This Podcast Will Kill You - Ep 62 Leishmaniasis, Relationship Status: It's Complicated

Episode Date: December 15, 2020

The neglected tropical disease known as leishmaniasis is really more of a collection of diseases caused by a variety of parasites transmitted through the bite of a diversity of sandfly species. Sounds a bit complicated? You’re not wrong. But have no fear. Because in this episode, we walk you through the ins and outs of leishmaniasis. From the biology of visceral vs cutaneous vs mucocutaneous leishmaniasis to the archaeological and modern history of these parasites, we give you the basics on one of the most globally prevalent parasitic infections. See omnystudio.com/listener for privacy information.

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Terms and conditions apply. Visit blueapron.com slash terms for more information. I'm Amanda Knox, and in the new podcast, Doubt, the case of Lucy Letby, we unpack the story of an unimaginable tragedy that gripped the UK in 2023. But what if we didn't get the whole story? Evidence has been made to fit. The moment you look at the whole picture, the case collapsed. What if the truth was disguised by a story we chose to book?

Oh, my God, I think she might be innocent. Listen to Doubt, the case of Lucy Letby, on the IHeartRadio app, Apple Podcasts, or wherever you get your podcasts. This is Special Agent Regal, Special Agent Bradley Hall. In 2018, the FBI took down a ring of spies working for China's Ministry of State Security, one of the most mysterious intelligence agencies in the world. The Sixth Bureau podcast is a story of the inner workings of the MSS and how one man's ambition and mistakes opened its fault of secrets. Listen to the Sixth Bureau on the Iheart Radio app, Apple podcasts, or wherever you get your podcasts. On one burning day in April in a village in Bihar,

Susheila Devi was worried about her sick child. Her decision to seek medical help required brave determination. There was the overpowering heat through which she would have to walk, carrying her sick child most of the eight miles to the government health center. The child was ill, but not emergency ill in any of the too familiar life-threatening ways, the acute fever and coma of childhood malaria, the rapid wasting diarrhea and death of cholera, or the labored gasping of pneumonia. It was merely that the child seemed somewhat feverish this past month and was becoming emaciated, despite a reasonably good appetite, with a distended abdomen. The young doctor was brusque, unfriendly, and uncommunicative. He told Susceola to put her frightened child on the bare wooden

examination table. To the doctor, the constellation of science and symptoms could point to only one diagnosis. The prolonged fever, the greatly enlarged liver and spleen, the anemia, the serum that gelled when mixed with formaldehyde, all meant visceral luschmeniasis. Realizing the gravity of what he was about to tell Suscella, his pomposity fell away. Mother, he said gently, your child is very ill with Kala Azar. It does not mean death. Your child can be cured. You must buy medicine. Then you must come here every day for 20 days so the nurse can inject the medicine. How much is it, Susheila asked fearfully. For you, I will give you a bottle of the drug, enough for her whole treatment, for 300 rupees, about $15. It was an astronomical sum,

more than the family's income for some months. Suscella picked up her child and began the long walk back to her village. Even if by some miracle they could buy the medicine, there was no way that Susceola and the child could travel these long miles to the health center for 20 consecutive days. No, for the child they would have to do the best they could. They would pray to the gods. They would consult the doctor in the adjoining village. In the end, as the weeks passed, the child became progressively more ill. She grew even more emaciated. Her skin turned a dusky gray. Her hair became brittle. Small bleeding sores covered her body, and the abdomen, burdened with a grossly enlarged liver, distended even further. One day, some three months after Susheila's visit to the health center,

the child began to cough and gasp for breath. During the night, the little girl died, a fragment of life sacrificed for want of $15. That was rough to even read out loud. Yeah. That is from a book called The Malaria Capers by Robert S. Desowitz. Hi, I'm Aaron Welsh. And I'm Aaron Alman Updike. And this is, this podcast will kill you. It is. It's a depressing one today, Aaron. I mean, when are they not? Yeah. Could we ever, like maybe one time this season we could find a not depressing one? Sure. I don't know. We could try. We could try.

Oh, gosh. So, as you may have guessed, this week we are covering leshminiasis, which includes not just visceral leshminiasis, as described in the first-hand account, but also cutaneous and mucocutaneous leshmaniasis. It sure does. It's a lot more complex of a story than I think we realized. Really, really complicated, a lot more than I ever knew. So it was good to learn this stuff, but also, oh my gosh, I hope that I do it even a shred of justice.

I trust you. Oh, gosh. I trust you. Well, Erin, I think we have a couple pieces of business to take care of, or at least one. Yep. Is it that it's, let me check, quarantini time? It is indeed quarantine time. You are absolutely exactly right.

What are we drinking today, Aaron? Today we are drinking a sandfly in the ointment. A-o! So named because this is a disease transmitted by sandflies. And in sandfly in the ointment, there is lime juice, grapefruit juice, some simple syrup, all-spice liqueur. So I finally get to use that stinking all-spice liqueur that's been on my shelf for ages. And some rum. Yum. Yeah. And we will post the full recipe to the quarantini as well as the non-alcoholic placebo-rita on our website. This podcast will kill you.com as well as all of our social media channels. So check it out there.

Yeah. Any other business that we have? I don't believe so. All right then. Shall we just dive in season four, episode two? Oh my gosh. 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 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.

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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. It's non-greasy,

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Unfortunately, it didn't go according to plan. He became the first Bachelor to ever have his final rose rejected. The internet turned on him. If I could press a button and rewind it all I would. But what happened to Clayton after the show made even bigger headlines. It began as a one-night stand. and ended in a courtroom with Clayton at the center of a very strange paternity scandal. The media is here. This case has gone viral.

The dating contract. Agree to date me, but I'm also suing you. Please search warrant. This is unlike anything I've ever seen before. I'm Stephanie Young. This is Love Trapped. This season, an epic battle of He Said She Said, and the search for accountability in a sea of lies. Listen to Love Trapped on the IHeart Radio app, Apple Podcasts, or wherever you get your podcasts. So like we mentioned already, the biology of this disease is quite a lot.

So I tried really hard, which is the opposite of what I normally do in my notes. I tried to really keep this organized so that we can go through it in a way that makes sense. Okay. So let me just go ahead and get started. All right. So Leschmeniasis, like you mentioned already, Aaron, it's not just a single disease. It's a group of at least three different disease syndromes, which are caused by a number of different species of protozoan parasites in the genus Lesh Mania. It's kind of interesting that like they're all, like when we say Leshmaniasis, it's like. It means all of them. It means so many different types of diseases and so many different. like caused by so many different species of parasites.

Yeah, like over 20. It's a little over simplification. Yeah. Yeah. I can't believe that we call this all the same disease, quite honestly. It blows my mind. I mean, historically we didn't, but we'll get to that anyway. Oh, great. I can't wait.

That makes a lot of sense, actually. Okay. Yeah. So at least 20 different species of protozoan parasite transmitted by a whole number of different species of insect vectors. In this case, like we said, we're dealing with. a new type of insect vector that we haven't dealt with on the podcast before, and that is the sandfly. Yeah, this is our first new vector. Yeah, we've only done mosquitoes and ticks so far.

How interesting, I didn't realize that. Yeah, so that's fun. So sandflies, for anyone who's not familiar, they're another sort of biting fly. Similar to mosquitoes, it's primarily the females who take blood meals, whereas both males and females also feed on like floral nectar and sugar water. So in this case, we're talking about sandflies in two different genera, leutsomia, and phlebotomus. Okay. So so far we have over 20 species of parasite and two whole genera of sandfly. Okay.

It's a lot. Uh-huh. It's going to get to be more because Leshminiasis affects humans, which is what we're going to talk about today. but it also affects like at least a hundred other mammal species. So in addition to different forms of the disease that we see in humans, there are different cycles of the disease. There's a zoonotic cycle of disease wherein humans become infected from vectors that got infected from animals, so from animal to vector to human.

And then there's also anthroponautic cycles, wherein humans are the dominant reservoir host, and humans are infecting other humans through a vector. And it's not just mammals, right? Isn't it also reptiles? I think that reptiles and some birds have been known to be infected. How much of a role they really play in the zoonotic disease in humans is pretty minimal as far as I know. Yeah, I don't think they do, but I think it is just amazing the sheer number of species. I know. And different, like very different groups of animals that these parasites can infect. Bananas, truly. So yeah. Okay. That's a lot.

already. So for this biology section, because that's so much, we are really going to focus on the disease or the three big disease states of luschmeniasis in humans. I'm not going to touch on luschmeniasis in animals because it's just going to make things more complicated. So let's get into this disease by going over the parasite life cycle, which will tell us how it's transmitted, and then we'll talk about how we see the disease manifest in humans, okay? Sounds great. So, Lechamania species, the parasite that causes Lechmeniasis, like plasmodium parasites that cause malaria or tripanasoma parasites that cause Shagas disease,

are a eukaryotic single-celled parasite that has multiple different, distinct life stages in their different hosts, whether a mammal or reptile, and insect. In the case of Lechmaniasis, they have two different forms, the A. Mastigote and the pro-mastigote. One is a little ball that lives inside of ourselves, and one is a cute little kind of sperm-y-shaped thing. I guess maybe that doesn't sound cute, but it is, with a little flagella tail that can swim. Okay, so a Lesh Mania life cycle goes something like this. A sandfly takes a bite of an infected animal host, ingest a blood meal that contains the amastigote form of the parasite. Those parasites travel through the gut of the sandfly, transform into the promastigotes, which have that flagella

and can swim. And those parasites continue to divide. They make their way out of the gut of the sandfly and into their proboscis, which is the biting part of the fly. And then when that sandfly takes another blood meal, those parasites are regurgitated into that new host. In that host, let's say it's a human, since that's what we're talking about, those promastigotes, which are swimming, are taken up by our white blood cells, mostly are macrophages, which we've talked about a lot on this podcast. Those are a white blood cell that usually helps clear infection by like engulfing bacteria and parasites and killing them. Turns out in the case of Lechmania, when a macrophage ingest it, that's actually where they become amastogotes and then continue to divide and reproduce.

Yeah. So how do they avoid death? Oh, such a good question. Aaron, I wish that I had a full good answer to that. So Lechmeniasis is a disease of what's called the reticulo-endothelial system. So that means that it infects and replicates white blood cells, especially macrophages, and then affects, in theory, any organ where those white blood cells tend to congregate. So the exact mechanisms by which it evades our immune response are really, really complicated to kind of sum it up in the simplest terms that I can. Gosh. Is it basically suppress the immune system overall?

Exactly. It suppresses our immune system and how exactly they're able to survive inside of macrophages, I don't fully know. But by living inside of macrophages, they evade any other of our immune responses. Okay. That makes sense. So very sneaky and smart. Very, very sneaky.

Okay. And overall, we know that infection with Lechmeniasis, it causes our body to mount an immune response. Like, we make antibodies to it, but those antibodies don't do much. It turns out that to develop immunity towards Lechmeniasis, it's more about cell mediated. So you need a strong T-cell response to eventually kill those macrophages that are infected. Does that make sense? That does. And so basically because it lives intracellularly, the antibodies don't even reach them. Right. Yeah, exactly. But yeah, overall, infection with Lechmania species decreases our overall immune response. Okay. So there's really strong interactions going on between this parasite and our immune system, which is fascinating and complicated.

Yeah. So let's get more complicated. All right. Like you mentioned, Erin, there are three major forms and some others, actually, that will touch on in terms of the disease that we know of as luschmeniasis. There's cutaneous, mucosal, or mucosal cutaneous, called a couple different things, and visceral. What type of disease a person gets depends on the parasite species. So some species generally cause a visceral luschmaniasis, while others generally cause. cutaneous infection, but it also depends on host factors that we don't fully understand, whether that's genetics, like genetic susceptibility, or overall immune response.

Like, if you have a poor cell-mediated immune response to begin with, you might be more predisposed to infection, et cetera. So it's complicated. That's the subtitle of this episode. I was going to say, Leshmania, relationship status, it's complicated. I like it. So when you say generally this species causes visceral versus cutaneous, whatever, what does that generally actually look like? Is it like 95% or is it much, is it more variable than that? Very good question. I don't have a solid number on it.

So in most of the literature, for example, visceral Leshmaniasis, is most often caused by Leishmania Donovani, but also by Lechmania in Phantom, which is also kind of the same thing as Leishmania Shagasai. Okay, those are essentially... Seems to be the same species. Okay. So those two species are the dominant species that cause visceral Lechmeniasis. However, in a few cases, a couple of other species have been found to cause visceral Lechmaniasis that normally cause cutaneous. The rest of the species tend to only cause cutaneous luschmeniasis,

except in those cases. Does that answer your question? Yeah. And then what about mucocutaneous? So muco-cutaneous will get into. It tends to be a longer-term consequence of cutaneous lest maryasis. Oh. Yeah. And that, but that is also associated with, I assume, some parasitic species more than others? Yes. Yep. Exactly. Okay. So like, okay. Okay. Interesting. Yeah. It's very interesting. And I fully did not know that before researching for this episode. Like, I knew there was cutaneous and visceral, but I did not know that they were caused by two different species, and that was what distinguishes which one you get for the most part. Yeah, yeah. But it's got to get more complicated. Of course. Because some people can be infected with either the species that

cause cutaneous or visceral leshmeniasis and be entirely asymptomatic. Yeah. Okay. For infection with cutaneous species, it's generally about 10% of people are asymptomatic. Whereas, and this is really interesting, asymptomatic infection with species that cause the disseminated visceral infection really varies depending on region, but not necessarily depending on species. What?

Ah. So, this is so much, Aaron. That implies, I don't know what that implies. I don't either. Hold on. So in the people who are asymptomatic but infected, is the parasite, like, what is it doing in their body? Good question. I wish I knew.

Okay. Yeah. Do they go through like a course of infection essentially where it's there and then it's gone? They mount an immune response. Okay. So what exactly does that mean? Because immunity, as we'll talk about more later, increases with age, which likely has to do with repeated exposure eventually producing long-lasting immunity. So in a lot of cases, it's not necessarily like one exposure and then boom, you're immune. It's like repeated exposures, especially for cutaneous leshmaniasis. So what's happening? How many times could you be infected and be asymptomatic? It's also, Let's throw some more complex things in there. In all cases of luschmeniasis, the incubation period is very long.

Okay? We're talking weeks to potentially months. So are people asymptomatic entirely, or are they asymptomatic at the time that we test them to see if they have any evidence of parasites? But then many months later develop infection, maybe for some portion of people. So in all three of these cases, cutaneous, mucocutaneous, and visceral luschmeniase, These parasites are infecting macrophages. The clinical disease that we see depends on where they localize and whether or not they disseminate to the rest of your body and cause like a systemic infection.

Okay. Yeah. Okay. So let's talk about the symptoms that we see. Cutaneous lesthachyosis, which is the most benign of the three. So that's what we'll talk about. And benign, by the way, does not mean that it's not severe. It can be debilitating.

It can be extremely scarring. And as I'm sure you will talk about, Aaron, it's associated with a lot of stigma, but it just kills people less than the other reforms. Yep. So it's generally caused, like I said, by a number of different species of Lechmania. The most common species are Lechmania, Mexicana, Brasilianzus, Major, and Tropica. but there are a whole bunch more, like 13 or 15 or something more. And cutaneous is exactly what it sounds like. It affects your skin.

So it causes a more localized infection. It usually starts as what looks like a bug bite from where the sandfly bit someone, but it doesn't heal. And over a long period of time, and the length of time depends a lot on the species, so we're talking anywhere from two months to 15, months, this lesion, where this sort of bug bite was, begins to ulcerate. And it eventually leads to, it can lead to pretty significantly large ulcers, like open sores, essentially,

which from what I've read are painless, but they look very painful. And then this is a localized and self-limited infection. So generally, these ulcers over the course of weeks and months, they begin to heal via granulation. So like our normal body's healing process eventually kicks in. But it takes a really long time. And that's probably because as much as our body is trying to fight off this parasite, it's inside of our white blood cells. So it's really difficult for us to really fully eradicate this quickly. Yeah. And these ulcers lead to significant scarring. So the Scar is generally a depressed and large, like the size or a little bit smaller than how large the ulcer was. Scar.

And that can be very debilitating depending on where it is. It can be disfiguring and be associated with significant stigma, especially if it's on the face, which something like 50% of sandfly bites tend to be on the face just because it's easily exposed. We don't generally have clothing on our face. So yeah, so that's cutaneous leshaminiasus. You can also imagine that since this is an open wound, you can get a secondary bacterial infection on top of it. Yep. Which can lead to more complications.

I'm starting to feel like benign is not even coming close to accurately describing this. No, it's not. It's just of these three, it is the least deadly. Okay. How about that? How about that? Okay. So next is mucosal or mucocutaneous leshminiasis.

This is a very destructive form of leshminiasis. that most of the time occurs after cutaneous leshminiasis. It's most commonly associated with Lechmania Brasiliansis, like you asked, which species, Aaron. But there are other species, especially in people who are immunocompromised and don't have a good cell-mediated immune response. Then you can get mucosal Lechmeniasis from other species as well. So this form of Lechmeniasis presents often with nasal stuffiness. nosebleeds, sloughing off of tissue from inside your nose or mouth, it can result in erosion of any of your mucosal surfaces. So inside your mouth, your cheeks, your nose, kind of the

worst thing that can happen is it can essentially eat away through your nasal septum and completely destroy your nose. So it can be very disfiguring. And if it's associated with your trachea or epiglottis, for example, then it can cause respiratory compromise. So this form can be deadly, especially if it affects the mucosal surfaces that we use to breathe, for example. So that's depressing. Now let's move on to the most depressing. And that is visceral leshmaniasis, which is also known as Kala Azar, which is Hindi for black fever, and that's what you heard in our firsthand account.

Like I mentioned earlier, it's most often caused by Leshmania Donovani, but also Leshmania in phantom and or Shagas. which are the same thing. And this is a truly horrible, horrible disease. I think that our firsthand account did a lot more justice than I'm going to to describe just how awful it is. Clinically, what we see is a very slow, insidious over weeks to months where you have this fever and general malaise, just not feeling well. You have significant weight loss that leads to what we call caeccia, which is just like emaciation. okay, but then on top of that, because this parasite is in our white blood cells that congregate in our spleen and liver, you get massive spino megaly, so enlargement of your spleen or

hypatospinomagely, so enlargement of your spleen and liver. And because the other place that our white blood cells congregate is our bone marrow, this can lead to massive infection in your bone marrow that causes pancytopenia, which means all of your body cells congregate, bloodlines are depressed. So you're anemic, but also all your white blood cell counts are very depressed, which means, as you can imagine, people are very susceptible to secondary infection, because they have no immune defense, essentially. Right. Visceral leshaminiasis is almost uniformly fatal if left untreated. Mortality is 95 to 100%. And is it caused typically by the parasitic infection directly or through secondary infections?

Both. And I don't have a number on the exact percentage of which is which, but absolutely both are cause of death. Yeah. And Lishmania Donovani, like I mentioned earlier, there's kind of two different cycles of this disease. There's the anthroponautic where humans are the main reservoir. And then there's the zoonotic where it's animals, whether domestic or wild, that are the major reservoirs for infection. And the main species that causes visceral luschmeniasis is also considered anthroponautic. So humans are the major reservoir rather than animals. Right. Okay. Do you have a timeline specifically for a mucocutaneous, how long it takes for cutaneous to turn into the mucosal variety if it's going to go that way? Very good question. I think a lot

of what I've seen is up to like six months or even a year or more after initial infection is when you can end up getting mucutaneous or mucosal luschmeniasis. Yeah. Gotcha. There's a little bit more. Okay. So I said there's three main syndromes of disease, but there's actually two others too. So there's a form called diffuse cutaneous licheminiasis, which as you can imagine is like cutaneous lichmanniasisis, but in, instead of one single ulcer, you have many. This is thought to be kind of an autoimmune-related disease. It's not entirely clear why some people get it and other people don't. But essentially what happens is those parasites travel through your lymph system along lymph lines and can cause

still a cutaneous only, so it's still just in your skin, but a more widespread infection than just one single ulcer. Huh. Okay. It's also possible, though, to get multiple ulcers at one time just from multiple sandfly bites. So this is more diffuse than just that. Okay. Can you have both visceral and cutaneous at the same time from like different species,

you know? That's a really, really good question. I don't know because I didn't ever see that anywhere, but these happen in the same locations, so I don't see why not. And like if, if immunity seems to develop over multiple exposures over time, right? And let's say that you, like, are you immune to just the cutaneous forms or like the ones, the parasites that cause the cutaneous form? Or are you also protected from visceral? It's a, this is a very, very good question. And it's one that I still don't fully understand the answer to because of how complex the immunology of this is, I think that immunity is at least

partially cross-protective from what I understand. But that's why when we'll talk about vaccines, it's so important to develop a vaccine that results in immunity to multiple species of Lechmania. Yeah. Okay. I mean, the vaccine thing seems very difficult to... Oh, my gosh, Erin, you have no idea. Okay. Okay. There's one more disease that we have to talk about. Okay, we're not done. And that is post-Kala Azar Dermal Lushmaniasis. Oh my gosh.

So let's break that down. Post-Kala-A-Zar. So this means after someone survives Kala-A-Zar, which is visceral luschmeniasis. So that means someone who has been treated and successfully supposedly cured of Kala-A-Azar, dermal lest mishmaniasis. So now this is a skin manifestation. of a prior visceral infection. What? What does that look like?

How does that happen? What proportion of cases does this happen? Like, yeah. Great questions. So the weirdest thing about this. Okay, first I'll answer, what does this look like? It actually looks a lot like leprosy. Oh, interesting.

Okay. Yeah. So it causes these kind of nodular lesions that can be throughout kind of all of your skin. Now, who gets it in what proportion? This is very bizarre. It generally has only been described in certain regions. So in the Horn of Africa and in South Asia, not in Latin America, where we also see a lot of Lechmeniasis.

So in, for example, Sudan, about 50 to 60 percent of people that were treated for visceral leshmaniasis went on to develop post-Kala Azar dermal Lechmeniasis. And this usually happens between six months and a year. after infection. Why does it happen? I don't know, Erin, and in South Asia, the incidence is much less. It's like 5 to 15 percent, and the interval is often longer. Is the treatment different, like the most common treatment used?

Good question. Overall, so we can talk about treatment. Sorry, jumping the gun. No, don't be sorry. So first I'll say that what we do know about this is it seems to be a reactivation of the infection That is, people who present with PKDA post-Colazar dermal luschmeniasis are infectious to sandflies. So they have parasites still in their system. So this suggests that whatever treatment was used didn't really eradicate that infection in their bodies.

Erin! So what do we do to treat it? Okay. My face is like utter shock and confusion. That's how my face has been through all of the same. this reading, okay? So for a long time, treatment for both visceral and cutaneous and mucosal luschmeniasis was with what's called pentavalent antymonials, okay? That's just a fancy term for the specific drug that was first used to treat lichmeniasis. As was mentioned in our

first-hand account, this drug requires daily administration via injection for anywhere from 28 to 30 days, so it's a very long course and it requires a healthcare provider to be able to give those injections. And nowadays, resistance is very widespread to these drugs. Oh my God. So those are not used as much anymore. Yeah. Luckily, there are other drugs, but drug treatment for Lushmaniasis is a pretty major problem, as you can imagine. One drug that seems very promising and has been shown, at least in some regions to be very effective is liposomal amphotericin B. I don't know if you remember we talked about amphotarison B in the context of cystic fibrosis of all things. Do you remember that? No, I have to be honest. No, I don't.

You don't have to. I just thought it was fun. Anyways, Amphotericin B, it's an antifungal, actually. But this specific formulation has been found to be effective at least, least in India and Bangladesh, as a single dose cure. Really? Yep, one single dose, which is major. It's still an injection. You have to give it by IV, but it's one dose. So not only does that make it less likely that we're going to develop resistance because you don't have to keep giving it over and over and over and over. But it also is great in terms of being able to treat people and not have to have them come back and back and back. But it is still really expensive. And I've also read that a lot of people do not react well to it.

Like it has a very variable tolerance. And so you may not be able to take it at all. And Amphoterrorism B itself is a very, very toxic drug. So this specific formulation is a little less toxic, but yes, for all of these drugs, the side effect profile and the cost and the root of administration and resistance. All those things are some of the barriers. to treatment for luschmeniasis. There's a lot going on here. The cost is unreal. Yeah. There are a couple of other drugs. There is at least one oral drug, which is you can imagine

being able to give someone a pill is a lot better than having to give injections. And that's Miltifossin. I'm guarantee I'm pronouncing that incorrectly. But anyways, that's an oral drug that was effective for a time, but now there's massive resistance to it. it. Yep. So to answer your question that you asked about post-Kala-Azarmal luschmeniasis, if different treatments are used in different areas, the answer is generally yes. We have all these different treatments available, but what is available in any given region can definitely vary, and what is still effective and or affordable in different regions also varies. So how much of a role that might play in PKDL is a really good question. I imagine it must play a role.

because this is a reactivation of an infection, which means that our cure didn't fully cure. Right. So there's also a lot of interest in using combination therapy, the way that we do for something like tuberculosis, which is also a very long-lasting disease or HIV. So there are a lot of different drug combinations that are being used as well. So, is that long enough for you? That's the biology. That was quite long. Wow.

Yeah, my goodness. So here's the thing, Erin. I have a lot of questions for you. Oh, boy. Where on earth, literally and figuratively, did this parasite come from? How are there so many that cause so many different diseases in humans? Like, just give it all to me. I want to know what's going on.

Please. I'll do the best that I can right after this break. Anyone who works long hours knows the reason. 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. It's non-greasy, unscented, and absorbs quickly. A little goes a long way. Moisturization

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The history of Leshmaniasis. Right off the bat, let me just say that these are some incredibly old parasites. Oh, yeah. Like, I'm not just talking, oh, ancient Egyptian papyri, although I will get there. I mean like millions upon millions upon millions of years old. I am not surprised by that. It's very cool. Okay.

The sheer diversity of Leshmania species and the range of hosts that they infect gives us some idea of their ancientness. But did you know that Leshmania-like fossils were found in the proboscis and elementary track of an extinct sandfly encased in amber from the Cretaceous period? Stop it. Over 100 million years old. I'm sorry. They found it in the proboscis of a sandfly? Yes. Yes. Yes. Yeah. A hundred million years old. And these are Leschmania-like, but they were probably, like, they were probably the ancestors of the current or present Lechmania species. So we're talking, like, dinosaur infections.

Oh, yeah. So this preserved sandfly was filled with reptilian blood. What? And the presence of a parasitic life stage of the parasitic life stage of the parasol. also in the blood suggests that this Lechmania-like species was actually a two-host parasite, with one of the hosts being reptiles. Oh, my. I can't explain how thrilling that is. So because, like, we see a lot of the ancestors of parasites as, like, oh, this had a

mutualism with this, and then it found an opportunistic host. But this parasitic life cycle goes back. to like millions and hundreds of millions of years. That's phenomenal. Like to have evidence of a dual host parasitic life cycle 100 million years ago. Yeah. It like, ooh. I know.

It's very cool. That is fascinating. Okay. But those aren't the parasites that we see today in humans. So let's talk about the origins of those guys. All right. Turns out it's not as simple as that. The theme of the episode.

So as you mentioned, Erin, as you went over, there are many different species of Lechmania that infect humans, and they can be found all over the world with the highest concentrations in the tropics and subtropics. But unlike many of the other pathogens we've talked about, their current worldwide distribution wasn't caused solely by human travel. So a lot of the times we talk about how, okay, it emerged in, let's say that there was a pathogen that emerged in Africa. Africa and then it sort of dispersed out from there as humans traveled. So this isn't the case. Is that because it infects so many other species? Yeah, that's what it seems to be. That's what it seems to be.

Actually, most of the Lechmania species that we see in the new world evolved there rather than being brought over from the old world, you know, during Columbus-era exploration. Cool. There is one notable exception, though, which is Lechmania-Sharmia. Shagasai, which is now thought to be, as we've talked about, synonymous with Lishmania and Phantom. And people think that was brought to South America about 500 years ago during the European settlement. So by either the settlers themselves or their dogs.

Oh, okay. Interesting. And there are a few different hypotheses as to the geographical origin of the different species of Lashmania or like the different genera. and I'm not going to go into each one of these because, to be honest, I didn't fully understand the papers that I read. That's how I felt about the immunology, Erin. I know. I'm like, ooh.

But it seems to me that the take home is that the genus probably evolved in the Mesozoic era, so like 252 to 66 million years ago. Oh, my gosh. On the supercontinent, Gondwana. Okay. And then after it broke up and the sandflies and vertebrate, host migrated and then diversified and then evolved into the different, you know, subgenera and species that we see today. Wow.

So there may have also been some bearing land bridge crossing by some rodent host during the Eocene that led to the subgenus Lechmania being brought to the Nearctic from Asia, which later gave rise to the American Lechmania species. So that, honestly, I don't know what that means entirely, but I did know it when I wrote it. Okay. Good, nice. Okay. Okay, so we've established that Lechmania is a very old, like dinosaur old.

Different Lechmania parasites have probably been infecting humans since before humans were humans. It stands to reason. Yeah. Ancient descriptions of Lechmania lesions go back thousands of years. There's a tablet from the 7th century, B.C.E. That is actually thought to be copied from earlier text dating back to 1,500 to 1200 to 20. 2,500 BCE that describes something awfully close to a Lechmania lesion. And of course, I have to mention legally the Ebers Papyrus.

Ebers Papyrus. From 1500 BCE, which mentions something called a Nile Pimple, which seems to refer to cutaneous Lechmaniasis. Okay. And then there's the famous Persian physician Avicenna who lived in a 10th century, B.C.E. And he also described something called Balk Soar from northern Afghanistan, which sounds a lot like the dry lesions caused by Leshmania Tropica. Okay. Okay.

And then as far as South America goes, there are some pre-Columbian ceramics from around the 5th century that depict disfiguring facial conditions that seem to suggest the presence of mechocutaneous leshamiasis. Wow. All right. Now, if you prefer physical evidence and mummies over tablets and papyri, we've got you covered. A study of 42 Egyptian mummies dating from around 2050 to 1650 BCE found DNA from Lashmania, probably Lashmania Donovani, in four of the mommies, which means that visceral Lashmaniasis was likely present in ancient Egypt. Whoa. Yeah. And on the other side of the ocean, researchers have found Lechmania DNA in a Peruvian mummy of a six-year-old girl dating from 800 BCE.

And because some types of Leishmania can leave traces on bones, mucocutaneous, namely, we can see the physical impact of Lechmaniasis on skulls found in Chile dating to the 11th century. Whoa. Which would indicate the presence of mucocutaneous lesth, along with those. pre-Columbian pottery. Oh my goodness. Yeah. It's kind of difficult to assess or to describe just how much of an impact that Leshmaniasis may have had on the establishment of like a village or a city in a particular area or whether

there were significant outbreaks associated with one of the types of Leshmaniasis. But we do know for sure that humans have taken note of the different forms, which gave rise to many times. different nicknames. And in some cases, it altered their behavior to try to prevent the disease. For instance, when the Spanish invaded South America in the 16th century, they noted that in the Peruvian Andes, disfiguring facial conditions were common among the coca growers who worked on the lower slopes, and that usually either people who were enslaved or of a lower social class tended to be the ones that worked at these lower altitudes. So it's sort of like there was, it seems

to suggest that the risk of working at lower altitudes was known. And over the years, some researchers have suggested that Incan settlements tended to be restricted to highlands and avoided in the lowland forest out of fear of Lechmaniasis. But I read a note that an article or a note in response to an article that actually seems that that's probably not the case. It seems to be based on a few false assumptions that wet tropical valleys and rainforests were empty of archaeological rooms. which is actually just turns out that they're just more difficult to spot and because the rainforest is like fairly resilient to some degree. So anyway, that makes sense. Yeah.

All right. So some of the very first descriptions of Leschmeniasis in like modern times were made by the Scottish physician and naturalist Alexander Russell in the mid-1700s. And he described what was known at the time as Oriental Soar, Aleppo, Boyle, Baghdad Boyle, Jericho buttons, et cetera, lots of different nicknames. All of these names that we don't use anymore for a good reason. We do not use them. But basically what he was describing was cutaneous luschmeniasis.

And he also described different forms. So a wet form and a dry form, which likely corresponded to either the zoonotic cutaneous lesh caused by Leshmania Major and dry anthroponautic cutaneous lest caused by L. Tropica. And he also noted. that the lesions tend to heal within eight to ten months, and that although many different treatments existed, he felt that they often did more harm than good. That's still true today for one of the treatments that are available. And he recommended doing nothing or at the very most apply a plaster of mercury, which I can't imagine would have been that great. From the DNA analysis of those

mummies from ancient Egypt, we know that visceral leshaniases had been around for thousands of years. But there doesn't seem to be any writings about it until the 19th century, which is interesting considering that it is pretty, like, unique or at least like recognizable. Yeah. And it also is associated with an extremely high mortality rate. Yeah. So I wonder, is it just that it's so prolonged of an infection that, like, other, I don't know. That's really bizarre. I think it could be a few things.

I think it could be like, you know, when I was researching this, it was, I would say, like a bit of a challenge to find good comprehensive historical descriptions of Lechmaniasis. So I wonder if it's just that we haven't been looking quite as much. Okay. Yeah. But the other thing is that it might have been more localized. Like it might have been, it might have not persisted in certain areas. Like there does seem to be a lot of inter-annual.

variation in exposure and in prevalence and so on. And so maybe it just, and we don't really know the reasons for that because a lot of vector-borne diseases are just so dang complicated in that way. Yeah. And so I wonder if that's part of it as well, is that it tended to be localized and in other areas it may have popped up but then disappeared. Okay. Yeah. Yeah. Yeah. And so in 1827, a military surgeon named William Twining published a full description, of visceral luschmeniasis, which, as we've talked about, is known as Kala Azar. And it was found to be prevalent in certain parts of India. And throughout the rest of the 19th century, Kala Azar seemed to spread, popping up in epidemic

form across much of India. And because of the way it spread and the timing of it spread, it earned the nickname government disease. Oh, interesting. Because it seemed to emerge, yeah, it seemed to emerge whenever and wherever the British government established colonial rule. That actually kind of makes some sense in some ways. Yeah.

I mean, I don't know much about the ecology of sandflies and whether certain species are more urban or like whether there's what the association is with land use change and so on. But I really wonder if just the increased movement of people overall. Maybe we'll talk about it a little more then. in the current events, shall we? Fantastic. Fantastic. But yeah, so during a highly epidemic period of around 25 years in the second half of the 1800s,

visceral luschmeniases killed 25% or more of the population in certain areas. What? And more people fled, leaving some villages nearly empty. So, like, there do seem to be, and there have been, like, a lot of, you know, epidemics, but I think what's driving it is a very interesting question. And while there can be epidemics of cutaneous luschmeniasis, I think that the extremely, you know, and as maybe you'll talk about, some of the more recent epidemics, the extremely high case fatality rate of untreated visceral luschmeniasis perhaps made these outbreaks more noticeable and alarming, especially

since during most of the 1800s, neither the causative agent nor. the vector had been discovered. Who? Okay. As with many of the neglected tropical diseases that we've talked about on this podcast, can you guess what spurred on researchers to try to figure out the mystery of the different forms of Leshmaniasis? Were they, like, colonizing places and then dying because of it? Yeah, precisely.

So the British presence in India in the 1800s and into the 1900s made, Leshmaniasis a priority for that country, and it didn't actually take all that long to uncover the secret behind the enlarged spleen and emaciation seen in some of the military that were stationed in some areas. In November of 1900, a Scottish pathologist named William Leshman. Can you guess what he did? No. You can't guess what someone named William Leshman did? Oh, like he discovered the parasite? I thought you meant like how he discovered it. That was one of those two obvious questions. That was a softball.

If there's ever been a softball. Wait, try again, try again. Okay. Can you guess what William Leshman did? Did he discover Leshmania? He did. Oh, my gosh. He, yeah, so he looked at some samples from a spleen of a soldier who had died.

I was going to guess he. looked at spleen samples, Aaron. Like, that's what I thought you were going for. Oh, oh. Well, then, you know, I would have been so impressed. Okay. Anyway, sorry. And then he also found the same parasites in experimentally infected rats. And so he reasoned that he had found the causative agent of this deadly illness that he called Dum Dum Fever, which is named after a town where he was working called Dum Dum. Like, D-U-M-D-U-M. Yeah. Oh, gosh. And he thought it was a type of tripanosome because he was like, oh, it looks like a little ovoid body. It's got to be a tropanosome.

But then a few weeks after Leshman's paper was published, an Irish doctor named Charles Donovan. Donovan. Donovani. He published similar findings, so ovoid parasite bodies in the spleen of an affected person. But he was like, no, this is not a type of tropanosome. Like, it's just not, but I don't know what it is. So he got a few more people involved. And ultimately, it was the British medical doctor Ronald Ross, who declared that these ovoid bodies represented a new species of parasite, a new type of parasite, and proposed that they be called Leshmania Donovani to give credit to the two major discoverers.

So at least they didn't name it after themselves. Someone else named it after them. I think, I mean, even historically, it didn't happen a lot, right? That people named things after themselves? Yeah. I don't think so. Okay. You never know.

Someone tell us if we're wrong, because we're probably wrong. We're often wrong. The majority of the time. Okay. I should note that there was a third discoverer who actually published his finding several years before Leshman and Donovan, a Russian scientist whose name was Piotr Borovsky. Okay. But he did so in an obscure Russian language journal.

And so his contribution was realized only long after the fact. That's a bummer. That's English language bias. It is, yeah. The discoveries of the causes of cutaneous and mucutaneous luscheminiacist followed pretty quickly after that of visceral lesh. In 1903, the American pathologist James Homer Wright published a description of the parasite that he observed in a sample from a patient's sore. That makes sense. But he didn't immediately realize that it was a species of lush mania. but that would happen a few years later, the recognition that it was actually Lechomania, so reclassification.

And then in 1909 is when Brazilian doctor Adolfo Carlos Lindenberg and Italian physician Antonio Carini discovered parasites in the ulcers of those suffering from mucocutaneous Lechmeniasis. Okay. Okay. Yeah. But despite these advancements and knowledge about the causes of these very feared diseases, there were huge gaps in knowledge that remained, and closing the gaps was necessary if there was going to be any successful control efforts.

First of all, how do people even get this disease? Understanding how a disease is transmitted is huge for identifying how you can reduce the likelihood of transmitting it. Makes sense. Hence masks and social distancing. Still relevant. Still relevant. Not long after the first descriptions of Lechmania parasites, researchers thought that the disease was likely vector-borne, since the parasite shared some morphological similarities with other parasites that were transmitted by biting insects, like hypnosis. So with that to guide them, the search was on.

And maybe surprisingly, the search went on for years. Like, it took a long time. You know, that's interesting. Yeah, because the parasites themselves are easily observable. And, I mean, okay, granted, there are a lot of biting insects. There are a lot of biting insects. And sandflies are very small. They're very small.

Very small. I mean, but they looked into, like, literally everything. Mosquitoes, fleas, mitches, stableflies, ticks, titsy flies, houseflies, you name it. But maybe they didn't think about sandflies as biting? Anyone who's better on sandflies, you know they're biting. They're the worst. They're the actual worst. Horrible.

Horrible. Yeah, I don't know. Maybe they just didn't think of them as vectors. Yeah. Because they hadn't been before. I mean, so I think it also, the confirmation might have been what took. so long as well. And also for a while, I think because in certain areas it might just be so prevalent, but in certain, in other areas where different sandfly species maybe exist, it's not

as prevalent, like maybe it's just the association. And so for a while, bedbugs actually seemed like the likeliest culprit. Interesting. Because of the housing aggregation. Exactly. Yeah. Yeah. But then a few findings steer the ship towards sandflies. First was a 1912 report of flagellates found in the guts of sandflies caught at Aleppo, a place that historically has had a very high prevalence of anthroponautic cutaneous luschmeniasis. And the second was in 1921 when two French biologists and brothers, the sergeant brothers, Sergent, I don't know. Sergent. Put some ground sandflies into the skin of volunteers who then developed cutaneous luschmeniasis lesions. Can you say quote unquote?

Volunteer quotes? I think from this point on in the podcast, I think long ago, hopefully people assume air quotes around volunteers whenever it's mentioned. That's a good rule of thumb for this podcast if you hear the word volunteers. Just no, it doesn't really mean volunteers. But this was not taken as conclusive proof, the emergence of their lesions. and doubt over the life cycle of cutaneous and visceral luschmenias as parasites lingered for almost 20 years until in 1941 five volunteers were bitten by sandflies infected with Lechmania tropica and lesions were produced.

Okay, okay. There's no mention of where those volunteers came from, but there was a note saying that they all survived their infections. Great. A year later, sandflies were shown to also transmit visceral luschmeniasis, and the link between mucocutaneous luschmeniasis and sandflies had actually been uncovered back in 1922. It's interesting because now we tend to think of them as just like one, like an umbrella luschmeniasis. Yeah, I think back then it was still so divided, like, oh, well, this is another type of parasite. And so I think the connections weren't easily made in addition to.

in the fact that, like, scientific knowledge spread a lot more slowly back in those times. So anyway. So the second big gap in knowledge about Lushmaniasis, which is effective treatment, that was filled in the 1940s with discovery that Pentostam was effective against the parasites. And then again, in the late 1950s with Amphateros and B. And then throughout the 80s and into the 90s, Luschmeniasis sort of took on an increased importance when during the HIV pandemic when it seemed to be highly correlated and also a cause of like, you know, increased mortality among people who are already immunosuppressed and sort of like

one infection feeding into the other. But despite our longstanding knowledge of these parasites and their existence, and despite the fact that we know more and have more technology to study them to develop drugs, et cetera, there doesn't really seem to be much improvement regarding the widespread prevalence of Lechmeniasis and the absolutely enormous devastation that it causes. Not just death, not just disfiguration leading to stigma, but its role in the cycle of poverty, which I'm sure you'll talk more about. It is one of the biggest contributors to that. Widespread travel, civil unrest, land use change, global climate change.

These have all not only perpetuated the cycle of infection in infected areas, but have also led to the emergence of different forms of luschmeniasis in areas previously unexposed, which is honestly some of the only times that it ever gets headlines in places like the U.S. when it's like global climate change could lead to you getting this skin-eating parasite. And it's like, people live with this on a daily basis. And like, okay, sorry. Taking it down. I love when your section, at the end of your history section and then my epi section are just like the same thing.

It's my favorite. Oh, my gosh. Yeah. It's, I mean, I feel like the history has come to just such an abrupt end because it's not over. Yeah. That's, you know, where we are today is very much where we were 100 years ago, if not, in a worse situation. Wow, that's depressing, Erin. Yeah. You know, we have a lot of this information, but it doesn't always reach the areas that need it. So, for instance, there's, you know, in the places where there's a lot of stigma, there's also enormous problems in misconceptions regarding how the disease is transmitted.

And so sometimes, for instance, it's believed in many places to be transmitted directly from direct contact, so skin to skin. And so people are often not allowed to their babies are taken away from them or they're forced to be like, oh, no, you have to go isolate for a really long time, even though that doesn't really, like, they are not infectious to other individuals directly. So. Right. Yeah. It's honestly, this is, this is one of the. most frustrating diseases, I think, that we've covered lately because it really does seem like why? Why has there not been more? And people are doing a lot of work, but I just feel like this is

one of the big guys. And yeah, so Aaron. Oh, gosh. Aaron, why don't you fill us in on where we stand with Leshaminias's today? Oh, I'd love to. I'll be able to answer at least some of your why, why questions right after this break. Oh gosh, Erin. The answer as to why, why, why, why. The short answer is that, so luschmeniasis is considered a neglected tropical disease. We've talked about neglected tropical diseases on this podcast before. But even as far as neglected tropical diseases go, Leschmeniasis is often considered the most neglected by some people. And that's because, in large part, of how strong the association is between Lechmeniasis and poverty, which is true for almost all neglected tropical diseases.

But for Lechmeniasis, it's really not enough to just say, oh, this is a disease of poverty. The end. Right. We have to understand the role that income and poverty play in infectious disease, and then the role like you mentioned, that this disease plays in reinforcing that cycle of poverty. And it's very multifactorial. So I'll kind of just touch on the highlights, but I do want to shout out a great paper on this topic that was by Alvar at all. Really great paper on this exact topic, if you'd like to read more. But basically, it's very multifactorial. So in a lot of the world where Leshmaniasis is

endemic, people living in poverty live in housing conditions that are very multifacorial. And so in a lot of very suitable for sandfly growth and development, whether it's because they have cracks in the walls or damp floors or mud floors that make it very easy for sandflies to grow and live in the domestic environment. Then on top of that, they're living with poor sanitation and maybe not often trash pickup, things like that, that also provide habitat for sandfly growth and development. they often live in closer proximity to animals and with a greater density of animals that can play a complicated role in the zoonotic transmission in places where this is mostly a zoonotic disease. And then you have a lack of access to treatments, which can increase both anthroponotic and zoonotic

transmission, but especially anthropotic transmission within households. So a lot of the like small scale epidemiology of Lechmeniasis is clustered in household groups because of the anthroponatic transmission. So that's how kind of the ecological ways that poverty and disease can go hand in hand. Poverty also leads to malnutrition, which can absolutely and does exacerbate and worsen the symptoms and outcome of disease, especially Lechmaniasis. it makes it much more likely that someone will get severely ill or die from infection rather than having an asymptomatic infection. And then on top of that, displacement, whether due to war or economic necessity, or, like you mentioned, Aaron, climate change.

Climate change can have so many effects on this disease. And it will continue to do so for, yeah. Yeah. There are some really interesting modeling papers that will link you. 2.2. Like you said, people only care if it's in our backyard. Well, that's what the modeling suggests that it will be soon. So those things can absolutely increase the risk of disease transmission and also change its distribution so that new people who have never been exposed before are now exposed for the first time to infection, rather than having been exposed over time and developed

some sort of immunity, if that makes sense. Yes, yeah. Oh, but there's more because poverty also increases barriers to accessing health care, like we heard in our first hand account, whether it's leaving further from access to health care and having transportation barriers in getting there. Education barriers, like you kind of touched on errands, such that people are either less likely to recognize disease or know how it's transmitted or seek care until too late in the course of disease. A lot of home remedies, especially for cutaneous leshaminiasus, result to, in worse outcomes compared to either just leaving cutaneous lushemeniasis alone or treating it with kind of standard treatments. And there's a lot of difficulty in paying for and receiving treatment even if you can access it. Because it's expensive. It's, oh my gosh, it's, it's enraging how expensive it is. Yes. Okay. And it's been well documented that for women, especially, the stifference, The stigma associated with infection and the scarring from cutaneous luschmeniasis is so severe that women are substantially less likely to seek care, so they have even longer delays in seeking treatment compared to men in a lot of endemic areas. There has been well-documented psychological burdens of lichmanniasis as well.

It's strongly associated with major depressive disorder, largely because of the scarring and the stigma associated with it. Let's back up a minute and talk about actual numbers for a second. Now that we kind of understand just how important this is in like the cycle of poverty and that it has effects on psychosocial outcomes as well. Right. It is, yeah. The numbers are important because wow. Yes.

So a 2012 paper that's really commonly cited that has estimated because you can imagine this is such a neglected disease that underreporting, is just like we absolutely don't know the true incidence of disease. But so this 2012 paper that's very well cited estimated between 200 and 400,000 cases of visceral Leshmaniasis every year. The one that causes death. The one that causes death. And here's something also important that I haven't even said yet. It's almost entirely fatal if untreated. Even if it's treated, the mortality can be as high as 10 to 20 percent. So the total number of deaths per year is estimated at anywhere from 20 to 40,000 people dying from Leshmaniasis. And I wonder how many of those

are also because of like not being able to afford treatment. Exactly. Right. Yeah, for sure. And again, that's just an estimate. Like, that's our best estimate. And on top of that, another 700,000 to 1.2 million cases of cutaneous luschmeniasis worldwide each year. So that was from 2012. There are a couple of newer papers in 2015 and 2016 that estimate not only the incidence of infection, so the number of new cases per year, but also the prevalence of infection. So the total number of cases, because again, cutaneous fleshyminaeus and visceral are both very low. long-lasting disease. So someone might get infected in, say, 2020, but still have it in 2021 or even all the way till 2022. So the prevalence of disease tells us how many people are living with that

disease currently. So the 2016 estimates said that overall worldwide, over 4.8 million people are living with Leshmaniasis. And that's all forms. And that overall, there were likely 800,000 new cases. Wow. Yeah. 120,000 of those were likely visceral luschmeniasis and over 600,000 of cutaneous luschmeniasis for new cases. Now, that's just incidents and prevalence. Another thing that we have to look at for a disease like this is the disability adjusted life years, okay, which in 2016 overall was estimated in one year at over 980,000. So almost a million disability-adjusted life years for all of Leshmaniasis combined. Oh my gosh. But, and this I think is really interesting and important. I found a paper just from last year, 2019, that suggested that we shouldn't consider having gone through cutaneous Lechmaniasis.

and survived as no longer being affected by Lechmeniasis, essentially. So they suggested that the scarring phase, because we know that Lechmeniasis causes these massive scars, that that scarring phase should actually be considered a part of the disease process, since this is something that people are still living with and should therefore be counted in the prevalence estimates. Because then, based on their, because we also know that it's so strongly associated with things like major depressive disorder and stuff like that. So they estimated that if you include that, then we're looking at over 40 million people that are living with the stigma, the psychosocial burdens, and these other things that are associated

with cutaneous luschmeniasis. 40 million people worldwide was their estimate. 40 million. Wow. So I think that that's very interesting because it really changes. your disability-adjusted life years if you include psychosocial disorders like major depressive disorder, which is not included in our estimates of disability-adjusted life years. Right. Mental illness is not included in that. So geographically, luschmeniasis can be found almost worldwide, pretty much. But visceral lesthminiasis, 90% of the cases occur in a few countries.

India, Bangladesh, Sudan, South Sudan, Ethiopia, and Brazil. That's the major places where like 90% of visceral luschmeniasis occurs. And cutaneous luschmaniasis is most common in Afghanistan, Algeria, Colombia, Brazil, Iran, Syria, Ethiopia, North Sudan, Costa Rica, and Peru. So there's like a lot of places in the world. It's a lot of places. It's a lot of places. And the distribution is likely changing due to climate change. Okay. I want to say it's not all depressing, but it's mostly all depressing, but there are a lot of people doing a lot of work to try and make this better. Yes, that is important to remember. Yeah. We've talked a lot about Peter Hotez on this podcast.

Oh, yeah. Peter Hottes. He is one of many people really doing so much work on vaccine development and really just, I think, bringing awareness to diseases like Lechmeniasis as well. So in terms of where we stand on a vaccine, it's still not great news. There is a lot of good evidence to suggest that at least from the perspective of people being able to theoretically mount a protective immune response, that we should be able to develop a vaccine. and actually people like even in ancient times have practiced leshmanization. Right. Which is basically inoculation of parasites under the skin to like intentionally induce an infection, not on your face but on your body to then protect you from more worse and disfiguring infection later on. And that's like effective.

But of course it does result in infection, which is not good. And it's not perfect either. And so the big stumbling blocks to the creation of a vaccine are both financial and also logistical. We don't have a perfect vaccine. There are a few different vaccines that are being tested right now in phase one and phase two trials. There are recombinant vaccines. So like just a protein that we know would cause an immune response along with different adjuvents to increase the immune response. There are also killed.

parasite vaccines that are under investigation. There's talk about DNA vaccines, but I don't know that any of those are in kind of later stages of development. So it'll be interesting to see how those go on, as well as therapeutic vaccines. So vaccines that you give to someone who has like cutaneous lichiniasis to prevent the development of mucocutaneous lichiniasis, etc. Dogs, as it turns out, for zoonotic luschmeniasis are a pretty important reservoir host. So there are a couple of canine vaccines that have shown some promise in preventing dogs from becoming infected, which may be useful in some areas. But it probably won't have the full impact that we need, especially because a lot of regions with visceral lachmaniasis

especially have mostly anthroponotic transmission. So dogs don't play as big of a role in that. I mean, they don't play a role at all. So yeah. So that's a we stand. There's a lot of people working on it. There's a lack of funding. Even though it's been shown, like in a lot of different modeling studies, to be very cost effective, like the cost to develop and implement a vaccination program would be way cheaper than treating people for visceral and cutaneous lechidiniasis. Yeah, but there's no money in it. If you vaccinate someone against a disease, then you're not going to be able to get the year, you know, the month's supply of... But you get so many disability-adjusted life years back. Isn't that what people want? You can then work. Whatever.

Anyways. I know. There's a lot of problems with like why certain things are funded and others are not. Yes. So, you know, hoity ho. Also, Maria Elena Botazi, who we talked to in one of our COVID episodes. She's on a couple of these papers, too. She's doing a lot of work on this. There's a lot of other people. I probably should shout them all out. But those are the two we've talked to. So I feel cool. Well, I think it's, I mean, I think it's really amazing and important because, like, this research isn't easy to do because the funding just, like, isn't sufficient. It isn't, yeah, but it's hugely important. And so. It is hugely important. Yeah. So that's where we stand, Aaron. Oh, boy. Well, I learned a lot. I learned a lot. It's a big disease. And I really feel like I didn't do the history just. but I also feel like there's just, like I couldn't find as much as I normally can find on stuff like this. And so someone needs to write a book about this. You're right, Erin. Someone needs to write a book. Guys, let us know if you would like to read a book that Aaron Walsh writes about

Lushmaniasis. Or if you'd prefer a different topic, let us know what do you want her first book to be about. Are you volunteering me to do a lot of work, Erin? Okay. Yes. I want to read it. Appreciate. Speaking of books and things, should we do source it? We should. So I have a bunch of different articles, but I want to shout out a few. So one that I found super helpful for the overview of the history is by Steaverding from 2017, called The History of Leshmaniasis. And then there are a few different papers about the origin of Lechmania and the Sandflies.

And so there's one by Momin and Kupo Lilo from 2000 called Speculations on the Origin and Evolution of the Genus Lushmania. There's a paper by Killick Kendrick from 2013, The Race to Discover the Insect Vector of Kala Azar. And then there's a paper by Garan from 2018 called an overview of Leshmanias' historic to future perspectives. And there are many more all post-em-all. I already shouted out a few of the papers that I read. There is a lot. We post the full references to this episode and all of our episodes, every source we've ever used on our website. This podcast will kill you.com.

So check them out there under the episodes tab. Yeah. Well, thank you to Bloodmobile for providing the music for this episode and every single one of our episodes. All 62 now episodes. Not including the COVID ones. Yeah. Wow. That's a lot.

Thank you to you, listeners. For listening to all 62 plus episodes of this podcast. We love making it and we hope that you keep enjoying it. Yes, we do. Well, until next time, wash your hands. You filthy animals. I'm Amanda Knox and in the new podcast, Doubt the Case of Lucy Letby, we unpack the story of an unimaginable tragedy that grips.

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