearly impossible, because it's very difficult to stop the establishment of an infection. Yeah. This is so interesting. Okay. Yeah. I just want to keep gushing about how interesting this is also from an evolutionary perspective

because I think this really does kind of provide some insight into like if there are so many protein variants of the like so much antigenic variation. Right. Then this has to be like a long period of exposure to humans. Absolutely. Yeah. Wow. Okay.

Okay. Okay. Speaking of exposure to humans, T. Brusiya Gambiancy tends to be a primarily anthroponotic disease. So while this tripanosome can also infect animals, humans are the predominant reservoir. So it's much more common to have human-to-human transmission via, of course, the glacina fly. Tripanosoma brucei-rodisiensi is generally a zoonotic disease that's often transmitted from animals to humans, especially cattle, which are a very important reservoir. And that's just one of the differences between these two subtypes.

And we'll talk a little bit more in a minute about the differences in terms of their symptoms. But basically, the disease known as human African tropanosomyasis or sleeping sickness has two phases. The first phase is when the parasite is in the blood or the lymphatics and making its way into various organs. And then the second phase is when it invades our central nervous system and results in the symptoms that have given it the name sleeping sickness. And we will get there. But first, I want to talk briefly about the differences in the two subtypes, Gambiancy and Rhodesiancy. The disease itself, for the most part, is the same, or at least very similar between these two subtypes. But the big, big difference is that in Gambiancy, which again is the subspecies that tends to have humans as

the primary reservoir rather than animals, in this subtype, the disease course tends to be prolonged. That first stage might last months or even years, and it can be more mild and have vague symptoms. That's not to say that it's a mild disease because it's not at all. But the average duration of Gambiancy disease is about three years and there's a huge amount of interperson variability. So like in our first hand account, what was described was a very prolonged disease. But in some people, it might be a matter of months. On the other hand, disease caused by the subspecies rhodesiency tends to have a much faster and more severe course, where over a few weeks or a couple of months, people end up

very sick, progress to the second stage of disease, and usually die within six months if they're untreated. Wow. And for both subtypes of this disease, almost all of the accounts report that the disease is almost universally fatal if it's left untreated. But there have been a handful of case reports of Gambiency where people either recover or have like a self-cure, where they do actually recover from the infection, or of being relatively healthy carriers.

Okay, yeah. But that's the very minority. It's like a few case reports. Gotcha. In terms of the distribution, Rhodesiancy, the one with animals as the primary reservoir, accounts for about 5% of cases and is more prevalent in the eastern and southern parts of Africa.

And Gambiancy accounts for about 95% of cases and is more prevalent in the western and central parts of Africa. Does this is definitely jumping the gun, but does treatment work equally well on both of these sub-types? Nope. Nope. That is definitely jumping the gun and we'll get there. Okay. Yeah. So let's first talk about what this disease actually looks like in these two different stages. First stage of this disease is really pretty generalized symptoms. Usually there's fever. And this fever is often intermittent so it can last a day or, or it can last up to a week. It can come and go every few days or even every few months. Does that sound familiar at all, Erin?

It does. Malaria. It sounds like malaria. Yeah. So the symptoms can overlap a lot with malaria. And as you can imagine, that can make the diagnosis really challenging since the distribution of these two diseases overlaps. Yeah. Is there any sort of diurnal pattern?

because I know that like tsetzi flies have a, you know, behavioral pattern, like they're more active during the day than at night, for instance, right? And malaria is the same kind of thing. Like they're more active. They're more crepuscular, right? That wonderful word. Yeah, that's a good question. Not that I read. And I anticipate that because the mechanisms of the fever with malaria are a little bit more like very specifically associated with the parasites and the infectivity and that kind of a thing. So I think that's probably why you see more of that in malaria than you would in this, where it's a more generalized. Like you have fever for like a whole day or a whole week or something like that rather than like at certain times of day. Okay. It's a good question though. Other symptoms are equally general. Things like headache are very common, sometimes itching. You commonly can get swelling of the lymph nodes and it tends to be different lymph nodes and the two different subtypes of disease.

of disease. Hepatospillinomegaly, one of our favorite T-PWK-Y words. So swelling of the spleen and the liver. It can also cause abnormal menstrual bleeding or sometimes even spontaneous pregnancy loss just because of this kind of overwhelming infection. And this can kind of just go on and on, on and off, on and off, really. And it can do so for as long as it takes essentially to progress to the second stage of the disease, which is when the tripanosomes actually invade the central nervous system.

So the second stage is how human African tripanosomiasis got its name, sleeping sickness, but it's not all about sleep. Once this parasite invades our central nervous system, it can cause a huge range of neuropsychiatric findings. And histologically, it causes a very generalized encephalitis or inflammation of the brain and the central nervous system. So the findings, I mean, there are almost anything that you can imagine that has to do with the nervous system. It can cause tremors. It can cause motor weakness. It can cause ataxias or that like discoordinated motor movement that we've talked about in a few other episodes. It can cause behavioral changes that can range from anything from apathy to aggressive

behavior to psychosis or manic episodes. It can cause confusion and dementia. And all of these various symptoms progress with the severity of the disease. So they might start out as more mild and then continue to change and progress as this parasite still persists in the nervous system. How predictable are these psychological manifestations? As far as I read, not vary. Like it really can very person to person. Certainly the more severe the symptoms, likely the more severe the disease. Okay. And the later the stage. Now, the effects on sleep are very characteristic. And from what I can tell, and I didn't get like as good of a number on this as I really like to, like this percentage of people have the sleeping signs. But it seems like they happen in most cases if it progresses that far.

Okay. So the infection with this parasite results in changes to our circadian rhythm such that people end up with disruptions in their REM and non-REM sleep. So we have different cycles of sleep. Rem when we're dreaming and you have those rapid eye movements and then non-REM sleep. And what happens with tripanasomyasis is that your REM sleep happens at the beginning. Like you fall asleep and you have what's called sleep onset REM. Instead of REM happening after you have these periods of actually restful sleep, of non-REM sleep. And then you also have during the night episodes of wakefulness during the night, not being able to fall asleep, being up and active,

and then sleepiness and frequent napping or just falling asleep like very rapidly the way you would in something like narcolepsy during the day. It's not typically a complete reversal. Like some older descriptions say people will completely reverse their cycles and sleep all day and be awake all night. It tends to not be that black and white. But it is a significant disturbance in our circadian rhythm that normally regulates how we wake and sleep. That is so fascinating. I can't even handle how interesting it is.

and I will be completely honest. I read several really great papers about this. There's one from Nature 2018 that was called Sleeping Sickness is a Circadian Rhythm Disorder. It goes into a lot more detail about it. But I would not do it justice to try and, like, explain all of the nuances of sleep and then the effects that this parasite has on sleep. But it has a lot of hormonal effects where it, like, actually,

changes the hormones that our body produces that affect sleep. It's so interesting, Aaron. And despite all of this disturbance in sleep and disruption of our circadian rhythms, the total amount of sleep that people get is actually similar in people with severe tropanosomyasis and in healthy controls. Oh, interesting. It's just a different, it's like different times. A completely different pattern of sleep. Yeah. Okay. Why? Why does it do this? Great question. We still don't fully know, but we have a lot of clues. Okay.

So one clue is that tripanosomes tend to localize to parts of our brain, and like the places that they enter into our central nervous system, tend to be places that are like just outside our blood brain barrier. And many of those places are either responsible for or have a lot of neurons which travel through them that are involved in the regulation of our sleep-wake cycles, that are involved in our circadian rhythm. So tripanosomes localized to this part of the brain that allows them easier entry through that blood-brain barrier,

and it just so happens that those areas are involved in some way in our sleep-wake cycles. We still don't know exactly what it is about these parasites that causes these changes. What we do know is that it is, it requires two different things. It requires the presence of the parasite. It's not inflammation alone, despite the fact that inflammation is running rampant when you have this infection.

But it's not inflammation alone because we don't see this with other kinds of inflammation or in studies where they induce similar inflammation but without the parasite. But we're not sure if it's the parasite itself or something that the parasite produces that has an effect on our hormones and metabolites. But it's also not direct damage to our central nervous system, and we know this because these sleep disturbances resolve with treatment, which is really wonderful, really wonderful, and fascinating. So it's something about the parasite,

and its interaction with our immune system and our hormonal regulation that then causes this massive dismal, disruption, but doesn't cause any direct damage to the structures involved in our circadian rhythms. I have a hypothesis. Okay. Give it to me. This is, so this is not about the mechanism at all, but it's more about like the why this might be something that the parasite does. So if people are having sleep disruptions and they're napping more throughout the day, if they're infected with this, the day is when setsy flies are the most active.

And so if someone is sleeping, they're less likely to be able to fend off the flies, right? That's a really good point, Erin. Yeah. I wonder if that's... But why not have someone sleep all day? I mean, because evolution's not perfect. It's not. But that's a really good point, Aaron.

That's a really, really interesting way to look at it. There's so much more. I want to ask a thousand questions. There's so much. Reading all of this really made me feel like we need to, do an episode on sleep. Okay. Yep. Let's do it. We should probably do an episode on narcolepsy. Okay. Okay. So we've got a lot more learning to do. Yeah. And we have to do an episode on viviparous insects. Oh my gosh. I would love that. I feel like May Baron Baum would be so proud.

Oh my gosh. We'll have her on. So that is kind of the basics of the biology of this disease. how does the treatment work? Yeah. I was wondering if you were going to ask or if you just wanted me to bring it up again. So the diagnosis and treatment of this are both important to talk about and both leave a bit to be desired at this point.

And one thing that at least in the past has posed a significant additional challenge when it comes to human African tripinosomyasis is that historically, it was very important to distinguish between those first and second stages when you make the diagnosis, because the treatment was actually completely different if that central nervous system invasion had begun. And historically, as was briefly mentioned in our first-hand account, the treatment for late stage central nervous system associated disease was actually very gnarly for a really long time, very toxic medicine that caused really severe reactions in up to 10% of people and was really not a great drug.

Yeah. The good news is that very recently there is a new treatment option available that at least for tripanosoma brucei Gambiancy can be used to treat both stage one and stage two disease. And this means that not only do you have a medication that works and that works well, but it also means you don't necessarily have to distinguish between, has this parasite made it into your brain or not? Because that diagnosis is actually really challenging and there's not like a great, like perfect kind of gold standard to diagnose that essentially. And once someone is treated and recovers, they can become infected again, right? Far as I know, yes.

Okay. Yeah. Unfortunately. Yeah. So, yeah, that's the biology, Erin. It's so interesting. It's a lot. It's a lot. And I know that I missed a lot of parts. Don't worry. We have lots of papers. Aaron. I have so many questions. Okay. I will do my best to answer every question you have about the history, or at least what I know.

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And part of the reason for this change is because we've learned a lot more about the parasites and the vectors themselves and how the whole ecology of the system works, which has helped to fill in some of the picture of how sleeping sickness spread across the African continent in the late 1800s and early 1900s. But another big part of it is the gradual shift in what people have recognized as the primary drivers of these epidemics and in how they're, they talk about them. So because the history of sleeping sickness is so intertwined with the history of colonialism in Africa, and for a good chunk of time, the bulk of what was written about the disease was written by the people actively participating in colonialism, it can be hard sometimes to read through that imperialist rhetoric. Like, for instance, take human movement. Human movement did play a role in increasing the distribution of sleeping sickness in these big epidemics, but was it because people could move around more freely in the newly peaceful continent

thanks to the arbitrary partitioning by the European imperial powers? Or was it actually because people had to move around more to escape the violence, famine, and oppressive conflict that these colonists seem to bring with them? Spoilers, it's definitely more the latter than the former, but in a lot of the early texts, you're going to see a lot more of the former than the latter. Yeah. But I'm getting ahead of myself. And so maybe before we try to examine what actually went on with those sleeping sickness epidemics of the early 20th century, we should figure out maybe where these parasites came from in the first place. Yes, can we please?

Mm-hmm. Well, we can try. because I have kind of vague answers, but actually vague answers that became a little bit clearer with the biology section, which is pretty fun. Love it when that happens, Erin. Yeah. Okay, so let's start broadly with the group of tripanosomes that these two causative agents of human African tripanasomyasis are a part of.

And like you said, Aaron, you know, you made this distinction between the tripanosome that causes Shagas disease and how it's transmitted through the feces of the kissing bug, and these two subspecies that are transmitted through the bite of a setzy fly. So these subspecies that cause human African tripanasomiasis, these are known as salivarian tripanosomes. Isn't that fun? I love it. Yeah, because they're transmitted through the saliva of their insect vector. I don't know why that sounds like an alien life form or something. Salivarian. It sounds like a, yeah, like an evil character, evil-dienous character. Well, and then, you know, accompanied by Sterkerarian, which means transmitted through the feces. My other favorite word. Yeah. And so

the Salivarian tripanosomes, they are thought to have originated in Africa and split off from the other tripanosomes around 300 million years ago is one estimate I saw. So very long time. Long time. And when they split off, this is the point at which they probably became gut commensals or maybe even parasites of these early insects. And there they stayed in the guts in these insects for a very, very long time, which is how they got into setsy flies, who evolved around 35 million years ago. And by got into setsy flies, I really mean that they were probably there from the beginning, like they evolved. with these flies as the flies evolved. And it's not clear exactly when this group of tripanosomes began venturing out of their

fly hosts into mammalian animals. But it certainly doesn't seem to have been a recent development, considering that many African wild animals show a degree of tolerance towards SETC transmitted tripanosomes, suggesting like a long association. So in addition to tripanosoma, brucii, and that whole story, you know, that whole story, you know, species complex with those three subspecies, there are also a bunch of other species in the tripanasoma genus that cause tripanasomyasis in wild animals and especially domestic livestock. So anyway, I just wanted to throw that out there. I actually had no idea just how

many species there are. Like there's so many. So many. So many. And so the fact that a lot of these African wild mammals show a degree of tolerance towards these tripanosomes that kind of suggests this long association with those, right? Like you would expect that like, oh, the longer they were together, the more likely it is for them to evolve some sort of tolerance or resistance mechanism. And the same goes, actually, like you said, Aaron, for humans. So humans don't seem to be susceptible to those other species of tripanosomes that can call. cause disease in animals, which is fascinating. Because we're really good at just kicking him out.

Mm-hmm. And so I wrote in my notes that, like, maybe humans developed resistance or maybe these tripanosomes didn't evolve any sort of mechanism to infect humans. But it's clear now from what you said that the humans actually developed resistance. And it's thought that this happened when the early ancestors of humans came down from the trees and began to live in the savannah where they would have encountered these parasites. And this is supported in part by the finding that primates that mostly live in trees still are susceptible to these parasites that humans and other ground-dwelling primates rarely get infected

with. Wow. So they lack the tripanosome killing protein, which is so interesting. Oh, my gosh. Cool. And so like you said, Erin, this long exposure to tripanosomes has definitely left its mark on the human genome, right, with these tripanalytic factors that we seem to have. But, and this research is, I think, still a little bit under discussion. But I found it really interesting. So I wanted to include it. There seems to be variation even within those tripanalytic factors, right, with some being maybe more effective than others. And so there are two variants of a gene that seem to be especially common in people of African descent. And these variants seem to show signs of positive selection, meaning like they've provided some sort of evolutionary advantage.

And so they're at higher rates than we would expect them to be. And that's an interesting finding, considering that these variants are also associated with an increased risk of kidney disease. And so it seems, though, that a closer look at these variant proteins shows that they may be able to lice tripanasomes specifically tripanosoma brusiae rhodesiance. Huh. So it might be kind of like in the way that sickle cell trait and malaria has this sort of like, well, this is beneficial to protect against this disease, but it also in, you know, homozygous form might lead to an increased risk of other disease. That is very interesting. It's also

interesting in the context, and I didn't even get into this, but there are some slightly different descriptions of especially the early stages of the course of disease in people who travel to Africa versus people who live and were born in endemic regions. Interesting. And I wonder if there's any component of differences in selection for some of those specific different tripanismalytic factors that might. That's so interesting. Yeah. Again, there's definitely a lot more there and I think it's still in like early stages, but I will post the articles for sure. Yeah. Okay. So historically, these setzy flies associated tripanosomes, they probably had a wider distribution than they do today, reaching up at least into the Nile Delta, but they probably didn't make it to all the

places that Setsi flies did, given the fact that domestic animals still seem to be very susceptible to most of these tripanosomes. And so if there was like a global distribution of them, then we would expect to see, you know, more resistance or tolerance like we do in wild mammals in Africa. And I'm not sure what limited these historical tripanosome distributions, if anything, but there is evidence of setsy flies well outside of Africa. Like even here in Colorado. Really? Fossils.

Yeah. In the fluorescent fossil beds. Oh, so not active, but like in the past. In the past. In the past, yeah. And it's thought, though, that climate is really the big factor in where it's setsy flies can make their home, which does, you know, raise the question of future climate change and current climate change.

And sleeping sickness distributions. Okay, so that's a lot about the evolution of African tripanosomes in general, but what about the two subspecies that cause disease in humans? So I honestly couldn't find good timing on when this might have happened, but given that they seem to have this, you know, there seems to be like we're in the process of an arms race, I would guess it's like a pretty long amount of time, whatever that means. And honestly, I mean, the taxonomy and phylogeny of these two subspecies, it seems to be under debate or at least discussion. Okay, okay. Because tripanasoma brucei Gambience does seem to be distinct from tripanosoma brucei, brucei, which is one that does not cause disease in humans generally. But Rhodesiansei and Broussiye seem to be incredibly similar to one another, both morphologically as well as genetically. with one exception, and that is the gene that allows Rhodesianca to infect humans.

Oh, wow. Yeah. And so this has led to questions about whether Rhodesiancée could be just considered a variant of tripanosoma brucii-brusii that has an increased host range. Oh, man. Right? So if you look at it in just the picture of host range and we're like, oh, this can infect X, Y, and Z species. Right. And this can infect WX, Y, and Z. Like, does the W matter? And it does in a public health sense for sure. But it's just an interesting way to frame it, I think. Right. But does it qualify as a different subspecies or not? Right.

Oh, that is interesting, Aaron. Yeah. So it's possible that we'll see some reshuffling and rearranging of the taxonomy or phylogeny or whatever of these parasites and the. future, but not just because the evolutionary relationships don't seem to be represented in their current arrangement. Because there's also been some discussion recently about decolonizing the species' name tripanasoma brucii-rodisiense. So like tripanosoma brucei Gambiansei, Rhodesianse was named after the region it was first found, Rhodesia, which is a historical region in southern Africa, which got its name after white

settlers began calling it that informally after Cecil Rhodes, the British mining magnate and managing director of the British South Africa Company and also owner of many diamond mines and the De Beers Diamond Company. Rhodes was born in 1853, and I'm not going to go into the biography here. There's plenty on, I mean, just skim Wikipedia and you'll get the feel. But he essentially, long story short, turned out to be a huge white supremacist and imperialist. And over the past few decades, there's been an increasing push to remove statues of him or his name from buildings or scholarships named after him. And in 2021, a paper also called for the renaming of the parasite that bears his name. And I think it's an interesting conversation because, you know, we've talked about so many times on this podcast how names have meaning and power.

And I think it's good to reexamine why we name things the way we do and whether there are less harmful. or more accurate names that could be used instead. And the authors make the point that if tripanasoma brucii-Roudizience is just a variant of tripanosoma brucei-Brusi-Brusi, then might it be most accurate to just completely strike out Rhodesiensei and just call it tripanoma brucei-I-Brucii? I don't know. Problem solved. I'll post that paper also on our website if you want to read more, but I'm going to move on

for now. So I've mentioned that although we don't know exactly when humans began getting sleeping sickness, it's probably been around for thousands and thousands of years. And, you know, we can see this in some of the longstanding practices that many people in Africa used to avoid conflict with the tsetse flies. And it's also reflected in early writings, one of which is from 1373 or 1374 CE, describing the death of the king of Molly. Quote,

He told me that Jata had been smitten by the sleeping sickness, a disease which frequently afflicts the inhabitants of that climate, especially the chieftains who are habitually affected by sleep. Those afflicted are virtually never awake or alert. The sickness harms the patient and continues until he perishes. He said that the illness persisted in Jata's humor for a duration of two years, after which he died in the year 775, which is actually like 1373. Sleeping sickness gained more European recognition as the slave trade began.

Medical officers who were supposed to inspect enslaved people noticed certain signs and symptoms of the disease and also how deadly it could be. In 1742, it was described in an article about the neurological symptoms as a, quote, sleepy distemper. And in 1803, the English physician Thomas Winterbottom published a report describing how the lymph glands on the back of the net were often swollen from this disease, which is something that would later be called Winterbottom sign. But even according to Winterbottom, this was not a new discovery, because apparently Arabian slave traders would use those swollen glands in the past to determine whether or not to buy an enslaved person.

So despite the recognition by some of these early physicians that this disease was not new, the prevailing notion during the beginning of the enormous imperialist efforts in Africa was that this was a sporadic disease that African people knew nothing about and had never seen before. Right? But like all you had to do was just ask, but you know, who was going to do that? Not only had this disease been at least present throughout big chunks of the continent for thousands of years, there was actually quite a bit of knowledge about it, of course, and about animal African trapanasamyasis as well. For instance, it was known that traveling with livestock through certain regions during the day, it shouldn't be done because that's when setsy flies were active, and it was better to travel at night.

And this is actually what the explorer David Livingstone was told in the mid-1800s during his travels. And of course, there were many different names for the disease. And knowledge and practices to prevent the disease varied across different populations as well, such as like setting intentional fires to clear areas of flies and the animals that they fed on, simply avoiding infested areas, or isolating people with sleeping sickness. But however sleeping sickness was traditionally kept at bay, or at least kept relatively at bay, all of those structures and practices essentially broke down or collapsed, beginning with the widespread European colonization that began in the late 1800s.

And the consequences of this for sleeping sickness were horrific. So I'm going to focus on the two big epidemics of sleeping sickness that occurred in Africa in the early 1900s, one in the Congo Basin and the other in parts of Uganda. Between 1896 and 1906, these epidemics killed over 500,000 people in the Congo Basin, and 250 to 300,000 people, which is about a third of the entire population in the affected area, in Uganda. Yeah. So what caused these epidemics?

What did we learn from them? What were some of the lasting impacts? And I'm going to try to answer these questions, starting with what researchers believe led to this surge in sleeping sickness. Unsurprisingly, it was really a combination of many different factors. There was famine, wide-scale movement, often forced, landscape alteration, and rinder pest. Rinder pest. Rinder pest. And all of these were either directly caused by or exacerbated.

by the increasing colonialism that was going on. In the late 1800s, European colonialism was in full swing, and the so-called Scramble for Africa had begun, kicked off especially with the Berlin Conference in 1884, where basically the European power sat down and they were like, all right, who wants this chunk of the continent? Who wants this? Okay, you get this part of East Africa,

you get this part of West Africa. And so you have like Britain, France, Germany, and Portugal, as some of the major players, you know, deciding who gets what. And a lot of East and West Africa had been sort of partitioned off. But much of Central Africa was still viewed as being up for grabs. And so King Leopold the second of Belgium, he threw his hat into the ring. And he didn't want to claim this big bit of the Congo Basin for Belgium necessarily. Like he didn't want to make it a colony, but he wanted to keep it as a private, free state where he didn't want to. He didn't could sort of be the unquestioned ruler and make as much money as he possibly could,

and also to keep trade open between Western and Eastern African states. And so I mentioned Leopold and the Congo Free State in particular, because this is where that deadly epidemic occurred, and because it provides such a clear example of how sleeping sickness was spread, not because the European self-proclaimed saviors made peaceful movement possible, but because the brutality in violence that was perpetrated by these colonial powers, it drove the disease to be more widespread and prevalent. So to set the stage for sleeping sickness, I need to start with another disease.

Rinderpest. Rinder pest. By the late 1800s, Rinderpest, which is a cattle disease, it's a virus, it's a virus that kills cattle, like kills ungulates, and it's viciously deadly. It's horrific. We did a whole episode on it. When was it? Season two?

Season three. Season three. Check it out. It's been eradicated, but it's, yeah, check it out. I'm going to go over a little bit of the, just like, a brief, you know, listeners digest, but because it's important to go into here. And so in the late 1800s, Rinderpest was brought to, Ethiopia, and from there, it spread south rapidly across the continent. And it killed, I mean,

millions and millions, just unfathomable numbers of cattle and wild ungulates. In some places, like 95%. Just wiped them out. Wiped out. And in our Rinderpest episode, I talked about how the spread of rindermest was in some places accompanied by a drought and then extreme rains, bringing locusts that ate all the crops. And so by the mid-1890s, you've got this combination of livestock deaths, wild ungulate deaths, and crop failure that leads to a horrible famine in many regions. And we know from our typhus episode how times of famine leave people super vulnerable to many infectious diseases. The loss of cattle, which for many people was either entirely or at least a huge part of their livelihood meant that people had less autonomy and they had to turn to other

ways to survive in these colonial states, like working in deadly mines or harvesting rubber. This shift in labor wasn't always voluntary. In Leopold's Congo-free state, people were forced, threatened with death or mutilation, either of themselves or family members, if they didn't work or fill their quotas. As I mentioned in our Rinderpest episode, this panzoate was used by European colonial powers to extend their reach. And what they didn't accomplish in that regard through Rinderpest, they would with sleeping sickness. So at the end of the Rinderpest epidemic, around 1896 or so, the social, political, and natural landscape of much of Africa had changed substantially. Famine was widespread.

More and more Africans had been forced to work in mines or collect rubber and not do subsistence farming. and the wild ungulate population had nearly disappeared, along with domestic cattle. And at first, this could be viewed as a good thing in terms of sleeping sickness, because with the absolute annihilation of so many hosts, Tetsi-fly populations dropped. But then, as the forest recovered and wildlife came back in, and as people began to bring livestock and settled into these newly Tetsi-fly free zones, places where they couldn't before because of the risk of animal African tripanasomyasis, that setsy flies then recovered.

And they did so to a huge extent. And when they came back, the setsy flies found ample mammals to feed on, and their tripanasomes found plenty of hosts to replicate and differentiate in, including humans. So it's not a coincidence, really, that the sleeping sick, epidemics began as the Rinderpest panzoatic ended. But it wasn't just that Rinderpest suddenly meant that humans and Setsyflies and trapanasomes were in contact more than they had been before. There was also the aspect of human movement. And this wasn't done just by Rinderpest either.

In the Congo free state, as I mentioned, Leopold had established a rule that was motivated by the ruthless pursuit of economic gain. Any resistance was met with extreme violence, burning villages, outright slaughter, holding women and cattle hostage. So many people fled the brutality or had to travel farther and farther from their village in order to find enough wild rubber to meet this rubber tax that had been imposed on all of them. It was demanded of each person. You don't pay the tax, I'm going to chop off your hand, or just kill you, or chop off the hand of your family member. So they would be spending 21 to 25 days per month in the forest, far away from home, and in excellent Setsi Fly habitat. There's a lot more to the story of the Congo Free State and

Leopold, and I highly recommend reading the book Leopold's Ghost. But to sum up, it's estimated that 10 million people died in what was first the Congo. free state and then later the Belgian Congo under Leopold's reign. That was about half the population. Ten million people died. And they died due to these violent practices due to famine and due to disease and then also due to just like a drop in the overall birth rate because people were, you know, not able to. Yeah. Just. Yeah. Oh dear. There's a lot more to unpack there that I just. don't, I can't do it justice here. Yeah.

But yeah, sleeping sickness did contribute a substantial amount to that, you know, horrifically enormous number. But the Belgian Congo wasn't the only place where colonial rule led to forced labor and forced movement. Uganda was under British rule during the big sleeping sickness epidemic that affected the Boussoga region along Lake Victoria. And they had put into place a so-called high. hut tax, where each household had to pay a certain amount in taxes, and that was often more

than the building could actually be sold for. This need for cash shifted labor away from subsistence farming, and if someone couldn't pay the tax, they would have to do a month's labor, usually far away from their village. So it was just like, suddenly here was stress and movement and disruption and like a complete lack of autonomy and everything was just, yeah. And so how much did these movements contribute to the geographic spread of sleeping sickness and any changes in its distribution? And it's not really clear. So historically, it was thought that sleeping sickness was brought to East Africa from the Congo Basin,

but now people suggest that the parasites, both subspecies, had probably been present everywhere the vectors could be found, and it just appeared to spread because of the rapid jump in cases. And I should also point out here that these epidemics have long been thought to be caused by the Gambianse subspecies, but more recently some researchers have said, oh, actually, maybe the Uganda one was Rhodesianse because of the clinical picture. Okay. Okay, so the combination of the ecological cascades of Rinderpest. increased movement under colonial rule and the huge amount of stress from famine and brutality

led to a situation where the Tse fly and its sleeping sickness parasites could flourish. Okay, so now let's see what happened once sleeping sickness had awakened in Uganda and the Congo free state in the late 1800s. European imperialists had long seen much of Africa as being held back by disease. But what that really meant, if you read between the lines of rhetoric, was that they felt that disease was preventing Europeans from taking control of the continent and exploiting people in resources the way they wanted to. So quionine, which was introduced in the 1820s, was helpful for treating malaria, but there were still many tropical diseases for which there was no treatment or cure. And not long after the birth of germ theory in the mid-1800s, researchers began to specialize in studying pathogens and parasites that were found in tropical regions of the world, many of which happened to also be targets for colonialism. And I think I've discussed this before

in our Leshmaniasis episode or maybe our schistisomyasis episode. I didn't look back. I might have mentioned it in both. But the field of tropical medicine was motivated in large part by protecting the financial interests of European colonial powers and the health of Europeans in those colonies. So when sleeping sickness began to appear in large numbers, there was this big push to try to understand what was causing it and how it was transmitted so that its spread could be stopped or at least slowed. Microbiologists and parasitologists flock to the shores of Lake Victoria or to the Congo Basin to try to make a name for themselves. Robert Koch was one of these, and another John Lancelot Todd, who would later join this Liverpool expedition to study the disease in the Congo Free State, wrote home, quote, trips are a big thing, and if we have luck, I may make a name yet. There was even a poem published around this time in the British satire magazine Punch about sleeping sickness. Quote, men of science, you that dare, beard the micro,

in his lair, tracking through the jungly thickness, Afriks germ of sleeping sickness. Here, oh here, my parting plea, send a microbe home to me. Send a microbe home to me. Isn't that what we all write? Yeah, of course. But many people did send a microbe home, or at least find luck with tripanosomes. The Scottish microbiologist David Bruce first observed one of the causative agents of Nagana and cattle in 1895. Six years later, in 1901, British colonial surgeon Robert Michael Ford identified

tripanosomes in the blood of a steamboat captain in the Gambia. Actually, he thought they were worms at first. And a few months later, English physician John Everett Dutton was like, no, man, these are definitely tripanosomes. I'm going to name them tripanosoma Gambianse. They were all thought to be the three tripanosoma brimps. Rusei, Gambiance, and Rhodesianzzi were all thought to be separate species at the beginning. The next link was made that same year in 1901 when Italian physician Aldo Castellani observed tripanosomes

in the cerebrospinal fluid of people with sleeping sickness and said, hey, these might be the cause. And the last pieces of the puzzle fell into place when the setzy fly was found to, yes, indeed, transmit. these tripanosomes that cause sleeping sickness. In 1910, finally, the other subspecies of tripanosome that causes sleeping sickness, Rhodesianca, was identified by John William Watson Stevens and Harold Benjamin Phantam. And a bunch of other animal tripanosomes were discovered in the meantime. But these efforts in tropical medicine, they weren't just about identifying the parasite and the vector. They were also about treatment. Robert Koch, and Paul Aarlich, whose names certainly should sound familiar.

I would hope so by now. They had a hand in the development of the first drugs used to treat sleeping sickness around 1905. The first of these drugs, whose name was atoxal, meaning non-toxic, was arsenic-based, and often led to death in about 5 to 10 percent of the people who were treated, and blindness in about 30 percent. The amount you needed to inject into someone to have an effect on the parasitic infection was about the amount that someone could handle without just dying outright. Yeah, the arsenic-based compounds were used for until relatively recently. Oh, yeah.

And are still used for rhodesiancy. They are still used. They are less deadly. They are less deadly. But that's not saying all that much. No. Like, they're not good. So what did people do with this new knowledge about sleeping sickness and a deadly drug to treat it? Well, it partly depended on where you were. Both colonial powers, of course, use the declaration of an epidemic as a tool to gain even more power. But specific disease control efforts differed in Uganda and the Congo-free state with a more ecological focus, control the Tse-fly, in Uganda,

and a more human focus control the human reservoir in the Congo-free state. What did this mean in practice? In Uganda, it meant often the burning of setzy habitat, the destruction of tripanosome animal hosts, and the forced relocation of people away from sleeping sickness-infested areas, in particular the shores of Lake Victoria. There was some identify and isolate, but not nearly as much as there was in the Congo-free state.

There, Leopold had commissioned a survey of the entire country to create a map with labels of uninfected and infected regions. Armed soldiers patrolled the borders of uninfected zones, and the movement of people in and out of the zones was strictly controlled. On top of this, there were enormous efforts made for public health teams to go out and find every case of sleeping sickness. And the easiest way to do this was to see if the glands on the back of their neck were And if someone was determined to be infected using this incredibly subjective method and not

necessarily accurate, they were sent, sometimes forcibly, often forcibly, to a lazarette to receive treatment or just weighed out their illness. These lazarets were basically like kind of prisons in a way. Like you weren't allowed to leave. You weren't really allowed visitors often. and you were kind of just told, wait here and die. They were poorly staffed, medical treatment was not at all guaranteed, and a lot of the time neither was food.

They became known as death camps, and at some of these camps, mortality rates reached 25 to 30 percent. Even one of the doctors who worked at one of these Lazarettes said that a sign should be put up on the entrance that said, abandon all hope. who enter here. Aye, aye, aye. Mm-hmm. So did these interventions do anything, like the burning of habitat or the identification of human

hosts? I mean, it's possible, yeah? I mean, we don't really have any way of measuring now how much of the decline of the sleeping sickness epidemics was due to the availability of treatment or the destruction of habitat or any ecological shifts or something else entirely. But even though cases dropped by 1910 or so, sleeping sickness didn't just cease to be a problem. And the way that the ruling colonial powers handle these epidemics paved the way for future efforts, particularly in how public health services were organized.

So historically, public health in European colonies in Africa meant health services for European residents only. And sleeping sickness marked a turning point where administrators realized that they needed to extend those services to Africans as well as Europeans. Maybe partly due to like a humanitarian intention. I can't rule it out entirely. But it was also the simple matter of labor. As more and more people became infected with the tripanosomes, that meant fewer and fewer people who could be forced to labor at the mines or deliver the rubber or maintain the rubber. roads. The sleeping sickness campaigns, which were really the first of their kind in parts of Africa, were aimed at preventing or controlling this one disease. And that kind of set the

pattern for future health services to also be pretty targeted. And this is what's called a vertical health service approach. So with these vertical health services already in place, where it's like, okay, one program, one disease, it's harder to transition to something that's more broad or integrated in its organization. And so you end up with a bunch of these individual programs that may not really talk to one another and may end up being inefficient or even neglectful of certain things. And the legacy of this is still being felt,

and it's part of the conversation that goes on today about some current disease or eradication campaigns that tend to be very targeted. But going back to sleeping sickness and wrapping up very quickly, after these two big epidemics, incidents of the disease did seem to go down, though both World Wars saw a bit of an increase, especially as movement for more rubber and resources increased. The widespread use of DDT led to further declines and the Tse-Fly populations as well as in tripanosomes. And so the overall trend in the first half of the century after these big epidemics was one of a general decline in sleeping sickness. However, in the second half, cases began to rise again, usually following political upheavals and

conflicts that led to the displacement of many people and the breakdown of medical infrastructure in countries, many of which were newly independent. And by the 1970s, there was another big epidemic over one million people happening in Angola, Congo, Southern Sudan, and the West Nile District of Uganda. Since then, there have been other improvements in treatments for this disease and a lot of incredible accomplishments in actually eradicating it from certain regions. But the story of sleeping sickness definitely doesn't seem like it's over, especially with land use change and climate change happening. So, Aaron, can you fill me in on what's going on with sleeping sickness today? I can't wait to, Aaron, right after this break.

Well, Erin, like you alluded to, we finally get the chance to end on a semi-happy note this season. Ooh. I know. So, World Health Organization, along with many partners, has been targeting sleeping sickness or human African trupinesomyasis for control. And then they change their targets to elimination as a public health problem by 2020 and further reduction. and towards total elimination by 2030. Okay. And they've gotten shockingly close.

They really have. Really shockingly close. So after the kind of historical outbreaks that you mentioned, Aaron, there was lows of tripanasomyasis for a while. And then another resurgence in the 90s that resulted in World Health Organization and other public health institutions really focusing on. trip anisomyosis even more. And it's been really effective. In 2009, the number of reported cases fell to below 10,000 for the first time since the 1960s. Wow. Right? Below 10,000 reported cases worldwide.

And in 2019, so 10 years after that, there were only 992 cases reported. That's amazing. It's incredible. Now, does that mean that only 992 people were affected? Certainly not. Underreporting is, of course, a factor as in any disease, but especially in neglected diseases. And especially for a disease such as sleeping sickness that largely affects remote populations. But the efforts that have been made to identify and treat cases have been phenomenal. So screening of about 2.5 million people takes place annually, and that number hasn't really changed. So this drop in cases between 2009 and 2019 is with the same intensity of screening, if that makes sense. So it's a true drop, even though underreporting exists. That's great news. It's incredible. Now, all that good

news being said, it is estimated that 65 million people live in areas that put them at risk for human African chrysanomyasis or sleeping sickness because they are within the distribution of the Tzzi fly. And of course, climate change, displacement, political unrest, natural disasters, land use change, etc. The list goes on. Global respiratory viral pandemics, for example. No big deal. all of these things certainly threaten not just the distribution of this disease or the burden of this disease, but also threaten the surveillance and treatment infrastructure. And on top of that, we don't fully understand the role of wild and domestic animals in the transmission cycle

or of potentially latent or longstanding infections in humans and how that might affect like elimination long term. elimination goals. So I will link to an interesting mathematical modeling paper that was kind of trying to look at these two aspects of it, the latent infection in humans and these kind of silent reservoirs or more rare animal reservoirs, especially for Gambiense, human African trapanesomyasis, which is largely a human reservoir disease, but can be found in other animals as well. And just looking at those two factors in the context of these efforts towards elimination. The paper didn't really have any solid answers, but it just kind of underscores the importance of having a better understanding of these different reservoir populations and that we have a lot to learn, but we've

come such a long way. Yeah, we have. That's amazing to think in 100 years how much progress has been made in terms of actually helping people. And even between 2009 and 2019. Like, what? It's amazing. That is. Diagnostic testing still does leave much to be desired, and that's one of the problems, even with all of these screenings in place, that actually becomes even more important as prevalence of this disease drops, because the tests essentially become a little less reliable, the more rare a disease is in the population. And so having access to very accurate, but also rapid and easy to use testing is really important, and that's still an area for improved research.

Okay. But like I did mention, we have had massive developments in the last just few years for treatment. So the new guidelines that were published in 2019 included a treatment that not only, like I mentioned, can treat stage one and early stage two disease when it's caused by Gambiancy, but it also is an oral medication. And that's the first time that there's been an oral medication that doesn't have to be either an intramuscular injection

or an IV drug, which are, of course, a lot more difficult to administer. That's the first time that that's available for a tropanosomyosis. So that's another really big step. That's huge. But lots of progress has been made in a relatively short amount of time. And that's something to be glad about. Agreed.

Yeah, that's sleeping sickness, Erin. And if you want to know more, you don't have to wait all that long. You just have to wait one week to hear so much more about the drugs that are used to treat sleeping sickness and how we actually get them to the people that need them. It's going to be a very fascinating bonus episode, so put it on your calendars. I am really excited about it. I can't wait. Should we do sources? We should. We should do sources.

Okay. I have a ton. I'm going to shout out just a few here that I highlighted and used heavily. So one is by Marinez Lyons. It's a book called The Colonial Disease, a social history of sleeping sickness in northern Zaire. And then a few papers that I found really helpful. One is by Steve Ridding from 2008 called The History of African Trapanosomyasis. Another is by Balmer at all from 2011, phylogyography and taxonomy of Tripannosoma, Broussi.

And finally, by Hedric from 2014, sleeping sickness, epidemics, and colonial responses in East and Central Africa in 1900 to 1940. Excellent. I had a number of papers, a few different Lancet reviews, one from 2010 and then an update from 2017. another review paper that was in the Lancet Neurology 2013 that was more about, it was titled Clinical Features, Diagnosis and Treatment of Human African Trapinosomyasis, a few years old, but still had a lot of good information in there. Two of my favorites about the kind of neurologic and circadian rhythm effects were diagnostic and neuropathogenesis issues in human African tropanosomyosis, and that one I mentioned already, a sleeping sickness as a circadian disorder from Nature Communications 2018.

Really, really loved those ones as well. We've got a lot more sources from this episode and every one of our episodes on our website, this podcast will kill you.com. Have you checked it out yet? If this is the episode that we finally got you to check it out, I want to know. Also, there is one more source that I forgot to mention. And it's a video about this new or. pill for sleeping sickness. And it's so wonderful. It's beautiful. It's on YouTube. We'll post a link. It's

called A Doctor's Dream, A Pill for Sleeping Sickness. And it's, again, by the Drugs for Neglected Diseases Initiative. Awesome. Thank you to Blomobile for providing the music for this episode and all of our episodes. Thank you to exactly right. And thank you to you, listeners. We hope you found this interesting and informative and you learned something new. Extra thank you also to to our patrons, like we can't even express in real words how thankful we are for you. It's true. Well, until next time, wash your hands. You filthy animals!

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