Speaker 1: On one burning day in April, in a village in Biha,
Speaker 1: Sushila Devy was worried about her sick child. Her decision
Speaker 1: to seek medical help required brave determination. There was the
Speaker 1: overpowering heat through which she would have to walk, carrying
Speaker 1: her sick child most of the eight miles to the
Speaker 1: government health center. The child was ill, but not emergency
Speaker 1: ill in any of the too familiar life threatening ways,
Speaker 1: the acute fever and coma of childhood malaria, the rapid
Speaker 1: wasting diarrhea and death of cholera, or the labored gasping
Speaker 1: of pneumonia. It was merely that the child seemed somewhat
Speaker 1: feverish this past month and was becoming emaciated despite a
Speaker 1: reasonably good appetite, with a distended abdomen. The young doctor
Speaker 1: was brusque, unfriendly, and uncommunicative. He told Sushila to put
Speaker 1: her frightened child on the bare wooden examination table. To
Speaker 1: the doctor, the constellation of signs and symptoms could point
Speaker 1: to only one diagnosis. The prolonged fever, the greatly enlarged
Speaker 1: liver and spleen, the anemia, the serum that jelled when
Speaker 1: mixed with formaldehyde all meant visceral leshmaniasis. Realizing the gravity
Speaker 1: of what he was about to tell Sushila, his pomposity
Speaker 1: fell away. Mother. He said, gently, your child is very
Speaker 1: ill with kala azar. It does not mean death. Your
Speaker 1: child can be cured. You must buy medicine. Then you
Speaker 1: must come here every day for twenty days so the
Speaker 1: nurse can inject the medicine. How much is it, Sushila
Speaker 1: asked fearfully, for you, I will give you a bottle
Speaker 1: of the drug enough for her whole treatment for three
Speaker 1: hundred rupees about fifteen dollars. It was an astronomical sum,
Speaker 1: more than the family's income for some months. Sushila picked
Speaker 1: up her child and began the long walk back to
Speaker 1: her village. Even if by some miracle they could buy
Speaker 1: the medicine, there was no way that Sushila and the
Speaker 1: child could travel these long miles to the health center
Speaker 1: for twenty consecutive days. No for the child, they would
Speaker 1: have to do the best they could. They would pray
Speaker 1: to the gods, they would consult the doctor in the
Speaker 1: adjoining village.
Speaker 2: In the end.
Speaker 1: As the weeks passed, the child became progressively more ill.
Speaker 1: She grew even more emaciated, her skin turned a dusky gray,
Speaker 1: her hair became brittle, Small bleeding sores covered her body,
Speaker 1: and the abdomen, burdened with a grossly enlarged liver, distended
Speaker 1: even further. One day, some three months after Sushila's visit
Speaker 1: to the health center, the child began to cough and
Speaker 1: gasp for breath. During the night, the little girl died,
Speaker 1: a fragment of life sacrificed for want of fifteen dollars. Ooh,
Speaker 1: that was rough to even read out loud.
Speaker 2: Yeah, that is from a book called The Malaria Capers
Speaker 2: by Robert S. Desowitz.
Speaker 3: Hi.
Speaker 2: I'm erin Welsh.
Speaker 1: And i'm erin allman updyke.
Speaker 2: And this is this podcast will kill you? It is.
Speaker 1: It's a depressing one today, erin.
Speaker 2: I mean, when are they not?
Speaker 1: Yeah? Could we ever, like maybe one time this season
Speaker 1: we could find a not depressing one just to try.
Speaker 2: We could try. Oh gosh, So, as you may have guessed,
Speaker 2: this week we are covering leshmaniasis, which includes not just
Speaker 2: visceral leshmaniasis as described in the first hand account, but
Speaker 2: also cutaneous and muco cutaneous leshmaniasis.
Speaker 1: Sure does.
Speaker 2: It's a lot more complex of a story than I
Speaker 2: think we.
Speaker 4: Realized really really complicated, a lot more than I ever knew.
Speaker 1: So it was good to learn this stuff. But also,
Speaker 1: oh my gosh, I hope that I do it even
Speaker 1: a shred of justice.
Speaker 2: I trust you, Oh gosh, I trust you well. Erin,
Speaker 2: I think we have a couple pieces of business to
Speaker 2: take care of, or at least one.
Speaker 1: Yep, is it that it's let me check quarantiny time.
Speaker 2: It is, indeed quarantine time. You are absolutely exactly right.
Speaker 1: What are we drinking today, Erin?
Speaker 2: Today we are drinking a sand fly in the ointment
Speaker 2: he oh so.
Speaker 4: Named, because this is a disease transmitted by sand flies.
Speaker 2: And in sand fly in the ointment there is lime juice,
Speaker 2: grapefruit juice, some simple syrup, all spice liqueur, so I
Speaker 2: finally get to use that stink and all spice liquor
Speaker 2: that's been on my shelf for ages, and some rum yum. Yeah.
Speaker 2: And we will post the full recipe to the quarantine
Speaker 2: as well as the non alcoholic place Barrita on our
Speaker 2: website This podcast will Kill You dot com, as well
Speaker 2: as all of our social media channels, so check it
Speaker 2: out there. Yeah. Any other business that we have I
Speaker 2: don't believe.
Speaker 1: So all right, then shall we just dive in season four,
Speaker 1: episode two?
Speaker 2: Oh my gosh, let's do it, okay.
Speaker 1: Right after this break. So, like we mentioned already, the
Speaker 1: biology of this disease is quite a lot. So I
Speaker 1: tried really hard, which is the opposite of what I
Speaker 1: normally do in my notes. I tried to really keep
Speaker 1: this organized so that we can go through it in
Speaker 1: a way that makes sense. Okay, So let me just
Speaker 1: go ahead and get started, all right. So, leshmaniasis, like
Speaker 1: you mentioned already, aarin, it's not just a single disease.
Speaker 1: It's a group of at least three different disease syndromes
Speaker 1: which are caused by a number of different species of
Speaker 1: protozoan parasites in the genus lesh Mania.
Speaker 2: It's kind of interesting that like they're all like when
Speaker 2: we say leshmaniasis, it's like means all of them. It
Speaker 2: means so many different types of diseases and so many
Speaker 2: different like caused by so many different species of parasites.
Speaker 1: Yeah, like overimplification. Yeah, yeah, I can't believe that we
Speaker 1: call this all the same disease. Quite honestly, it blows
Speaker 1: my mind.
Speaker 2: I mean historically we didn't, but we'll get to that.
Speaker 1: Oh any great, I can't wait. That makes a lot
Speaker 1: of sense actually, okay, yeah, so at least twenty different
Speaker 1: species of protozoan parasite transmitted by a whole number of
Speaker 1: different species of insect vectors. In this case, like we said,
Speaker 1: we're dealing with a new type of insect vector that
Speaker 1: we haven't dealt with on the podcast before, and that
Speaker 1: is the sand fly.
Speaker 2: Yeah, this is our first new vector.
Speaker 1: Yeah, we've only done mosquitos and ticks so far.
Speaker 2: How interesting. I didn't realize that.
Speaker 1: Yeah, so that's fun. So sandflies, for anyone who's not familiar,
Speaker 1: they're another sort of biting fly similar to mosquitoes. It's
Speaker 1: primarily the females who take blood meals, whereas both males
Speaker 1: and females also feed on like fluoral nectar and sugar water.
Speaker 1: So in this case, we're talking about sandflies in two
Speaker 1: different genera, Lutzomia and Phlebotomus. Okay, so so far we
Speaker 1: have over twenty species of parasite and two whole genera
Speaker 1: of sandfly.
Speaker 2: Okay, it's a lot.
Speaker 1: Uh huh. It's gonna get to be more. Because leshmaniasis
Speaker 1: affects humans, which is what we're going to talk about today,
Speaker 1: but it also affects like at least one hundred other
Speaker 1: mammal species. So in addition to different forms of the
Speaker 1: disease that we see in humans, there are different cycles
Speaker 1: of the disease. There is a zoonotic cycle of disease
Speaker 1: wherein humans become infected from vectors that got infected from animals,
Speaker 1: so from animal to vector to human. And then there's
Speaker 1: also anthroponotic cycles wherein humans are the dominant reservoir host
Speaker 1: and humans are infecting other humans through a vector.
Speaker 2: And it's not just mammals, right, isn't it also reptiles.
Speaker 1: I think that reptiles and some birds have been known
Speaker 1: to be infected. How much of a role they really
Speaker 1: play in the zoonotic disease in humans is pretty minimal
Speaker 1: as far as I know.
Speaker 2: Yeah, I don't think they do, but I think it
Speaker 2: is just amazing the sheer number of species I know
Speaker 2: a different, like very different groups of animals that it's
Speaker 2: these parasites can infect bananas truly.
Speaker 1: So yeah, okay, that's a lot already.
Speaker 2: Okay, yep, So for.
Speaker 1: This biology section, because that's so much, we are really
Speaker 1: going to focus on the disease or the three big
Speaker 1: disease states of leshmaniasis in humans. I'm not going to
Speaker 1: touch on leshmaniasis in animals because it's just going to
Speaker 1: make things more complicated. So let's get into this disease
Speaker 1: by going over the parasite life cycle, which will tell
Speaker 1: us how it's transmitted, and then we'll talk about how
Speaker 1: we see the disease mana fest in humans.
Speaker 2: Okay, sounds great.
Speaker 1: So leshmania species the parasite that causes leshmaniasis, like plasmodium
Speaker 1: parasites that cause malaria or tripanasoma parasites that cause Shaggas disease,
Speaker 1: are a eukaryotic, single celled parasite that has multiple different
Speaker 1: distinct life stages in their different hosts, whether a mammal
Speaker 1: or reptile and insect. In the case of leshmaniasis, they
Speaker 1: have two different forms, the a mastigote and the pro mastigot.
Speaker 1: One is a little ball that lives inside of our cells,
Speaker 1: and one is a cute, little kind of spermy shaped thing.
Speaker 1: I yes, maybe that doesn't sound cute, but it is
Speaker 1: with a little flagella tail that can swim. Okay, So
Speaker 1: a leshmania life cycle goes something like this, a sand
Speaker 1: fly takes a bite of an infected animal host in
Speaker 1: just a blood that contains the a mast goat form
Speaker 1: of the parasite. Those parasites travel through the gut of
Speaker 1: the sandfly, transform into the pro mastigotes, which have that
Speaker 1: flagella and can swim, and those parasites continue to divide.
Speaker 1: They make their way out of the gut of the
Speaker 1: sandfly and into their proboscis, which is the biting part
Speaker 1: of the fly. And then when that sandfly takes another
Speaker 1: blood meal, those parasites are regurgitated into that new host.
Speaker 1: In that host, let's say it's a human, since that's
Speaker 1: what we're talking about. Those pro mastagoats which are swimming
Speaker 1: are taken up by our white blood cells mostly are macrophages,
Speaker 1: which we've talked about a lot on this podcast. Those
Speaker 1: are a white blood cell that usually helps clear infection
Speaker 1: by like engulfing bacteria and parasites and killing them. Turns out,
Speaker 1: in the case of lesh mania, when a macrophage ingest it,
Speaker 1: that's actually where they become a master to goats and
Speaker 1: then continue to divide and reproduce.
Speaker 2: Yeah, so how do they avoid death?
Speaker 1: Oh, such a good question. Aaron, I wish that I
Speaker 1: had a full good answer to that. So leshmaniasis is
Speaker 1: a disease of what's called the reticulo endothelial system, So
Speaker 1: that means that it effects and replicates white blood cells,
Speaker 1: especially macrophages, and then affects in theory any organ where
Speaker 1: those white blood cells tend to congregate. So the exact
Speaker 1: mechanisms by which it evades our immune response are really
Speaker 1: really complicated To kind of sum it up in the
Speaker 1: simplest terms that I can, Gosh.
Speaker 2: Is it basically suppress the immune system overall?
Speaker 1: Exactly it it's press our immune system? And how exactly
Speaker 1: they're able to survive inside of macrophages, I don't fully know.
Speaker 1: But by living inside of macrophagis they evade any other
Speaker 1: of our immune responses?
Speaker 2: Okay? That makes sense and also very sneaky.
Speaker 1: And very very sneaky. Okay, And overall we know that
Speaker 1: infection with leshmaniasis it causes our body to mount an
Speaker 1: immune response, like we make antibodies to it, but those
Speaker 1: antibodies don't do much. It turns out that to develop
Speaker 1: immunity towards leshmaniasis, it's more about cell mediated So you
Speaker 1: need a strong t cell response to eventually kill those
Speaker 1: macrophages that are infected. Does that make sense?
Speaker 2: That does? And so basically the ant because it lives intracellularly,
Speaker 2: the antibodies don't even reach them.
Speaker 1: Right, Yeah, exactly. But yeah, overall infection with lesh mania
Speaker 1: species decreases our overall immune response. Okay, so there's really
Speaker 1: strong interactions going on between this parasite and our immune system,
Speaker 1: which is fascinating and complicated. Yeah, so let's get more complicated,
Speaker 1: all right. Like you mentioned, Aaron, there are three major
Speaker 1: forms and some others actually that we'll touch on. In
Speaker 1: terms of the disease that we know of as leshmaniasis,
Speaker 1: there's cutaneous, mucosal or mucosal cutaneous called a couple different things,
Speaker 1: and visceral. What type of disease a person gets depends
Speaker 1: on the parasite species. So some species generally cause a
Speaker 1: visceral leshmaniasis, while others generally cause cutaneous infection. But it
Speaker 1: also depends on host factors that we don't fully understand,
Speaker 1: whether that's genetics like genetic susceptibility, or overall immune response.
Speaker 1: Like if you have a poor cell mediated immune response
Speaker 1: to begin with, you might be more predisposed to infection,
Speaker 1: et cetera. So it's complicated. That's that's the subtitle of
Speaker 1: this episode.
Speaker 2: I was gonna say lash mania relationship status. It's complicated.
Speaker 1: I like it.
Speaker 2: So when you say generally this species causes visceral versus
Speaker 2: cutaneous whatever, what does that generally actually look like? Is
Speaker 2: it like ninety five percent? Or is it much? Is
Speaker 2: it more variable than that?
Speaker 1: Very good question. I don't have a solid number on it.
Speaker 1: So in most of the literature, for example, visceral leshmaniasis
Speaker 1: is most often caused by leshmania donovanni, but also by
Speaker 1: leshmania in phantom, which is also kind of the same
Speaker 1: thing as leshmania shagasai. Okay, those are the same thing,
Speaker 1: seem to be the same species. Okay, So those two
Speaker 1: species are the dominant species that cause visceral leshmaniasis. However,
Speaker 1: in a few cases, a couple of other species have
Speaker 1: been found to cause visceral leshmaniasis that normally cause cutaneous
Speaker 1: The rest of the species tend to only cause cutaneous
Speaker 1: leshmaniasis except in those cases. Does that answer your question?
Speaker 2: Yeah? And then what about muco cutaneous?
Speaker 1: So muco cutaneous will get into it tends to be
Speaker 1: a longer term consequence of cutaneous leshmaniasis.
Speaker 2: Oh yeah, and that but that is also associated with
Speaker 2: I assume some parasitic species more than others.
Speaker 1: Yes, yep, exactly.
Speaker 2: Okay, So like, okay, okay, interesting.
Speaker 1: Yeah, it's very interesting. And I fully did not know
Speaker 1: that before researching for this episode. Like I knew there
Speaker 1: was cutaneous and visceral, but I did not know that
Speaker 1: they were caused by two different species, and that was
Speaker 1: what distinguishes which one you get for the most part. Yeah, yeah,
Speaker 1: but it's got to get more complicated, of course, because
Speaker 1: some people can be infected with either the species that
Speaker 1: cause cutaneous or visceral leshmaniasis and be entirely asymptomatic. Yeah, okay.
Speaker 1: For infection with cutaneous species, it's generally about ten percent
Speaker 1: of people are asymptomatic. Whereas, and this is really interesting,
Speaker 1: asymptomatic infection with species that cause the disseminated visceral infection
Speaker 1: really varies depending on region, but not necessarily depending on species.
Speaker 1: What this is so much aarin that implies.
Speaker 2: I don't know what that implies.
Speaker 1: I don't buiere. Okay, hold on, So.
Speaker 2: In the people who are asymptomatic but infected, is the parasite, like,
Speaker 2: what is it doing in their body?
Speaker 1: Good question?
Speaker 2: I wish I knew, Okay, And do they do? They
Speaker 2: go through like a course of infection assent where it's
Speaker 2: there and then it's gone.
Speaker 4: They mount an immune response. Okay, So what exactly does
Speaker 4: that mean?
Speaker 1: Because immunity, as we'll talk about more later, increases with age,
Speaker 1: which likely has to do with repeated exposure eventually producing
Speaker 1: long lasting immunity. So in a lot of cases, it's
Speaker 1: not necessarily like one exposure and then boom your immune
Speaker 1: it's like repeated exposures, especially for cutaneous leshmaniasis. So what's happening?
Speaker 1: How many times could you be infected and be asymptomatic?
Speaker 1: It's also let's throw some more complex things in there.
Speaker 1: In all cases of leshmaniasis, the incubation period is very long, Okay,
Speaker 1: We're talking weeks to potentially months. So are people asymptomatic
Speaker 1: entirely or are they asymptomatic at the time that we
Speaker 1: test them to see if there have any evidence of parasites,
Speaker 1: but then many months later develop infection maybe for some
Speaker 1: portion of people. So in all three of these cases, cutaneous, mucocutaneous,
Speaker 1: and visceral leshmaniasis. These parasites are infecting macrophages. The clinical
Speaker 1: disease that we see depends on where they localize and
Speaker 1: whether or not they disseminate to the rest of your
Speaker 1: body and cause like a systemic infection. Okay, yeah, okay,
Speaker 1: So let's talk about the symptoms that we see. Cutaneous leshmaniasis,
Speaker 1: which is the most benign of the three. So that's
Speaker 1: what we'll talk about. And benign, by the way, does
Speaker 1: not mean that it's not severe. It can be debilitating,
Speaker 1: it can be extremely scarring, and as I'm sure you
Speaker 1: will talk about aaron, it's associated with a lot of stigma,
Speaker 1: but it just kills people less than the other reforms.
Speaker 2: Yep.
Speaker 1: So it's generally caused, like I said, by a number
Speaker 1: of different species of leshmania. The most common species are
Speaker 1: Leshmania mexicana, Braziliensis major and tropica, but there are a
Speaker 1: whole bunch more like thirteen or fifteen or something more.
Speaker 1: And cutaneous is exactly what it sounds like. It affects
Speaker 1: your skin, so it causes a more localized infection. It
Speaker 1: usually starts as what looks like a bug bite from
Speaker 1: where the sandfly bits someone, but it doesn't heal and
Speaker 1: over a long period of time, and the length of
Speaker 1: time depends a lot on the species, so we're talking
Speaker 1: anywhere from two months to fifteen months. This lesion where
Speaker 1: this sort of bug bite was begins to ulcerate, and
Speaker 1: it eventually leads to it can lead to pretty significantly
Speaker 1: large ulcers like open sores essentially, which from what I've read,
Speaker 1: are painless, but they look very painful. And then this
Speaker 1: is a localized and self limited infection. So generally these ulcers,
Speaker 1: over the course of weeks and months, they begin to
Speaker 1: heal via granulation. So like our normal body's healing process
Speaker 1: eventually kicks in, but it takes a really long time.
Speaker 1: And that's probably because as much as our body is
Speaker 1: trying to fight off this parasite, it's inside of our
Speaker 1: white blood cells, so it's really difficult for us to
Speaker 1: really fully eradicate this quickly. Yeah, And these ulcers lead
Speaker 1: to significant scarring. So the scar is generally a depressed
Speaker 1: and large like the size or a little bit smaller
Speaker 1: than how large the ulcer was scar and that can
Speaker 1: be very debilitating. Depending on where it is, it can
Speaker 1: be disfiguring and be associated with significant stigma, especially if
Speaker 1: it's on the face, which something like fifty percent of
Speaker 1: sandfly bites tend to be on the face, just because
Speaker 1: it's easily exposed. We don't generally have clothing on our face.
Speaker 1: So yeah, so that's cutaneous lashmaniasis. You can also imagine
Speaker 1: that since this is an open wound, you can get
Speaker 1: a secondary bacterial infection on top of it. Yep, which
Speaker 1: can lead to more complications.
Speaker 2: I'm starting to feel like Benign is not even coming
Speaker 2: close to accurately describing.
Speaker 1: Those It's not. It's just of these three, it is
Speaker 1: the least deadly.
Speaker 2: Okay, how about that?
Speaker 1: How about that?
Speaker 2: Okay?
Speaker 1: So next is mucosal or muco cutaneous leshmaniasis. This is
Speaker 1: a very destructive form of leshmaniasis that most of the
Speaker 1: time occurs after cutaneous leshmaniasis. It's most commonly associated with
Speaker 1: Leshmania braziliensis. Like you asked which species erin, but there
Speaker 1: are other species, Especially in people who are immunocompromised and
Speaker 1: don't have a good cell mediated immune response, then you
Speaker 1: can get mucosal leshmaniasis from other species as well. So
Speaker 1: this form of leshmaniasis presents often with nasal stuffiness, nose bleeds,
Speaker 1: sloughing off of tissue from inside your nose or mouth.
Speaker 1: It can result in erosion of any of your mucosal surfaces,
Speaker 1: so inside your mouth, your cheeks, your nose. Kind of
Speaker 1: the worst thing that can happen is it can essentially
Speaker 1: eat away through your nasal septum and completely destroy your nose.
Speaker 1: So it can be very disfiguring. And if it's associated
Speaker 1: with your trichia or epiglottis, for example, then it can
Speaker 1: cause respiratory compromise. So this form can be deadly, especially
Speaker 1: if it affects the mucosal surfaces that we use to breathe,
Speaker 1: for example. So that's depressing. Now let's move on to
Speaker 1: the most depressing and that is visceral leshmaniasis, which is
Speaker 1: also known as kala azar, which is Hindi for black fever.
Speaker 1: And that's what you heard in our first hand account.
Speaker 1: Like I mentioned earlier, it's most often caused by leshmania donovanni,
Speaker 1: but also leshmania in phantom and or shagasai, which are
Speaker 1: the same thing. And this is a truly horrible, horrible disease.
Speaker 1: I think that our first hand account did a lot
Speaker 1: more justice than I'm going to to describe just how
Speaker 1: awful it is. Clinically, what we see is a very slow,
Speaker 1: insidious over weeks to months where you have this fever
Speaker 1: and general malaise, just not feeling well. You have significant
Speaker 1: weight loss that leads to what we call cachexia, which
Speaker 1: is just like emaciation. Okay, But then on top of that,
Speaker 1: because this parasite is in our white blood cells that
Speaker 1: congregate in our spleen and liver, you get massive splenomegaly,
Speaker 1: so enlargement of your spleen, or hippatosplenomegaly, so enlargement of
Speaker 1: your spleen and liver. And because the other place that
Speaker 1: our white blood cells congregate is our bone marrow, this
Speaker 1: can lead to massive infection in your bone marrow that
Speaker 1: causes pan cytopenia, which means all of your bloodlines are depressed,
Speaker 1: so you're anemic. But also all your white blood cell
Speaker 1: count are very depressed, which means, as you can imagine,
Speaker 1: people are very susceptible to secondary infection because they have
Speaker 1: no immune defense. Essentially, visceral leishmaniasis is almost uniformly fatal
Speaker 1: if left untreated. Mortality is ninety five to one hundred percent.
Speaker 2: And is it caused typically by the parasitic infection directly
Speaker 2: or through secondary infections.
Speaker 1: Both, and I don't have a number on the exact
Speaker 1: percentage of which is which, but absolutely both are cause
Speaker 1: of death. Yeah, and leshmania Donovani. Like I mentioned earlier,
Speaker 1: there's kind of two different cycles of this disease. There's
Speaker 1: the anthroponotic, where humans are the main reservoir, and then
Speaker 1: there's the zoonotic where it's animals, whether domestic or wild,
Speaker 1: that are the major reservoirs for infection, and the main
Speaker 1: species that causes visceral leshmaniasis is also considered anthroponautics, So
Speaker 1: humans are the major reservoir rather than animals, right, Okay.
Speaker 2: Do you have a timeline specifically for muco cutaneous how
Speaker 2: long it takes for cutaneous to turn into the mucosal
Speaker 2: variety if it's going to go that way?
Speaker 1: Very good question. I think a lot of what I've
Speaker 1: seen is up to like six months or even a
Speaker 1: year or more after initial infection is when you can
Speaker 1: end up getting muco cutaneous or mucosalleshmaniasis. Yeah, gotcha, there's
Speaker 1: a little bit more. Okay, So I said there's three
Speaker 1: main syndromes of disease, but there's actually two others too,
Speaker 1: So there's a form called diffuse cutaneous leshmaniasis, which, as
Speaker 1: you can imagine, is like cutaneous leshmaniasis, but instead of
Speaker 1: one single ulcer, you have many. This is thought to
Speaker 1: be kind of an autoimmune related disease. It's not entirely
Speaker 1: clear why some people get it and other people don't,
Speaker 1: but essentially what happens is those parasites travel through your
Speaker 1: lymph system along lymph lines and can cause still a
Speaker 1: cutaneous only so it's still just in your skin, but
Speaker 1: a more widespread infection than just one single ulcer.
Speaker 2: Huh. Okay.
Speaker 1: It's also possible, though, to get multiple ulcers at one time,
Speaker 1: just from multiple sandfly bites, so this is more diffuse
Speaker 1: than just that. Okay.
Speaker 2: Can you have both visceral and cutaneous at the same
Speaker 2: time from like different species?
Speaker 1: You know, that's a really really good question. I don't
Speaker 1: know because I didn't ever see that anywhere, but these
Speaker 1: happen in the same locations, so I don't see why not.
Speaker 2: And like if immunity seems to develop over multiple exposures
Speaker 2: over time, right, and let's say that you, like, are
Speaker 2: you immune to just the cutaneous forms or like the
Speaker 2: ones the parasites that cause the cutaneous form, or are
Speaker 2: you also protected from visceral.
Speaker 1: It's this is a very very good question, and it's
Speaker 1: one that I still don't fully understand the answer to
Speaker 1: because of how complex the immunology of this is. I
Speaker 1: think that immunity is at least partially cross protective from
Speaker 1: what I understand. But that's why when we'll talk about vaccines,
Speaker 1: it's so important to develop a vaccine that results in
Speaker 1: immunity to multiple species of leshmania.
Speaker 2: Yeah, okay, I mean the vaccine things seems very difficult to.
Speaker 1: Oh my gosh, you have no idea. Okay, okay, there's
Speaker 1: one more disease that we have to talk about. We're
Speaker 1: not dying, and that is post kala azar dermal leshmaniasis.
Speaker 2: Oh my gosh.
Speaker 1: So let's break that down. Post kala azar So this
Speaker 1: means after someone survives kala azar, which is visral leash niasis.
Speaker 1: So that means someone who has been treated and successfully
Speaker 1: supposedly cured of cola azar dermal leshmaniasis. So now this
Speaker 1: is a skin manifestation of a prior visceral infection.
Speaker 2: What what does that look like? How does that happen?
Speaker 2: What proportion of cases does this happen? Like?
Speaker 1: Yeah, great questions. So the weirdest thing about this? Okay,
Speaker 1: first I'll answer what does this look like? It actually
Speaker 1: looks a lot like leprosy.
Speaker 2: Oh interesting, okay, yeah, So.
Speaker 1: It causes these kind of nodular lesions that can be
Speaker 1: throughout kind of all of your skin. Now who gets
Speaker 1: it and what proportion? This is very bizarre. It generally
Speaker 1: has only been described in certain regions, so in the
Speaker 1: Horn of Africa and in South Asia, not in Latin America,
Speaker 1: where we also see a lot of leshmaniasis.
Speaker 2: So in for.
Speaker 1: Example, Sudan, about fifty to sixty percent of people that
Speaker 1: were treated for visceraa leshmaniasis went on to develop post
Speaker 1: cola as our dermal leshmaniasis. And this usually happens between
Speaker 1: six months and a year after infection. Why does it happen?
Speaker 1: I don't know aarin. And in South Asia the incidents
Speaker 1: is much less, It's like five to fifteen percent and
Speaker 1: the interval is often longer.
Speaker 2: Is the treatment different like the most common treatment used?
Speaker 1: Good question overall, so we can talk about treatment.
Speaker 2: Sorry, no, no, don't be sorry.
Speaker 1: So first I'll say that what we do know about
Speaker 1: this is it seems to be a reactivation of the infection.
Speaker 1: That is, people who present with PKDA post cola as
Speaker 1: our dermal leshmaniasis are infectious to sandflies, so they have
Speaker 1: parasites still in their system. So this suggests that whatever
Speaker 1: treatment was used didn't really eradicate that infection in their
Speaker 1: bodies erin, So what do we do to treat it?
Speaker 2: Okay, my face is like uttershock and confusion.
Speaker 1: That's how my face has been through all of this reading. Okay, So,
Speaker 1: for a long time, treatment for both visceral and cutaneous
Speaker 1: and mucosal leshmaniasis was with what's called pentavalent antimonials. Okay,
Speaker 1: that's just a fancy term for the specific drug that
Speaker 1: was first used to treat leshmaniasis. As was mentioned in
Speaker 1: our first hand account, this drug requires daily administration via
Speaker 1: injection for anywhere from twenty eight to thirty days, so
Speaker 1: it's a very long course and it requires a healthcare
Speaker 1: provider to be able to give those injections. And nowadays
Speaker 1: resistance is very widespread to these drugs. Oh my god,
Speaker 1: So those that are not used as much anymore. Yeah,
Speaker 1: Luckily there are other drugs, but drug treatment for leshmaniasis
Speaker 1: is a pretty major problem, as you can imagine. One
Speaker 1: drug that seems very promising and has been shown at
Speaker 1: least in some regions to be very effective, is liposomal
Speaker 1: amphoteraesin B. I don't know if you remember we talked
Speaker 1: about amphoterrasin B in the context of cystic fibrosis of
Speaker 1: all things.
Speaker 2: Do you remember that, No, I have to be honest.
Speaker 1: Now that's okay, you don't have to I just thought
Speaker 1: it was fun. Anyways, amphoterrasin B. It's an anti fungal, actually,
Speaker 1: but this specific formulation has been found to be effective
Speaker 1: at least in India and Bangladesh as a single dose cure.
Speaker 1: Really yep, one single dose, which is major. It's still
Speaker 1: an injection. You have to give it by IV, but
Speaker 1: it's one dose. So not only does that make it
Speaker 1: less likely that we're going to develop resistance because you
Speaker 1: don't have to keep giving it over and over and over,
Speaker 1: but it also is great in terms of being able
Speaker 1: to treat people and not have to have them come
Speaker 1: back and back and back. But it is still really expensive.
Speaker 2: And I've also read that a lot of people do
Speaker 2: not react well to it, like it has a very
Speaker 2: variable tolerance yees, and so you may not be able
Speaker 2: to take it at all.
Speaker 1: And amphitereism B itself is a very very toxic drug,
Speaker 1: so this specific formulation is a little less toxic. But yes,
Speaker 1: for all of these drugs, the side effect profile is
Speaker 1: the side effect profile, and the cost and the root
Speaker 1: of administration and resistance, all those things are some of
Speaker 1: the barriers to treatment for leshmnisis there's a lot going
Speaker 1: on here.
Speaker 2: The cost is unreal.
Speaker 1: Yeah, there are a couple of other drugs. There is
Speaker 1: at least one oral drug, which is you can imagine
Speaker 1: being able to give someone a pill is a lot
Speaker 1: better than having to give injections. And that's mill to phocine.
Speaker 1: I'm guarantee I'm pronouncing that incorrectly, but anyways, that's an
Speaker 1: oral drug that was effective for a time, but now
Speaker 1: there's massive resistance to it. So to answer your question
Speaker 1: that you asked about postcla as our dermal lashmaniasis, if
Speaker 1: different treatments are used in different areas, the answer is
Speaker 1: generally yes, we have all these different treatments available, but
Speaker 1: what is available in any given region can definitely vary,
Speaker 1: and what is still effective and or affordable in different
Speaker 1: regions also varies. So how much of a role that
Speaker 1: might play in PKDL is a really good question. I
Speaker 1: imagine it must play a role because this is a
Speaker 1: reactivation of an infection, which means that our cure didn't
Speaker 1: fully cure.
Speaker 2: Right.
Speaker 1: So there's also a lot of interest in using combination
Speaker 1: therapy the way that we do for something like tuberculosis,
Speaker 1: which is also a very long lasting disease or HIV.
Speaker 1: So there are a lot of different drug combinations that
Speaker 1: are being used as well. So that's Is that long
Speaker 1: enough for you? That's the biology.
Speaker 2: It's quite a long wow.
Speaker 1: Yeah, my goodness. So here's the thing here, and I
Speaker 1: have a lot of questions for you. Oh boy, where
Speaker 1: on Earth literally and figuratively did this parasite come from?
Speaker 1: How are there so many that cause so many different
Speaker 1: diseases in humans? Like, just give give it all to me.
Speaker 1: I want to know what's going on.
Speaker 2: Please, I'll do the best that I can. Right after
Speaker 2: this break, Okay, the history of leshmaniasis right off the bat,
Speaker 2: let me just say that these are some incredibly old parasites.
Speaker 2: Oh yeah, Like I'm not just talking oh ancient Egyptian papyri.
Speaker 2: Although I will get there. I mean, like millions upon
Speaker 2: millions upon millions of years old.
Speaker 1: I am not surprised by that.
Speaker 2: It's very cool. Okay. The sheer diversity of Leshmania species
Speaker 2: and the range of hosts that they infect gives us
Speaker 2: some idea of their ancientness. But did you know that
Speaker 2: Leshmania like fossils were found in the proboscis and elementary
Speaker 2: track of an extinct sandfly encased in amber from the
Speaker 2: Cretaceous period. Stop it over a one hundred million years
Speaker 2: old I'm sorry.
Speaker 1: They found it in thescuz of a sandfly.
Speaker 2: Yes, yes, yeah, one hundred million years old, and these
Speaker 2: are Leshmania like but they were probably like they were
Speaker 2: probably the ancestors of the current or present Lashmania species.
Speaker 1: So we're talking like dinosaur infection.
Speaker 2: Oh yeah. So this, this preserved sand fly was filled
Speaker 2: with reptilian blood, and the presence of a parasitic life
Speaker 2: stage of the parasite also in the blood suggests that
Speaker 2: this le that this Leshmania like species was actually a
Speaker 2: two host parasite, with one of the hosts being reptiles.
Speaker 1: Oh my, yeah, I can't explain how thrilling that is.
Speaker 2: So because like we we see a lot of the
Speaker 2: ancestors of parasites as like, oh, this had a mutualism
Speaker 2: with this and then it found an opportunistic host. But
Speaker 2: this parasitic life cycle goes back to like millions and
Speaker 2: hundreds of millions of years.
Speaker 4: That's phenomenal, Like to have evidence of a dual host
Speaker 4: parasitic life cycle one hundred million years ago.
Speaker 2: Yeah, like, ooh, I know, it's very cool.
Speaker 1: That is fascinating.
Speaker 2: Okay, but those aren't the parasites that we see today
Speaker 2: in humans. So let's talk about the origins of those guys,
Speaker 2: all right. Turns out it's not as simple as that
Speaker 2: of the episode. So, as you mentioned Aaron, as you
Speaker 2: went over, there are many different species of leshmania that
Speaker 2: infect humans, and they can be found all over the world,
Speaker 2: with the highest concentrations in the tropics and subtropics. But
Speaker 2: unlike many of the other pathogens we've talked about, their
Speaker 2: current worldwide distribution wasn't caused solely by human travel. So
Speaker 2: a lot of the times we talk about how okay
Speaker 2: it emerged in Let's say that there was a pathogen
Speaker 2: that emerged in Africa and then it sort of dispersed
Speaker 2: out from there as humans traveled. This isn't the.
Speaker 1: Case, is that because it infects so many other species.
Speaker 2: Yeah, that's what it seems to be. That's what seems
Speaker 2: to be. Actually, most of the leshmania species that we
Speaker 2: see in the New World evolved there rather than being
Speaker 2: brought over from the Old World, you know, during Columbus
Speaker 2: era exploration.
Speaker 1: Cool.
Speaker 2: There is one notable exception, though, which is Leshmania shagasai,
Speaker 2: which is now thought to be, as we've talked about,
Speaker 2: synonymous with leshmania and phantom and they think and people
Speaker 2: think that was brought to South America about five hundred
Speaker 2: years ago during the European settlement, so by either the
Speaker 2: settlers themselves or their dogs.
Speaker 1: Oh okay. Interesting.
Speaker 2: And there are a few different hypotheses as to the
Speaker 2: geographical origin of the different species of leashmania, or like
Speaker 2: the different genera. And I'm not going to go into
Speaker 2: each one of these because, to be honest, I didn't
Speaker 2: fully understand the papers that I read.
Speaker 3: That's how I felt about the immunology erin I'm like, ooh,
Speaker 3: but it seems to me that the take home is
Speaker 3: that the genus probably evolved in the Mesozoic era, so
Speaker 3: like two hundred and fifty two to sixty six million.
Speaker 2: Years ago, oh my gosh, on the super continent Gondwana.
Speaker 1: Okay.
Speaker 2: And then after it broke up and the sandflies and
Speaker 2: vertebrate hosts migrated and then diversified and then evolved into
Speaker 2: the different you know, subgenera and species that we see today.
Speaker 1: Wow. Wow.
Speaker 2: So there may have also been some bearing land bridge
Speaker 2: crossing by some rodent hosts during the Eocene that led
Speaker 2: to the subgenus Leshmania being brought to the ne Arctic
Speaker 2: from Asia, which later gave rise to the American Leishmania species.
Speaker 2: So that honestly, I don't know what that means entirely,
Speaker 2: but I did know it when I wrote it. Okay, goodness, okay, okay.
Speaker 2: So we've established that Leshmania is a very old like
Speaker 2: dinosaur old different Leshmania parasites have probably been infecting humans
Speaker 2: since before humans were humans, stands to reason, ancient descriptions
Speaker 2: of Lashmania Alegians go back thousands of years. There's a
Speaker 2: tablet from the seventh century BCE that is actually thought
Speaker 2: to be copied from earlier text dating back to fifteen
Speaker 2: hundred to twenty five hundred BCE that describes something awfully
Speaker 2: close to a leshmania a lesion, And of course I
Speaker 2: have to mention legally the Ebers papyrus Ebers from fifteen
Speaker 2: hundred BCE, which mentions something called a nile pimple which
Speaker 2: seems to refer to cutaneous leshmaniasis.
Speaker 1: Okay.
Speaker 2: And then there's the famous Persian physician Avicenna, who lived
Speaker 2: in a tenth century BCE, and he also described something
Speaker 2: called balk sore from northern Afghani the stand, which sounds
Speaker 2: a lot like the dry lesions caused by leshmania tropica. Okay, okay.
Speaker 2: And then as far as South America goes, there are
Speaker 2: some pre Columbian ceramics from around the fifth century that
Speaker 2: depict disfiguring facial conditions that seem to suggest the presence
Speaker 2: of uco cutaneous leshmaniasis.
Speaker 4: Wow.
Speaker 2: All right, now, if you prefer physical evidence and mummies
Speaker 2: over tablets and papyri, we've got you covered. A study
Speaker 2: of forty two Egyptian mummies dating from around twenty fifty
Speaker 2: to sixteen fifty BCE found DNA from leshmania, probably Leshmania donavani,
Speaker 2: in four of the mummies, which means that visceral leshmaniasis
Speaker 2: was likely present in ancient Egypt.
Speaker 1: Whoa.
Speaker 2: Yeah, and on the other side of the ocean, researchers
Speaker 2: have found leshmania DNA in a Peruvian mummy of a
Speaker 2: six year old girl data from eight hundred PCE. And
Speaker 2: because some types of leshmania can leave traces on bones
Speaker 2: muco cutaneous, namely, we can see the physical impact of
Speaker 2: leshmaniasis on skulls found in Chile dating to the eleventh century. Whoa,
Speaker 2: which would indicate the presence of mucocutaneous lesh along with
Speaker 2: those pre Columbian pottery.
Speaker 1: Oh my goodness.
Speaker 2: Yeah. It's kind of difficult to assess or to describe
Speaker 2: just how much of an impact that leshmaniasis may have
Speaker 2: had on the establishment of like a village or a
Speaker 2: city in a particular area, or whether there were significant
Speaker 2: outbreaks associated with one of the types of leshmaniasis. But
Speaker 2: we do know for sure that humans have taken note
Speaker 2: of the different forms, which gave rise to many different nicknames,
Speaker 2: and in some cases it altered their behavior to try
Speaker 2: to prevent the disease. For instance, when the Spanish invaded
Speaker 2: South America in the sixteenth century, they noted that in
Speaker 2: the Peruvian Andes, disfiguring facial conditions were common among the
Speaker 2: coca growers who worked on the lower slopes, and that
Speaker 2: usually either people who were enslaved or of a lower
Speaker 2: social class tended to be the ones that worked at
Speaker 2: these lower altitudes. So it's sort of like there was
Speaker 2: It seemed to suggest that the risk of working at
Speaker 2: lower altitudes was known, and over the years some researchers
Speaker 2: have suggested that Incan settlements tended to be restricted to
Speaker 2: highlands and avoided in the lowland forest out of fear
Speaker 2: of leshmaniasis. But I read a note that an article
Speaker 2: or a note in response to an article that actually
Speaker 2: seems that it's probably not the case. Seems to be
Speaker 2: based on a few false assumptions that wet tropical valleys
Speaker 2: and rainforests were empty of archaeological ruins, which is actually
Speaker 2: just turns out that they're just more difficult to spot,
Speaker 2: and because the rainforest is like fairly resilient to some degree, anyway,
Speaker 2: that makes sense, Yeah, all right. So some of the
Speaker 2: very first descriptions of leshmaniasis in modern times were made
Speaker 2: by the Scottish physician and naturalist Alexander Russell in the
Speaker 2: mid seventeen hundreds, and he described what was known at
Speaker 2: the time as Oriental sore, Aleppo, boil Bagdad, boil Jericho, buttons,
Speaker 2: et cetera.
Speaker 1: Lots of different nicknames, all of these names that we
Speaker 1: don't use anymore uses them.
Speaker 2: But basically what he was describing was cutaneous leshmaniasis, and
Speaker 2: he also described different forms, so a wet form and
Speaker 2: a dry form, which likely corresponded to either the zoonatic
Speaker 2: cutaneous lesh caused by Leshmania major and dry anthroponautic cutaneous
Speaker 2: lush caused by L. Tropica. And he also noted that
Speaker 2: the lesions tend to heal within eight to ten months,
Speaker 2: and that all the many different treatments existed, he felt
Speaker 2: that they often did more harm than good.
Speaker 1: It's still true today for any treatments that are available, and.
Speaker 2: He recommended doing nothing or at the very most apply
Speaker 2: a plaster of mercury, which I can't imagine would have
Speaker 2: been that great. But from the DNA analysis of those
Speaker 2: mummies from ancient Egypt, we know that visceral leshmaniasis had
Speaker 2: been around for thousands of years, but there doesn't seem
Speaker 2: to be any writings about it until the nineteenth century,
Speaker 2: which is interesting considering that it is pretty like unique,
Speaker 2: or at least like recognizable. Yeah, and it also is
Speaker 2: associated with an extremely high mortality rate.
Speaker 1: Yeah. So I wonder is it just that it's so
Speaker 1: prolonged of an infection that, like other I don't know that's.
Speaker 2: Really this r I think it could be a few things.
Speaker 2: I think it could be, like you know, when I
Speaker 2: was when I was researching this, it was I would say,
Speaker 2: like a bit of a challenge to find good comprehensive
Speaker 2: historical descriptions of leshmaniasis. So I wonder if it's just
Speaker 2: that we haven't been looking quite as as much. Okay, Yeah,
Speaker 2: But the other thing is that it might have been
Speaker 2: more localized, like it might have been, it might have
Speaker 2: not persisted in certain areas, like there does seem to
Speaker 2: be a lot of inter annual variation in exposure and
Speaker 2: in prevalence and so on, and so maybe it's just
Speaker 2: and we don't really know the reasons for that, because
Speaker 2: a lot of vector born diseases are just so dang
Speaker 2: complicated in that way. Yeah, And so I wonder if
Speaker 2: that's part of it as well, is that it tended
Speaker 2: to be localized and then in other areas it may
Speaker 2: have popped up but then disappeared. Okay, So yeah, yeah,
Speaker 2: and so in eighteen twenty seven, a military surgeon named
Speaker 2: William Twining published a full description of visceral leshmaniasis, which,
Speaker 2: as we've talked about, is known as kala azar, and
Speaker 2: it was found to be prevalent in certain parts of India,
Speaker 2: and throughout the rest of the nineteenth century, kala azar
Speaker 2: seemed to spread, popping up an epidemic form across much
Speaker 2: of India, and because of the way it's spread and
Speaker 2: the timing of it spread, it earned the nickname government
Speaker 2: disease because it seemed to emerge. Yeah, it seemed to
Speaker 2: emerge whenever and wherever the British government established colonial rule.
Speaker 1: I that actually kind of makes some sense in some ways.
Speaker 2: Yeah, I mean I don't to be I don't know
Speaker 2: much about the ecology of sand flies and whether they're
Speaker 2: like whether certain species are more urban or like, whether
Speaker 2: there's what the association is with land use change and
Speaker 2: so on. But I really wonder if just just the
Speaker 2: the increased movement.
Speaker 1: Oh maybe maybe we'll talk about it a little more
Speaker 1: than touch on that evstic plastic.
Speaker 2: But yeah, So, during a highly epidemic period of around
Speaker 2: twenty five years in the second half of the eighteen hundreds,
Speaker 2: visceral lushmaniasis killed twenty five percent or more of the
Speaker 2: population in certain areas. What and more people fled, leaving
Speaker 2: some villages nearly empty. So like there do seem to
Speaker 2: be and there have been like a lot of you know, epidemics,
Speaker 2: But I think what's driving it is a very interesting question.
Speaker 2: And while there can be epidemics of cutaneous lushmaniasis, I
Speaker 2: think that the extremely you know, and as maybe you'll
Speaker 2: talk about some of the more recent epidemics, the extremely
Speaker 2: high case fatality rate of untreated visceral lushmaniasis perhaps made
Speaker 2: these outbreaks more noticeable and alarming, especially since during most
Speaker 2: of the eighteen hundreds neither the causative agent nor the
Speaker 2: vector had been discovered. Who Okay, As with many of
Speaker 2: the neglected tropical diseases that we've talked about on this podcast,
Speaker 2: can you guess what spurred on researchers to try to
Speaker 2: figure out the mystery of the different forms of leshmaniasis.
Speaker 1: Were they like colonizing places and then dying because of it?
Speaker 2: Yeah, precisely.
Speaker 4: So.
Speaker 2: The British presence in India in the eighteen hundreds and
Speaker 2: into the nineteen hundreds made leshmaniasis a priority for that country,
Speaker 2: and it didn't actually take all that long to uncover
Speaker 2: the secret behind the enlarged spleens and emaciation seen in
Speaker 2: some of the military that were stationed in some areas.
Speaker 2: In November of nineteen hundred, a Scottish pathologist named William Leshmann.
Speaker 2: Can you guess what he did? No, you can't guess
Speaker 2: what someone named William Leshman did.
Speaker 4: Oh?
Speaker 1: Oh, like he discovered the I thought you meant? Like
Speaker 1: how he discovered it?
Speaker 4: Like?
Speaker 1: That was one of the two obvious.
Speaker 2: Questions in softball. There's ever been a softball Wait?
Speaker 1: Try again, try again?
Speaker 2: Okay, can you guess what William Leshman did?
Speaker 1: Did he discover leshmania?
Speaker 2: He did?
Speaker 1: Oh?
Speaker 2: My gosh, he yeah. So he looked at some samples
Speaker 2: from a spleen of a soldier who had died.
Speaker 1: I was gonna guess he looked at spleen samples erin like,
Speaker 1: that's what I thought you were going for.
Speaker 2: Oh oh, well, then you know I would have been
Speaker 2: so impressed.
Speaker 1: Okay, anyway, sorry.
Speaker 2: And then he also found the same parasites and experimentally
Speaker 2: infected rats, and so he reasoned that he had found
Speaker 2: the cause of agent of this deadly illness that he
Speaker 2: called dumb dumb fever, which is named after a town
Speaker 2: where he was working, called dumb Dum, like dumdum.
Speaker 1: Yeah, oh gosh.
Speaker 2: And he thought it was a type of trypanosome because
Speaker 2: he was like, oh, it looks like a little ovoid body.
Speaker 2: It's got to be a trypanosome. But then a few
Speaker 2: weeks after Leshman's paper was published, an Irish doctor named
Speaker 2: Charles Donovan don Vanni, he published similar findings, so ovoid
Speaker 2: parasite bodies in the spleen of an affected person. But
Speaker 2: he was like, no, this is not a type of
Speaker 2: tripanosome like this, It's just not. But I don't know
Speaker 2: what it is. So he got a few more people involved,
Speaker 2: and ultimately it was the British medical doctor Ronald Ross
Speaker 2: who declared that these ovoid bodies represented a new species
Speaker 2: of parasite, a new type of parasite, and propose that
Speaker 2: they be called Leshmania Donovanni to give credit to the
Speaker 2: two major discoverers.
Speaker 1: So at least they didn't name it after themselves. Someone
Speaker 1: else named it after them.
Speaker 2: I think, I mean, even historically it didn't happen a lot,
Speaker 2: right that.
Speaker 1: People named things after themselves. Yeah, I don't think so. Okay,
Speaker 1: you never know.
Speaker 2: Someone tell us if we're wrong, because we're probably wrong.
Speaker 1: We're often wrong the.
Speaker 2: Majority of the time. Okay. I should note that there
Speaker 2: was a third discoverer who actually published his finding several
Speaker 2: years before Leshman and Donovan, a Russian scientist whose name
Speaker 2: was Pyotr Borowsky. Okay, but he did so in an
Speaker 2: obscure Russian language journal, and so his contribution was realized
Speaker 2: only long after the fact.
Speaker 1: That's a bummer. That's English language bias.
Speaker 3: It is.
Speaker 1: Yeah.
Speaker 2: The discoveries of the causes of cutaneous and muco cutaneous
Speaker 2: leshmaniasist followed pretty quickly after that of viscera lesh. In
Speaker 2: nineteen o three, the American pathologist James Homer Wright published
Speaker 2: a description of the parasite that he observed in a
Speaker 2: sample from a patient's sore. That makes sense, but he
Speaker 2: didn't immediately realize that it was a species of leshmania,
Speaker 2: But that would happen a few years later the recognition
Speaker 2: that it was actually lushmania, so reclassification. And then in
Speaker 2: nineteen oh nine is when Brazilian doctor Adolfo Carlos Lindenberg
Speaker 2: and Italian physician Antonio Karini discovered parasites in the ulcers
Speaker 2: of those suffering from muco cutaneous lushmaniasis. Okay, okay, yeah,
Speaker 2: But despite these advancements in knowledge about the causes of
Speaker 2: these very feared diseases, there were huge gaps in knowledge
Speaker 2: that remained, and closing the gaps was necessary if there
Speaker 2: was going to be any successful control efforts. First of all,
Speaker 2: how do people even get this disease? Understanding how a
Speaker 2: disease is transmitted is huge for identifying how you can
Speaker 2: reduce the likelihood of transmitting it makes sense. Hence masks
Speaker 2: and social.
Speaker 1: Distancing still relevant, still relevant.
Speaker 2: Not long after the first descriptions of Lushmania parasites, researchers
Speaker 2: thought that the disease was likely vector born, since the
Speaker 2: parasites shared some morphological similarities with other parasites that were
Speaker 2: transmitted by biting insects like tripan. So with that toge them,
Speaker 2: the search was on, and maybe surprisingly, the search went
Speaker 2: on for years, Like it took a long time.
Speaker 3: You know.
Speaker 1: That's interesting, Yeah.
Speaker 2: Because the parasites themselves are easily observable, and I mean, okay,
Speaker 2: granted there are a lot of biting insects.
Speaker 1: There are a lot of biting insects, and sandflies are
Speaker 1: very small.
Speaker 2: They're very small, very small, I mean, but they looked
Speaker 2: into like literally everything mosquitoes, fleas, lice, midges, stable flies, ticks, tetc. Flies, houseflies,
Speaker 2: you name it.
Speaker 1: But they maybe they didn't think about sand flies as
Speaker 1: as biting.
Speaker 2: Anyone who's biting sand flies, you know, they're biting.
Speaker 1: And they're the worst, the worst, the actual worst.
Speaker 2: Horrible, horrible.
Speaker 1: Yeah, I don't know. Maybe they just didn't think of
Speaker 1: them as vectors, yeah, because they hadn't been before.
Speaker 2: I mean, so I think it also the conformation might
Speaker 2: have been what took so long as well, and also
Speaker 2: for a while, I think because in certain areas it
Speaker 2: might just be so prevalent, but in certain in other
Speaker 2: areas where different sandfly species maybe exists, it's not as prevalent,
Speaker 2: Like maybe it's just the association. And so for a while,
Speaker 2: bedbugs actually seemed like the likeliest culprit.
Speaker 1: Interesting because of the housing aggregation exactly.
Speaker 4: Yeah.
Speaker 2: Yeah, But then a few findings steered the ship towards sandflies.
Speaker 2: First was a nineteen twelve report of flagellots found in
Speaker 2: the guts of sandflies caught at Aleppo, a place that
Speaker 2: historically has had a very high prevalence of anthropronautic cutaneous lushmaniasis.
Speaker 2: And the second was in nineteen twenty one when two
Speaker 2: French biologists and brothers, the sergeant Brothers, Sir Jean, I
Speaker 2: don't know, Sir Jean put some ground sand flies into
Speaker 2: the skin of volunteers who then developed cutaneous lushmanias as leader.
Speaker 1: Sorry, can you say quote unquote volunteer air quote?
Speaker 2: I think from this point on in the podcast Long Ago,
Speaker 2: hopefully people assume air quotes around volunteers whenever it's mentioned.
Speaker 1: It's good.
Speaker 4: That's a good rule of thumb for this podcast. If
Speaker 4: you hear the word volunteers, just no, it doesn't really
Speaker 4: mean volunteers.
Speaker 2: No, But this was not taken as conclusive proof the
Speaker 2: emergence of their lesions, and doubt over the life cycle
Speaker 2: of cutaneous and visceral Leushmanias as parasites lingered for almost
Speaker 2: twenty years until in nineteen forty one, five volunteers were
Speaker 2: bitten by sand flies infected with Leshmania tropica and lesions
Speaker 2: were produced. Okay, okay, there's no mention of where those
Speaker 2: volunteers came from, but there was a note saying that
Speaker 2: they all survived their infections.
Speaker 1: Great.
Speaker 2: A year later, sand flies were shown to also transmit
Speaker 2: visceral leshmaniasis, and the link between mucocutaneous leshmaniasis and sandflies
Speaker 2: had actually been uncovered back in nineteen twenty two. It's
Speaker 2: interesting because now we tend to think of them as
Speaker 2: just like one, like an umbrella leshmaniasis. Yeah, I think
Speaker 2: back then it was still so divided, like, oh, well,
Speaker 2: this is another type of parasite, and so I think
Speaker 2: it the connections weren't easily made, in addition to the
Speaker 2: fact that like scientific knowledge spread a lot more slowly
Speaker 2: back in those times. So anyway, so the second big
Speaker 2: gap in knowledge about lushmaniasis, which is effective treatment, that
Speaker 2: was filled in the nineteen forties with discovery that pentistam
Speaker 2: was effective against the parasites, and then again in the
Speaker 2: late nineteen fifties with amphoters and b and then throughout
Speaker 2: the eighties and into the nineties. Leshmaniasis sort of took
Speaker 2: on an increased importance during the HIV pandemic, when it
Speaker 2: seemed to be highly correlated and also a cause of
Speaker 2: like you know, increased mortality among people who are already
Speaker 2: immunosuppressed and sort of like one infection feeding into the other.
Speaker 2: But despite our long standing knowledge of these parasites and
Speaker 2: their existence, and despite the fact that we know more
Speaker 2: and have more technology to study them to develop drugs, etc.
Speaker 2: There doesn't really seem to be much improvement regarding the
Speaker 2: widespread prevalence of leshmaniasis and the absolutely enormous devastation that
Speaker 2: it causes, not just death, not just disfiguration leading to stigma,
Speaker 2: but its role in the cycle of poverty, which I'm
Speaker 2: sure you'll talk more about. It is one of the
Speaker 2: biggest contributors to widespread travel, civil unrest, land use change,
Speaker 2: global climate change. These have all not only perpetuated the
Speaker 2: cycle of infection and infected areas, but have also led
Speaker 2: to the emergence of different forms of leshmaniasis in areas
Speaker 2: previously unexposed, which is honestly some of the only times
Speaker 2: that it ever gets headlines in places like the US,
Speaker 2: when it's like global climate change could lead to you
Speaker 2: getting this skin eating parasite, and it's like people live
Speaker 2: with this on a daily basis, and like okay, sorry,
Speaker 2: and I love.
Speaker 4: When your section at the end of your history section
Speaker 4: and then my EPI section are just like the same thing.
Speaker 1: It's my favorite.
Speaker 2: Oh my gosh, yeah, it's I mean, I feel like
Speaker 2: the history has come to just such an abrupt end
Speaker 2: because it's not over like, yeah, that's you know, where
Speaker 2: we are today is very much where we were one
Speaker 2: hundred years ago, if not in a worse situation.
Speaker 1: Wow, that's depressing, Aaron.
Speaker 2: Yeah, you know, we have a lot of this information,
Speaker 2: but it doesn't always reach the areas that need it.
Speaker 2: So for instance, there's you know, in the places where
Speaker 2: there's a lot of stigma. There's also enormous problems in
Speaker 2: misconceptions regarding how the disease is transmitted, and so sometimes,
Speaker 2: for instance, it's believed in many places to be transmitted
Speaker 2: directly from direct contact, so skin to skin, and so
Speaker 2: people are often not allowed to their babies are taken
Speaker 2: away from them, or they're forced to be like, oh no,
Speaker 2: you have to go isolate for a really long time,
Speaker 2: even though that doesn't really like they are not infectious
Speaker 2: to other individuals directly, so right, Yeah, it's honestly, this
Speaker 2: is this is one of the most frustrating diseases I
Speaker 2: think that we've covered, like, because it really does seem
Speaker 2: like why has there not been more? And people are
Speaker 2: doing a lot of work, but I just feel like
Speaker 2: this is one of the big guys. And yeah, so Aaron, gosh, Aaron,
Speaker 2: why don't you fill us in on where we stand
Speaker 2: with lushman Issis today?
Speaker 1: Oh? I'd love to. I'll be able to answer at
Speaker 1: least some of your why why questions right after this break. Oh, gosh, Aaron.
Speaker 1: The answer as to why why? Why why? The short
Speaker 1: answer is that so lashmaniasis is considered a neglected tropical disease.
Speaker 1: We've talked about neglected tropical diseases on this podcast before,
Speaker 1: but even as far as neglected tropical diseases go, leshmaniasis
Speaker 1: is often considered the most neglected by some people. And
Speaker 1: that's because in large part of how strong the association
Speaker 1: is between leshmaniasis and poverty, which is true for almost
Speaker 1: all neglected tropical diseases, but for lashmaniasis, it's really not
Speaker 1: enough to just say, oh, this is a disease of
Speaker 1: poverty the end, right, we have to understand the role
Speaker 1: that income and poverty play in infectious disease, and then
Speaker 1: the role like you mentioned that this disease plays in
Speaker 1: reinforcing that cycle of poverty, and it's very multifactorial. So
Speaker 1: I'll kind of just touch on the highlights, but I
Speaker 1: do want to shout out a great paper on this
Speaker 1: topic that was by alvar at All, really great paper
Speaker 1: on this exact topic if you'd like to read more.
Speaker 1: But basically it's very multifactorial. So in a lot of
Speaker 1: the world where leshmaniasis is endemic, people living in poverty
Speaker 1: live in housing conditions that are very suitable for sandfly
Speaker 1: growth and development, whether it's because they have cracks in
Speaker 1: the walls or damp floors or mud floors that make
Speaker 1: it very easy for sandflies to grow and live in
Speaker 1: the domestic environment. Then on top of that, they're living
Speaker 1: with poor sanitation and maybe not often trash pick up
Speaker 1: things like that that also provide habitat for sandfly growth
Speaker 1: and development. They often live in closer proximity to animals
Speaker 1: and with a greater density of animals that can play
Speaker 1: a complicated role in the zoonotic transmission in places where
Speaker 1: this mostly a zoonotic disease, And then you have a
Speaker 1: lack of access to treatments, which can increase both anthroponotic
Speaker 1: and zoonotic transmission, but especially anthroponotic transmission within households. So
Speaker 1: a lot of the small scale epidemiology of leshmaniasis is
Speaker 1: clustered in household groups because of.
Speaker 4: The anthroponotic transmission. So that's how kind of the ecological.
Speaker 1: Ways that poverty and disease can go hand in hand.
Speaker 1: Poverty also leads to malnutrition, which can absolutely and does
Speaker 1: exacerbate and worsen the symptoms and outcome of disease, especially leshmaniasis.
Speaker 1: It makes it much more likely that someone will get
Speaker 1: severely ill or die from infection rather than having an
Speaker 1: asymptomatic infection. And then on top of that displacement, whether
Speaker 1: due to war or economic necessity or like you mentioned Aaron,
Speaker 1: climate change. Climate change can have so many effects on
Speaker 1: this disease and it will continue to do so for Yeah, yeah,
Speaker 1: there are some really interesting modeling papers that will link
Speaker 1: to to Like you said, people only care if it's
Speaker 1: in our backyard, Well that's what the modeling suggests that
Speaker 1: it will be soon. So those things can absolutely increase
Speaker 1: the risk of disease transmission and also change its distribution
Speaker 1: so that new people who have never been exposed before
Speaker 1: are now exposed for the first time to infection, rather
Speaker 1: than having been exposed over time and developed some sort
Speaker 1: of immunity, if that makes sense. Yes, yeah, Oh, but
Speaker 1: there's more because poverty also increases barriers to accessing healthcare,
Speaker 1: like we heard in our first hand account, whether it's
Speaker 1: leaving further from access to healthcare and having transportation barriers
Speaker 1: and getting there education barriers like you kind of touched
Speaker 1: on Aaron, such that people are either less likely to
Speaker 1: recognize disease or know how it's transmitted, or seek care
Speaker 1: until too late in the course of disease. A lot
Speaker 1: of home remedies, especially for cutaneous leshmaniasis, result in worse
Speaker 1: outcomes compared to either just leaving cutaneous leshmaniasis alone or
Speaker 1: treating it with kind of standard treatments. And there's a
Speaker 1: lot of difficulty in paying for and receiving treatment even
Speaker 1: if you can access it, because it's expensive.
Speaker 2: It's oh my gosh, it's enraging how expensive it is.
Speaker 1: Yes, okay, And it's been well documented that for women,
Speaker 1: especially the stigma associated with infection and the scarring from
Speaker 1: cutaneous lashmaniasis is so severe that women are substantially less
Speaker 1: likely to seek care, so they have even longer delays
Speaker 1: in seeking treatment compared to men. In a lot of
Speaker 1: endemic areas. There has been well documentmented psychological burdens of
Speaker 1: leshmaniasis as well. It's strongly associated with major depressive disorder,
Speaker 1: largely because of the scarring and the stigma associated with it.
Speaker 1: Let's back up a minute and talk about actual numbers
Speaker 1: for a second now that we kind of understand just
Speaker 1: how important this is in like the cycle of poverty,
Speaker 1: and that it has effects on psychosocial outcomes as well.
Speaker 2: Right, it is, Yeah, the numbers are important because wow.
Speaker 1: Yes, So a twenty twelve paper that's really commonly cited
Speaker 1: that has estimated because you can imagine, this is such
Speaker 1: a neglected disease that underreporting is just like we absolutely
Speaker 1: don't know the true incidence of disease. But so this
Speaker 1: twenty twelve paper that's very well cited estimated between two
Speaker 1: hundred and four hundred thousand cases of visceral leshmaniasis every year.
Speaker 2: The one that call is death, the one.
Speaker 1: That causes death. And here's something also important that I
Speaker 1: haven't even said yet. It's almost entirely fatal if untreated.
Speaker 1: Even if it's treated, the mortality can be as high
Speaker 1: as ten to twenty percent. So the total number of
Speaker 1: deaths per year is estimated at anywhere from twenty to
Speaker 1: forty thousand people dying from leshmaniasis.
Speaker 2: And I wonder how many of those are also because
Speaker 2: of like not being able to afford treatment.
Speaker 1: Exactly right, Yeah, for sure, And again that's just an estimate, like,
Speaker 1: that's our best estimate. And on top of that, another
Speaker 1: seven hundred thousand to one point two million cases of
Speaker 1: cutaneous leshmaniasis worldwide each year. So that was from twenty twelve.
Speaker 1: There are a couple of newer papers in twenty fifteen
Speaker 1: and twenty sixteen that estimate not only the incidents of infection,
Speaker 1: so the number of new cases per year, but also
Speaker 1: the prevalence of an infection, so the total number of cases.
Speaker 1: Because again cutaneous leshmaniasis and visceral are both very long
Speaker 1: lasting disease, so someone might get infected in say twenty twenty,
Speaker 1: but still have it in twenty twenty one, or even
Speaker 1: all the way till twenty twenty two. So the prevalence
Speaker 1: of disease tells us how many people are living with
Speaker 1: that disease currently. So the twenty sixteen estimates said that Overall, worldwide,
Speaker 1: over four point eight million people are living with leshmaniasis,
Speaker 1: and that's all forms, and that overall there were likely
Speaker 1: eight hundred thousand new cases.
Speaker 2: Wow.
Speaker 1: Yeah, one hundred and twenty thousand of those were likely
Speaker 1: visceral leshmaniasis and over six hundred thousand of cutaneous leshmaniasis
Speaker 1: for new cases. Now, that's just incidents and prevalence. Another
Speaker 1: thing that we have to look at for a disease
Speaker 1: like this is the disability adjusted life years okay, which
Speaker 1: in twenty sixteen overall was estimated in one year at
Speaker 1: over nine hundred and eighty thousand, So almost a million
Speaker 1: disability adjusted life years for all of leshmaniasis combined.
Speaker 2: Oh my gosh.
Speaker 1: But and this I think is really interesting and important.
Speaker 1: I found a paper just from last year, twenty nineteen
Speaker 1: that suggested that we shouldn't consider having gone through cutaneous
Speaker 1: leshmaniasis and survived as no longer being affected by leshmaniasis essentially,
Speaker 1: So they suggested that the scarring phase, because we know
Speaker 1: that leshmaniasis causes these massive scars, that that scarring phase
Speaker 1: should actually be considered a part of the disease process
Speaker 1: since this is something that people are still living with
Speaker 1: and should therefore be counted in the prevalence estimates because
Speaker 1: then based on because we also know that it's so
Speaker 1: strongly associated with things like major depressive disorder and stuff
Speaker 1: like that, so they estimated that if you include that,
Speaker 1: then we're looking at over forty million people that are
Speaker 1: living with the stigma, the psychosocial burdens and these other
Speaker 1: things that are associated with cutaneous leshmaniasis. Forty million people worldwide.
Speaker 2: With theirst million.
Speaker 1: Wow. So I think that that's very interesting because it
Speaker 1: really changes your disability adjusted life years if you include
Speaker 1: psychosocial disorders like major depressive disorder, which is not included
Speaker 1: in our estimates of disability adjusted life years, right, mental
Speaker 1: illness is not included in that. So geographically, leshmaniasis can
Speaker 1: be found almost worldwide pretty much, but visceral leshmaniasis ninety
Speaker 1: percent of the cases occur in a few country trees India, Bangladesh, Sudan,
Speaker 1: South Sudan, Ethiopia, and Brazil. That's the major places where
Speaker 1: like ninety percent of visceral leshmaniasis occurs, and cutaneous leshmaniasis
Speaker 1: is most common in Afghanistan, Algeria, Colombia, Brazil, Iran, Syria, Ethiopia,
Speaker 1: North Sudan, Costa Rica, and Peru. So there's like a
Speaker 1: lot of places in the world, a lot of places,
Speaker 1: a lot of a lot of places, and the distribution
Speaker 1: is likely changing due to climate change. Okay, I want
Speaker 1: to say it's not all depressing, but it's mostly all depressing.
Speaker 1: But there are a lot of people doing a lot
Speaker 1: of work to try and make this better.
Speaker 2: Yes, that is important to remember.
Speaker 1: Yeah, we've talked a lot about Peter Hotez on this podcast.
Speaker 4: Oh yeah, peteryot He is one one of many people
Speaker 4: really doing so much work on vaccine development and really
Speaker 4: just I think bringing awareness to diseases like leshmaniasis as well.
Speaker 1: So in terms of where we stand on a vaccine,
Speaker 1: it's still not great news. There is a lot of
Speaker 1: good evidence to suggest that, at least from the perspective
Speaker 1: of people being able to theoretically mount a protective immune response,
Speaker 1: that we should be able to develop a vaccine. And actually,
Speaker 1: people like even in ancient times, have practiced leshmanization right,
Speaker 1: which is basically inoculation of parasites under the skin to
Speaker 1: like intentionally induce an infection not on your face but
Speaker 1: on your body to then protect you from more worse
Speaker 1: and disfiguring infection later on, and that's like effective, but
Speaker 1: of course it does result in infection, which is not good.
Speaker 1: And it's not perfect either, and so the big stumbling
Speaker 1: blocks to the creation of a vaccine are both financial
Speaker 1: and also logistical. We don't have a perfect vaccine. There
Speaker 1: are a few different vaccines that are being tested right
Speaker 1: now in phase one and phase two trials. There are
Speaker 1: recombinant vaccines, so like just a protein that we know
Speaker 1: would cause an immune response, along with different adjuvants to
Speaker 1: increase the immune response. There are also killed parasite vaccines
Speaker 1: that are under investigation. There's talk about DNA vaccines, but
Speaker 1: I don't know that any of those are in kind
Speaker 1: of later stages of development, so it'll be interesting to
Speaker 1: see how those go on. As well as therapeutic vaccines,
Speaker 1: so vaccines that you give to someone who has like
Speaker 1: cutaneous leshmaniasis to prevent the development of mucocutaneous leshmaniasis, etc. Dogs,
Speaker 1: As it turns out for zoonautic leshmaniasis are a pretty
Speaker 1: important reservoir host. So there are a couple of K
Speaker 1: nine vaccine that have shown some promise in preventing dogs
Speaker 1: from becoming infected, which may be useful in some areas,
Speaker 1: but it probably won't have like the full impact that
Speaker 1: we need, especially because a lot of regions with visceral
Speaker 1: leshmaniasis especially have mostly anthroponotic transmission, so dogs don't play
Speaker 1: as big of a role in that. I mean, they
Speaker 1: don't play a role at all. So yeah, so that's
Speaker 1: where we stand. There's a lot of people working on it.
Speaker 1: There's a lack of funding, even though it's been shown,
Speaker 1: like in a lot of different modeling studies, to be
Speaker 1: very cost effective, Like the cost to develop and implement
Speaker 1: a vaccination program would be way cheaper than treating people
Speaker 1: for visceral ancutaneous lash meniasis.
Speaker 2: Yeah, but there's no money in it. If you vaccinated
Speaker 2: someone against a disease, then you're not going to be
Speaker 2: able to get the year you know, the month's supply.
Speaker 1: Of but you get so many disability adjusted life your life.
Speaker 1: Isn't that what people want? You can then work anyways.
Speaker 2: I know there's a lot of problems with like why
Speaker 2: certain things are funded and others are not.
Speaker 1: Yes, so you know, Hoody Hot also Maria Elena Potazzi,
Speaker 1: who we talk to in one of our COVID episodes.
Speaker 1: She's on a couple of these papers too. She's doing
Speaker 1: a lot of work on this. There's a lot of
Speaker 1: other people. I probably should shout them all out, but
Speaker 1: those are the two we've talked to. So I feel cool.
Speaker 2: Well, I think it's I mean, I think it's really
Speaker 2: amazing and important because like this, this research isn't easy
Speaker 2: to do because the funding just like isn't it isn't sufficient,
Speaker 2: It isn't. Yeah, but it's hugely important and so.
Speaker 1: It is hugely important. Yeah, so that's where we stand erin.
Speaker 1: Oh boy, well I learned a lot.
Speaker 2: I learned a lot. It's a big disease, and I
Speaker 2: really feel like I didn't do the history justice. But
Speaker 2: I also feel like there's just like I couldn't find
Speaker 2: as much as I normally can find on stuff like this.
Speaker 2: And so someone needs to write a book about about this.
Speaker 1: You write erin, someone needs to write a book. Guys,
Speaker 1: let us know if you would like to read a
Speaker 1: book that Aaron Welsh writes about lashmaniasis, or if you'd
Speaker 1: prefer a different topic. Let us know what do you
Speaker 1: want her first book to be about?
Speaker 2: Volunteering me to do a lot of work eron. Okay, yes,
Speaker 2: I want to read it, appreciate speaking of books and things.
Speaker 2: Should we disource it?
Speaker 1: We should?
Speaker 2: So I have a bunch of different articles, but I
Speaker 2: want to shout out a few. So one that I
Speaker 2: found super helpful for the overview of the history is
Speaker 2: by stever Ding from twenty seventeen called the History of Lashmaniasis.
Speaker 2: And then there are a few different papers about the
Speaker 2: origin of Lashmania and the sandflies. And so there's one
Speaker 2: by Moment and Koupolilo from two thousand called Speculations on
Speaker 2: the Origin and of the genus Lashmania. There's a paper
Speaker 2: by Killick Kendrick from twenty thirteen, the Race to discover
Speaker 2: the insect vector of kala Azar. And then there's a
Speaker 2: paper by Guran from twenty eighteen called an overview of
Speaker 2: Leshmanias's historic to future Perspectives. And there are many more.
Speaker 2: All post them all.
Speaker 1: I already shouted out a few of the papers that
Speaker 1: I read. There's a lot. We post the full references
Speaker 1: to this episode and all of our episodes, every source
Speaker 1: we've ever used on our website This podcast will kill
Speaker 1: You dot com, So check them out there under the
Speaker 1: episodes tab.
Speaker 2: Yeah. Well, Thank you to Bloodmobile for providing the music
Speaker 2: for this episode and every single one of our episodes.
Speaker 1: All sixty two now episodes.
Speaker 2: Not including the covid ones. Yeah yeah a lot.
Speaker 1: Thank you to you listeners for listening to all sixty
Speaker 1: two plus episodes of this podcast. We love making it
Speaker 1: and we hope that you keep enjoying it.
Speaker 2: Yes so we do well. Until next time, wash your
Speaker 2: hands
Speaker 1: You fill the animals.