This Podcast Will Kill You - Ep 103 Leptospirosis: Don't blame the rats

Episode Date: August 16, 2022

The story of leptospirosis is chock full of variety. In terms of biology, any number of different Leptospira species and serovars can play a role in infection, and the resulting infection can run from asymptomatic to deadly. As for ecology, virtually any mammalian species can either act as an affected reservoir for the pathogens or fall victim to a deadly infection. The history of leptospirosis takes us across continents and through centuries, illustrating how changes in scientific thought and technology shaped our understanding of this and other zoonotic diseases. And the current status of this One Health disease is no less varied, both in the wide distribution of leptospirosis as well as the vastly differing (but disturbingly high) estimates of annual cases and deaths. In this episode, we do our best to tackle as much of the variety in this neglected disease as we can, from its impact on us and our furry friends, to the classic story of its discovery and the biggest remaining gaps in our knowledge today. Tune in for all this and more! See omnystudio.com/listener for privacy information.

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Hi, I'm Umat, and when I was a graduate student, I was doing fieldwork in Panama. It was just this amazing place with tropical birds, and I loved the fieldwork I did. I had to, like, hike up these rivers in the forest and find these insects. And it was so diverse and amazing. But, you know, it was also tropical. So we were getting bit by insects. We were getting water and foods. You know, we're dealing with a lot of animals and things.

And there was five of us living in this house. It was pretty crowded. Five of us and a cat. And then one morning I woke up exhausted. I had fever the night before in these awful dreams and a headache. And I knew that something was up. And so I just rested that day and I tried to kind of nourish myself, have a lot of water, have a lot of food. And I felt better, you know, by the afternoon, I was able to take a walk and everything.

I said, okay, maybe this was just a short-term thing. Everything would be fine. And then that night, it was worse. I had this awful fever, really, really bad headaches. And in the morning, I was just feeling awful. And so, you know, I didn't have a car at the time. And luckily, I got a friend of mine to drive me to a clinic. And so I got to the clinic and I explained my symptoms.

And, you know, they're like, well, this sounds like dengue and we're going to test your blood. And so they took a blood test and they didn't find dengue. So they sent me home and told me that, you know, this is probably some virus or something. And you should probably just recover on your own, just, you know, take lots of. water, vitamins, just take care of yourself. And so I said, okay, but the disease just progressed. And so I started getting more fevers. And the next day, I was really awful. But it would be also kind of cyclical. So I would feel better and, you know, think it's improving. And then suddenly it would hit me again. And I would get these fevers and headaches and be sensitive to light.

So two days after I went to the clinic, I woke up and my sister just happened to be visiting. And I was showing her the tropics, I was showing her my field site. And so we woke up in the morning. I was not feeling great, but I was feeling okay. And so we drove up to the canopy tower, saw some beautiful tropical birds. And I remember driving back and just suddenly being extremely sensitive to light, slowly feeling this weakness coming over my body, this fever coming. And by the time I got back, I was in bad shape.

I kind of hobbled to bed and my head was killing me. And luckily, I had a friend who said, you know, I think, you know, we should go right to the hospital right now. This is really bad. And we got to the hospital and I remember just having a hard time kind of even walking to hospital reception in the emergency room and stuff. And I remember somebody bringing me a wheelchair. And I thought, you know, I was like, I don't need that wheelchair. But as soon as, you know, they brought it to me, I. I did sit down in it and I just, I was like, who, okay, I definitely did need that in wheelchair.

And I remember my friends talking to the doctors and stuff and they immediately took a blood test. That was a moment when I knew things were way more serious than I had initially thought. I saw the doctor's expression and he came out with this paper and he said, this is a critical situation. some of my liver enzymes were off the charts. We need to get to the ICU immediately. So I got immediately admitted to a bed in the intensive care unit. They had me monitored by heart rate and my blood pressure and everything.

And then I was under 24-hour surveillance. Every 20 minutes, somebody would come and check on me because apparently that's how critical the situation was. So it progressed so quickly, at least from my perspective. And I remember just being extremely uncomfortable and confused. used. And so I did, I did improve slightly when I was in intensive care, but, but it still wasn't good and they still couldn't figure out what it was. And so I stayed in the hospital and I just remember there was this routine. Somebody would come and take a lot of blood from me. And then, you know,

I would spend my time in my room and I'd be very comfortable. I was still getting these headaches, this fever, but I'd also started getting pain in my stomach. I'd never, you know, I'd never, experienced this before, but apparently my liver was extremely swollen. And so my stomach had become tight and tender. And I, you know, it was kind of terrifying thinking that like a single organ has swollen to a level where it's like distending your body a little bit. And I spent almost two weeks in that hospital and they still couldn't figure out what it was. I was not getting any positive tests. They were prescribing me kind of general antibiotics. But eventually I started to feel a little better. I'd lost a lot of weight. I was weak, but after about two weeks, I was

released from the hospital. But I was still very weak, and it really bothered me that we didn't know what it was. I mean, is this something that was dormant, that could come back again and resourge something this serious? I really wanted to know, could it be, you know, it's just not knowing it was really, really stressful. And so I ended up going to Canada. I'm a Canadian citizen, and I went to Canada, and I called the hospital beforehand. And it turns out they had a tropical medicine program going on there with the med students. When I called them and told them my situation, they put me in touch with this doctor who's teaching this course.

And it turns out they don't get a lot of tropical disease patients in Canada. So I was talking to him about all the stuff I had read and trying to try to figure out what, you know, what I had in, he asked me if it was okay if I could participate in trying to help figure out what was going on. And so he had a bunch of these med students around the bed. And it was like an episode of House or something, one of those medical dramas where they tried to figure out what you have. And different medical students gave their hypotheses. They experienced doctor said, well, maybe that's something you should pursue or, oh, maybe that that's not right because, you know, of these chart readings or something.

And they were trying to figure out what it might be to try to look for antibodies or some indication of what I had. And so then I left the hospital and I was recovering slowly. And then it wasn't until three months later I got a call. And one of the medical students figured it out. It was leptospirosis. And so when I found out that it was leptosporosis, now I had, you know, a diagnosis. I could start thinking about what the mode of transmission was.

And I remembered when I was living in that house with those five people and that cat, that cat didn't like me very much. And I would go on these runs on pipeline, on this road, this muddy road, and I would leave my shoes outside. There was this one time this cat peed in my shoes. And I didn't realize until I was walking around and I could smell something weird. And it was an outdoor cat too. So it was probably grabbing all sorts of rats and rodents outside and also, you know, a potential vector for leptosporosis.

So that time I also happened to have this cut in my foot. And so there's this possibility that it was this direct blood transmission that got me infected. But yeah, so that's the story of me getting leptosporosis. It is, I remember that. so vividly and it was terrifying. It sounds awful. I remember hearing about it after the fact. Yeah.

Well, Umat, I'm so glad that you are better and that everything, you know, eventually turned out okay. And also thank you so much again for sharing your story. Because for those of you who are longtime listeners, you may have recognized Umat's voice from season one when he provided the first-hand account for malaria. Let's hope, Umant, that there's no more diseases that we need to have you provide a first-hand account for. Let's hope.

Hi, I'm Aaron Welsh. And I'm Aaron Alman Updike. And this is, this podcast will kill you. And today we're talking about leptosporosis. Leptosporosis. Yeah. Can I make a quick confess? I just want to say this off the bat.

Of course. I don't know why. But leptosporosis, legionella, and leshmaniasis, constantly confused in my brain. Interesting. Those three. And now we've covered all of them. That's like me and Gerard Butler and Clive Owen. They're the same person.

They actually are the same person. So it's very valid. Well, and now, so now you don't have to worry about getting them confused anymore because this is just redundant. Right. I'm really excited for this episode because when I was going through emails to be like, okay, what do people want to hear? I was so surprised at the number of requests for leptosporosis. Yeah.

And one of the reasons it seems like is because this is a disease that affects not just humans, but also many animal species. And it's just, it's so much more prevalent and important than I think I realized, even after, you know, watching Umat go through this horrible ordeal. Yeah, I think it's, it's easy to think of this as a disease of the tropics or as a disease of, you know, other places. But it's a worldwide pathogen, as we'll talk about. And I think a lot of pet owners and veterinarians are probably a lot more familiar with it than maybe the general public. Yes, totally. Yeah. Yeah. I'm excited. It's going to be good. For me. First things first. It's quarantine time.

It's quarantini time. What are you? we drinking this week? We're drinking, I smell a rat. And why are we drinking I smell a rat? It turns out, Aaron, that rats are a very important part of the overall distribution and prevalence and life cycle of leptospira. And I also want to say just right here that we are not trying to intentionally further the stigma against rats. Don't blame the rat. Don't blame the rat. Rats are just one piece of the puzzle. Many other animals do this, but the title was too good to pass up.

Yeah, because who doesn't want to drink? Who doesn't want to drink? I smell a rat. I mean, really. I mean, once you hear the recipe, though, you're definitely going to want to drink it. Please tell me, what is in it? It is a shrub. It's a mango, habanero mint shrub.

So this is like a drinking vinegar. you muddle all of these fruits and ingredients together with sugar, let it sit, and then you can use that as a great base for a cocktail, like this one with tequila, for instance, or you can use it as a placebo-rita as well with no alcohol. Delicious either way. And we will post the full recipe for I Smellerat the Quarantini, as well as the placebo-rita on our website,

this podcast will kill you.com, as well as on all of our social media channels. And on our website, this podcast will kill you.com, you can find all of the best website type things you can find. Do you think people even need to hear this at this point? I don't know, really. Just check out our website. Yeah. I like that. I like that. Erin, I am so ready to learn. So can we take a quick break and get started? Let's do it. 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

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different washes, so I'm about to go order some more. Refresh your wardrobe with Quince. Go to quince.com slash this podcast to get free shipping on your order and 365-day returns, now available in Canada, too. That's Q-U-I-N-C-E.com slash this podcast to get free shipping and 365-day returns. Quince.com slash this podcast. Leptosporosis is a disease caused by a bacterium in the genus Leptospira, or Leptospira. These are spirokete's, which means those little twirrely corkscrew dudes, like a few other pathogens we've covered, like Traponema, the causative agent of syphilis, Borrelia, which causes Lyme disease. Have we done any others? I was trying to think of that,

and I can't come up with anymore. Me neither. Those are the two I remember. Yeah. So this spirocate, it turns out, is not just one bug. It's not just one species. And it seems like, from what I could read, the classification and species definition seems to be in flux currently. So different papers have a lot of different numbers cited, but it seems like there's over 60 different species. I think that's the consensus in the genus Leptospira. And importantly, this includes more than 300 serovars. Asterisk, a note, Aaron. I would like to talk about this a little bit more. Okay. Because in our episode on Salmonella, we talked about the idea of like species and subspecies and seravars. And in that episode, I feel like I did a very bad job of trying to define what

serivars actually are. And when it comes to leptosporosis and salmonella and a lot of other bacteria, seravars are really important epidemiologically a lot of times in distinguishing, like, was this outbreak all from this source or from that source, etc. So I wanted to give a little bit of a better definition of what a seravar actually is in this case. Basically, serovars are determined based on the surface antigens. So differences in those surface proteins and things, which of course are some of the main things that our bodies use to recognize various pathogens, right? Right.

And so serovars are like strains or isolates that differ in their surface antigens. In the case of leptosporosis, there are over 60 different species, not all of which are pathogenic, but which include over 300 syrivar's, at least 200 or over 200 of which are pathogenic. It seems like more are being discovered all the time. I am not surprised. So anyways, I hope that was at least a little more helpful than my description in the Salmonella episode. It was. It's really interesting. Yeah. Before we move back to leptosporosis, I just want to take a moment to share something about salmonella. Oh, love it. A listener reached out to us and you know how in the Salmonella episode we were like, oh, is it pronounced Daniel Salman or Daniel Salmon? Yeah.

Person who Salmonella is named after. Uh-huh. So someone tweeted at us and said it's pronounced salmon because he is one of her ancestors, which is so thrilling. Oh, I love that. I feel like we've had a couple times where people have emailed us saying, like, I'm related to one of the people you talked about. And I don't know why it thrills me. Oh, 100% every single time. It's so cool. Now my heart is beating quickly. I love it. Back to leptosporosis. Back to leptosporosis. All right. If you're related to anyone, no. Okay. So anyways, that's the pathogen. A lot of different species, a lot of different syruvars. Like I said up top, this is a path. that is found worldwide. And while it is more prevalent or at least more common in the tropics,

this is mostly just because it can be an environmentally transmitted pathogen. This is something that can persist in the environment for weeks to months in the water and in the soil. And the climate in the tropics is just a little better suited for leptospira growth and survival. But this is a bacterium that can infect almost any mammal. Pretty much all mammals. Some of them, some mammal species, are very good reservoirs, which means that they can harbor this bacterium, mostly in their kidneys, at really high levels for months at a time,

and pee it out all over the place, often without showing any symptoms or getting sick at all. Other species are less great reservoirs, and they may get sick to varying degrees. But what's really important is that this can infect literally almost any mammal, including marine mammals, which I always find fascinating. Yeah. Question. Mm-hmm. You are saying this bacterium.

Do you mean like the genus overall? Or are there species differences in terms of like which animals are best reservoirs for which species or? species or seravars? Great, great, great, great question. Yes, there are differences where some species or some seravars are maybe more common in certain animal species and others are more common in other species. But of the pathogenic species of leptospira, they can have been shown in the lab to infect nearly any mammal if you expose them to it. Any given leptospira pathogenic species. Right, exactly. So I probably shouldn't be saying this bacteria. I'm like this genus. Okay. These pathogenic spirochetes. Yeah. But excellent question. So when it comes to humans, we generally get exposed either through

direct contact with infected domestic animals like cattle or dogs or more commonly through exposure to infected water sources or infected soil. And exposure happens in a variety of ways. These spirochetes can corkscrew their way in through any little cuts or abrasions on our skin. They can enter directly. If you get infected water in your eyes or your mouth, they can enter through your mucous membranes. Even if you swallow a bunch of contaminated water or drinking water sources become contaminated, you can get infected that way as well. And that is true for animals as well.

So that's the way that all other animals are also being infected through abrasions on their skin or through their mucus membranes. Which makes sense about high infection rate in some animals because if you just imagine dogs, a lot of dogs love drinking out of puddles. As I will. My veterinarian, when my dog was a puppy, was like, oh, we could vaccinate for a leptospher. Like, is your dog a puddle liquor? And I was like, are not all dogs puddle liquors? So yes, if you have a puddle liquor, that they will be exposed. A puddle liquor, unbelievable.

So these highly mobile little spirokets, once they get into our bodies, corkscrew their way directly into our bloodstream and begin to replicate. They cause a bacteremia, which is bacteria in our blood, that's all that means, over the course of usually about a week or so. And then once those bacteria reach high enough numbers, and what's fascinating about leptosporosis is that the amount of bacteremia can be incredibly high. Like we're talking millions of bacteria per milliliter of blood, which is very high, even before you show any symptoms.

And this is way higher than what we would see from a bacteremia in like an E. coli or something without our bodies freaking out about it. Why is that? Why does it produce such a high bacteremia? Well, it seems like our bodies are very good at detecting and mounting a response to very low levels of antigen from something like E. coli. But essentially just don't even recognize leptosporosis antigen until it's at very, very high levels. What? Interesting.

I know. Huh. Right? Then, after they get to these very, very high levels in our blood, these bacteria start burrowing their way through. our endothelial cells that line our blood vessels and into various organs. And that is usually the point at which symptoms will tend to start to appear. So the total incubation period is anywhere from seven to 14 days, could be as long as a month, and rarely is shorter than that. Okay. And once these bacteria leave the blood and start burrowing and finding their way to organs and whatnot,

does that mean that they straight up leave the blood? Would you be able to, to detect them in the blood? Excellent question. They don't leave the blood entirely, but these are still difficult bacteria to detect because like other spirochetes that we've talked about on this podcast, they don't gram stain very well. And so they're just not as easy to pick up. And I do think that the amount of bacteremia tends to go down once they enter our organs.

Okay. Yeah. Okay. That plays a relevant role in the history section. Oh, I bet. I can't wait. Bacteremia. Yeah.

Okay. All right. Spoilers. Or just foreshadowing. Foreshadowing. Yeah. Yeah. When it comes to animals, various animal species that get infected, they can remain infected and primarily in the proximal tubules of the kidney, which is just so interesting that this pathogen loves that particular part of a kidney for literally months, in some cases, up to a year. and then because they're in the tubules of the kidney where your kidney is making urine, this pathogen is just being shed beautifully at very high levels in the urine. So for some animals, this process can be completely asymptomatic. And for other animals, including dogs, and in some cases, including cattle,

they can also get sick from leptosporosis. And what's interesting is that especially in the case of dogs, which there's maybe more detailed clinical. information, at least that I could find, on dogs compared to some other animals, the disease actually can look a lot like the disease in humans. So let's talk about what those symptoms actually look like. First of all, this is something that even in humans can be entirely asymptomatic. You could just be shedding bacteria in your urine. Okay. And importantly, for humans, some papers call humans dead-end hosts. We're not truly dead-end hosts. We're not truly dead-end hosts.

But transmission from humans to humans is very, very, very, very rare. We can potentially shed leptospirate in our urine, but it tends to be at much lower levels than something like a rat. Okay. So the general root of infection and, like, course of infection, where the bacteria go from point A to point B and so on, is the same across these mammalian hosts, but the symptoms that they show is different and the amount that they excrete is different. Absolutely. Interesting. Yeah. Mm-hmm. I know.

Okay. But even in humans, it can be asymptomatic. And I tried to get a handle on how often, and that was very difficult to do. A couple of studies that I read suggested that up to 70% of the time people tested seropositive for leptosporosis, but couldn't call any febrile disease in the months prior. So it's kind of hard to say. Could it be that someone just is still. seropositive, but they had an infection, you know, a couple of years ago that they just don't remember. I don't really know. But we do know that in animals and in humans, it can be asymptomatic. And that's

really important when we're trying to control or reduce the prevalence of a disease. And then in. But when there are symptoms, here's how it usually starts. It starts with a fever. Yeah. It sure does. Usually, it's a sudden onset of fever along with chills. Usually there's a pretty severe headache that develops and body aches, generalized muscle aches. And the number of pathogens that we've covered, even in this season alone, that start out that exact same way, is a lot. So this is something that especially in the early stages is a very non-specific disease that can easily be mistaken for a number of other viral or bacterial infections. Yeah.

Interestingly, with leptosporosis, in contrast to the other spirochetes we've seen, you tend to not have any rashes or skin findings early on, and that's because of the way that lepto goes kind of straight into the bloodstream, rather than having any skin manifestations. Usually, you'll also then start to see GI symptoms like nausea, vomiting, maybe some diarrhea, And in a lot of cases, that might be where this disease ends. So you might get pretty sick, but it'll be self-limited and then you'll recover. But when this progresses to a severe illness, and this can happen over the course of a few days,

and sometimes people get a little better and then have a biphasic illness where then they get better and then start to get worse again. And at that point, whether you just progress immediately or have this bifacic illness, this progression to severe leptosporosis is when we start to see signs of real organ dysfunction. So what does that mean? It means we see signs of liver damage like jaundice, yellowing of the skin, and ecturus, yellowing of the eyes. This happens from buildup of bilirubin because of the damage to your liver, as well as hemolytic anemia. So this bacteria can cause breakdown of your red blood cells. That also contributes to the jaundice.

A lot of times you'll have dysfunction in various other blood cells as well. So you can have a lot of signs of bleeding because of a decrease in your platelets. So it might be mild like little purple spots on your skin called patiquiae or can be very severe and have massive gastrointestinal bleeding or pulmonary hemorrhage. so bleeding into your lungs that can be fatal. In fact, if you do see that pulmonary hemorrhage, it's an up to 50% mortality rate at that point. So this is something that can progress to a very, very severe illness. Okay, question. Give it to me.

How is it causing all of these different symptoms? Great question. We'll get there. Okay. My other question then is about who. who has these symptoms? Yeah. Are there characteristics that determine or play or seem to play a role in whether someone has an asymptomatic or a mild or a moderate or a severe case of this?

Yeah, that's another great question. The older people are, the more likely that they are to progress to severe disease. I didn't see a ton of data on if the same is true in people who are very young. But I'll talk more in just a little bit about how much specific, host factors likely play a role in the severity of infection. And we truly don't know what those specific host factors are at this point. And do the different seravars and species play a role, too? Potentially, yes. But again, we don't have like great, great data on like this serivar. There's a couple of serovars. Icto haemorrhagiae, I think that's it, is one that is known to be of like very

important human significance because it can cause pretty severe infection, but there's so many syrovars and we just don't have a ton of data. So we'll get into a little bit more detail on how it's causing these specific findings. When it comes to the pulmonary hemorrhage, it really is that this bacteria ends up causing damage directly in your lungs that then causes that bleeding to the point where you essentially can drown in your own blood. How is it causing that damage? So it's damaging the endothelial cells. It's damaging the lining of our blood vessels.

It's damaging our – it's reducing our platelets, so it's not allowing for our blood to clot, et cetera. Gotcha. Yeah. So that's the liver and the lungs and blood and blood vessels. But one of the other main target organs of leptosporosis, of course, is the kidneys. And so when this progresses to severe disease, it often results in what's called wheels disease, which essentially can cause progressive kidney damage to the point of kidney failure. Kidney failure, of course, can be extremely fatal unless you have

access to dialysis. And access to dialysis can drastically reduce the mortality rate in the case of severe kidney failure when it comes to leptosporosis. So it's a lot. It really can affect all of our organs. It can infect the heart and cause cardiac involvement. It can cause myocarditis. It can cause an aseptic meningitis so it can get into the CSF or at least cause enough inflammation in our brain and spinal cord. That headache that presented at the beginning can become incredibly severe. But overall, a lot of these symptoms can be really difficult to distinguish from viral hemorrhagic fevers, like dengue fever, for example, or from things like scrub typhus, which we technically haven't covered yet. No, we have not, but I remember, yeah, it comes up again. Oh, good.

Symptoms can last a pretty varied amount of time. When they get severe, they can persist for potentially weeks. And even in the case when symptoms are not that severe, there is some suggestion of like post-leptosporosis type syndrome with things like fatigue, persistent headache, myalgia, that can potentially last for months. If you get leptosporosis and recover, do you have immunity towards it in the future? And is there cross-protection with different sarovars or different species? What a great question, Aaron. That is such an important question because what it basically, like, if you circle on that

question long enough, you ask, can we make a vaccine? Do we have a vaccine, etc.? Yeah. You get at least some immunity. How much cross-protection there is on different syrivar's, unclear. How long that immunity might last, again, unclear. There is some data that suggests that like waning immunity over time in people who maybe lived in an endemic area and were exposed as young people and then get exposed again as they're older are susceptible again. So it doesn't seem to be something where you're immune for the rest of your life forever. we do mount immunity to it in a way that offers at least some protection against severe infection. Okay. But obviously this is a huge range in disease severity. And you kind of already asked the question of like what is the underlying pathology of this? Why do some people get so sick?

Other people don't get so sick. And it boils down to three major things, which we've already. already touched on, but I'll go in a little bit more detail. One is those virulence factors of the particular leptospira species or serifar that you get exposed to. So some that are more or less host specific might cause disease in certain animals and not in others. And some with particular virulence factors on them might be more or less virulent than others. The second factor is the inoculum. So, like, how much pea-contaminated water did you guzzle down or, like, how many spirochetes did you end up with initially? Right. And the third is my favorite, the most difficult,

the host factors. It's a very nebulous category. In the case of leptosporosis, what it seems to boil down to is our cytokine-related immune response. So cytokines are pro-inflammatory agents, right? These are proteins and stuff in our body that we make and secrete in response to an infection in order to get the rest of our immune system on high alert to go look for and eliminate this problematic spirochet. But as we've talked about time and again on this podcast, if our body goes on too high of an alert, if we get too intense about this inflammation, then we can end up with tissue damage that's not even directly due to the pathogen, but due to these inflammatory cytokines and all of the other immune response that they stir up. So while we don't know a lot of

the details on this, we think that that's a huge part of the pathogenesis, especially of severe leptosporosis, is this intense inflammatory and cytokine response that is generated. And that's what's causing a lot of these severe manifestations. That's what's causing the damage to our lungs. That's what's causing the damage to our liver. That's what's destroying our red blood cells and our platelets and causing us to bleed to death. Okay. Interesting. Seems like there's a lot more work to be done in that field. Absolutely. We don't have enough data just yet to say for sure what specific cytokines are being upregulated or causing the most damage when it comes to this very severe versus not so very severe infection. But I will link to a couple of papers that have

more detail on what we do know about particular cytokines. A question about diagnosis. Oh, great. So like you mentioned, this disease can be confused with many other diseases. It has kind of these nonspecific symptoms. And what would make someone suspect leptosporosis, number one, and number two, you said it's difficult to test for because it doesn't show up very well on gram stains. How do you then test for it? What are the samples you would take? Beautiful questions, Erin. So how you you would suspect it would be, of course, if someone is having these symptoms that I described, like these laboratory abnormalities that we see jaundice, signs of kidney failure, but also if they have a history of something that would make us think they've had an exposure to potentially contaminate environmental sources, if they've been whitewater rafting, if they've been jumping off of cliffs into freshwater sources, or if they work in a field like a rice paddy or something like that. So occupational exposures or recreational exposures, that might make us think,

maybe this is leptosporosis. It might be higher on your list to think about in areas where leptosporosis is more common and less likely that you'll think about it in places where it's less common, but it's important that it exists everywhere. So probably overlooked in some places. How you diagnose it can be really tricky. So it's hard to diagnose on culture alone, but that is like the gold standard. It is possible to do. It's just more tricky. So there's PCR tests that you can use,

but those, of course, aren't accessible everywhere across the globe because they're difficult and expensive. So it's mostly based on serologic testing. So looking for antigens or looking for antibodies against leptosporosis. Okay. Yeah. And there is treatment, which is the best news. A number of different antibiotics work.

But especially in severe cases, it's also really important to have access to supportive care, like potentially emergent dialysis if someone progresses all the way to kidney failure and things like that. In terms of antibiotics, you said that the first stage was this extreme replication in the bloodstream, just tons and tons of bacteria. And then that's asymptomatic. And then when they move into the organs is when people would tend to probably go seek treatment. Does the massive die-off of bacteria at that point hurt anything about you and your organs? Oh, what a good question. That's like a thing that can happen with a lot of other spirochet disease is not that I read. Yeah, but that's a really interesting question, especially for spirochetes. Okay. Because they are still replicating the whole time. They

don't just like stop replicating once they make it into our organs. Okay, yeah, of course. Keep on going. Just, yep, chugging away. Keep on trucking on. So that's kind of the disease in humans. Because this is a pathogen, like I said, that can infect essentially any mammal. It does cause slightly different disease in different animal species. But the spectrum, especially in things like dogs, can tend to be pretty similar. So there can be asymptomatic infection.

And then there can be this severe disease that often still has fevers, jaundice, nausea, vomiting liver failure, kidney failure. So it's very interesting to me how it tends to affect a lot of the same organs and then a lot of what you see might be very similar. Yeah. That's leptosporosis. All righty. So tell me, Erin. Where did this thing come from? How did we figure it out? Yeah, I will do my best right after this break.

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Just text train to 3232 right now. now. Get certified in as little as six weeks and ISSA guarantees you'll get a job. Text train to 32 32 32 32 32 32 32 32 32. Train to 32 32 32 32. I found it really interesting to read about the history of leptosporosis because I feel like although this is not the flashiest of diseases that we've covered, you know, it hasn't caused these widespread epidemics and left destruction in its wake. something like smallpox or plague, for instance. But the story of leptosporosis is a classic tale of observation and discovery. It's really sort of highlights the golden age of germ theory. And I think that what surprised me most about the history of leptosporosis was not how we learned about the transmission cycle or the causative agent of leptosporosis, but how much things haven't really changed. But I guess I'm getting ahead of things. So let's start at the beginning. Okay. Leptosporosis has existed for millennia. And it seems to have been globally distributed for quite some time.

So that's about as precise an answer as you're going to get for where did this thing come from. That's about as precise as I could find. Okay. Then? Yeah. And part of that is because of how many different leptospirous species and serovars, there are that can cause infection in humans and other animals. And so it's hard to say when leptospira emerged or when it evolved and where it evolved. Okay. And it's also hard to say when humans were first exposed in which particular species or seravars were responsible, because those are also things that would have likely varied geographically. And maybe those seravars aren't even around anymore. And in the scientific, literature discussing the history of leptosporosis, generally speaking, researchers refer more to

the disease leptosporosis rather than a particular pathogen. Yeah, I found that really interesting. I found that interesting too, and I think that just speaks to the importance, well, I think it speaks to two things, really. One is the importance of the group of pathogenic species rather than any one individually, at least historically. And I think the other thing is that maybe it's just kind of speaks to the fact that we don't maybe know that much about the different Saravars and their impacts. Yeah, and they're just so hard to culture. I think they're a difficult bug to work with. It seems like it. Yeah. And that's, of course, not to say that the differences among leptospiro species or sarovars isn't important medically or in terms of public health. Of course, like I'm always saying on the podcast, tracing the evolutionary relationships among these bacteria can greatly help in understanding things like transmission roots.

or reservoir species or disease-causing abilities, information that, like you talked about, Aaron, for some or even many leptosphera species, isn't that well known. Yeah. In general, the pathogenic leptospira are thought to have evolved from non-pathogenic species that just live in the environment, which some leptospira species still do. I sure do. And historically, that's how this group of bacteria was divided, along lines of the is it pathogenic or is it not pathogenic? And that is in like the classification. I think that

that division is still really important in terms of public health and medicine, but I'm talking about like classification systems. But more recently, that division into those two groups turned into three groups, essentially saprophytic, meaning living on decaying material and non-pathogenic, intermediate in terms of pathogenicity, and pathogenic. And some researchers are now arguing that this isn't the best way to classify leptospira because it just takes into account one characteristic of these bacteria, rather than looking at, I don't know, their entire genomes, for instance. Yeah.

But as far as I can tell, that's still under discussion and probably won't be resolved in... By the time. By the time this episode comes out. Yeah, certainly not. Yeah, it was really interesting how much it seemed to still be in flux. Yeah. The whole, like, classification of leptospira. Oh, absolutely.

And not just the classification, but just learning more about the ecology and which species are playing a role. There are new serivars that are constantly being discovered. Which species can cause disease? That's still kind of being learned. Oh, that one, no, that one's just an environmental. bacteria. Oh, wait a second, actually. Oops, actually. Yeah. The bottom line of all of this seems to be that leptospira is diverse.

Many different species and sarovars can cause disease. And there are so many research opportunities for understanding more about these pathogens from a public health perspective. So if anyone needs a master's or PhDU project, go for it. Yeah, do it. I love it. We support you. But that's just the bottom line for like the ecology evolution of these bacteria. What about the human history part of it? Yeah. Yeah.

Given how widespread leptospira are and how many of them can cause disease in humans and other animals, it's likely, of course, that leptosporosis has affected humans for millennia. As long as humans have been humans. Although there's an asterisk there. I didn't read anything specifically about the historical distributions of these pathogens. I'm not sure if it's known. But one paper I read suggested that an epidemic that occurred around 1616 to 1619 in the area that's now eastern Massachusetts could have been leptosporosis. It hit the Native American populations living in the area particularly hard,

with the death toll estimated to be as low as one third of the local population to as high as 90%. Whoa. And since the Europeans living in the area weren't as badly affected, some researchers have suggested that rats on the ships introduced lepto to the region. Got it. But also, there's like a huge laundry list of other diseases that it could have been. Right. And we may never know what it actually was. So lepto is one of the suggested options.

As with many other diseases that we've covered on the podcast, changing patterns in human settlement or any other practices that would have increased contact with rodents, especially rats, sorry rats, would have made catching the disease more likely. And if you look through historical medical literature, there are many, many mentions of things that could be leptosporosis or have retrospectively been decided to be leptosporosis. Like you said, Aaron, jaundice is of course one of the. primary symptoms of leptosporosis, and references to jaundice go back thousands of years. Whether or not that jaundice was caused as a result of leptosporosis is anyone's guess. Yeah, there's so many things that can damage your liver.

Uh-huh. There is this passage, though, in the Hippocratic text that some people believe maybe about lepto. Quote, when jaundice supervenes in fevers before the seventh day, it is a a bad symptom, unless there be watery discharges from the bowels. Interesting. Yeah. Huh.

I don't know. I mean, I'm sure that lepto was around. Yeah. How interesting. Yeah. And medical text from ancient China discussed diseases referred to as rice field jaundice or rice harvest jaundice. And the descriptions of those diseases seem very similar to leptosporosis.

and also old Japanese medical texts describe lepto-like diseases called autumn fever or seven-day fever. In Europe and Australia, there were diseases known as cane cutter's disease or swine herds disease and schlom fever, mud fever. I doubt I pronounce that remotely correctly. And all of these terms were used before anyone figured out, what caused these diseases or whether they were even related. Right. We should have some sort of jingle for when I mentioned Napoleon's name because here he is again. Oh, I can't wait.

D-D-D-D-D-D-D-D-D-D-D. Here he comes. On his horse. Here we go. Oh, Napoleon. His infamous troops in Cairo, Egypt, during the early 1800s may have experienced an outbreak of leptosporosis, which they called jaundice fever. Also, I have to shout out our Chlamydia episode

where I talked about trachoma and Napoleon's troops in Egypt, and I just at this point need to make a list of diseases that these poor troops were subjected to during their time under Napoleon. We should have just done a series on diseases of Napoleon. Yeah, just where all we do is list them because it would take two hours. But even before germ theory was a thing, what would be later known as leptosporosis had recognizable patterns. And you can tell that from some of these early nicknames. So one was that it was commonly associated with certain occupations.

And that these occupations, and hence the occurrence of this disease, were often associated with wet marshy areas. They were kind of geographically restricted. And this tight link, especially between. certain areas or certain times of year and this disease made it like a shoe in for miasma theory, which was this pre-germ theory idea that proposed that diseases and disease outbreaks were the result of bad air. And it's easy to see how that would have been a reasonable explanation for leptosporosis because it did occur in certain areas and it did occur in certain professions and it didn't really occur in large epidemics the way something like influenza or smallpox did.

And importantly, avoiding those areas or removing the source of the bad air, like draining water around mines, it decreased the incidence of the disease. So even before people knew that cane cutter's disease or swine herds disease or rice harvest disease were the same things, people were able to limit their exposure to it. That's amazing. So interesting. Yeah. Yeah.

I really, I love it when those kinds of things happen in these episodes, Aaron. Mm-hmm. Me too. But leptosporosis wasn't alone in causing jaundice and a fever and occurring in certain marshy environments. Mm-hmm. There was also yellow fever, infectious hepatitis, louseborne relapsing fever. And it wasn't until the late 1880s that leptosporosis, or, at least one manifestation of it was officially distinguished from the rest of these possible causes

of infectious jaundice. In 1886, a German physician named Adolf Weill described a disease that involved jaundice alongside spleenomegaly, renal dysfunction, conjunctivitis, and skin rashes. He called it infectious jaundice. His characterization of this disease stuck, but the name, obviously, did not. A couple years after his paper was published, another researcher named it Wheels disease. And like happens so often, giving this disease a name, giving it a description, increased awareness of it substantially. And soon papers were being published describing outbreaks of the disease in coal miners or sugar cane cutters,

association with rainfall or swimming in certain areas. but even though people were able to recognize patterns in where and when this disease occurred and in whom, without a causative agent identified, those were just patterns without a mechanistic explanation. And you were also a little bit limited in your ability to do anything. For that satisfying understanding of how all the pieces eventually fit together and whether the cases of wheeled disease in England were caused by the same pathogen as those in Japan, for instance, We needed a causative agent. And to get that, we have to wait almost 30 years after the clinical description of Weal's disease. Wow. Yeah. So 1886 was Weel's disease. Huh. And 1915, I believe,

was when leptosporosis was identified, was when leptospirro was identified. Oh, my goodness. Yeah. So why was there so long a wait? And, you know, none of that. the papers I read really went into that great detail about why, but I think it could have been many different things. So even though this period, the last decades of the 1800s and the first few decades of the 1900s was this golden age of germ theory and pathogen discovery, that doesn't mean that all diseases received equal attention. I mean, if you think about it, again, Leptosporosis is not a big name marquee disease, which isn't to say it doesn't deserve that attention, but at the time there were things like plague or syphilis or tuberculosis that people were trying

desperately to figure out because of the death toll, because the number of people that were infected with those diseases. Leptosporosis definitely attracted interest, but it maybe didn't get the focused attention that some of these flashier diseases did. But one thing was working in lepto's favor, which is that spirochetes, the kind of spiral-shaped bacterium that causes lepto, these had already been discovered and recognized to cause disease, the most important of which at the time was syphilis. And so people had spirochetes on their radar, and they should have maybe been able to pluck these little guys out as the cause of leptosporosis, except for, this quirk that you mentioned. Spirochetes don't stain well. So they're really difficult to isolate.

They can be difficult to culture. And what the eventual discoverers of leptospyra noticed was that, well, they blamed it on this anyway, is that after this huge influx of bacteria in the bloodstream, those levels drop. And they were like, if you don't catch it then, then it's going to be really difficult to isolate leptospheres. That's not unlike like malaria or something, where you have a lot of difference in even just like times of day on when you have a high enough burden in the bloodstream to be able to pick it up. Exactly. Yeah. And I think I think that's what they said. They were, they were like, yeah, we didn't see it in the bloodstream. And so if you test a blood sample of someone who's super duper sick, especially considering the microbiology technology that was around in the 1910s,

And I want to say because like I mentioned how like E. coli might be at low numbers, you can grow those other bacteria out in culture from blood. So even if you only have a tiny bit of it, you can grow it to be more. But that's really difficult to do with leptospira. So if you can't see it right away, it's a lot harder. Yeah. Yeah. That's a really important point too. Yeah. So how did people eventually discover what was causing Weill's disease? Seems super difficult. They went looking for it specifically. It wasn't just one of those serendipitous discoveries. A couple of researchers in Japan named Ryokichi Inada and Utaka Ido had an interest in wheels disease for years. And an outbreak of the disease among coal miners around 1914 to 1915 led them to run some experiments to see if they could isolate a pathogen from an infected person. And I also want to point out that their interest was not purely scientific, not like, oh, here's this curious little disease. Let's see if we can find a new pathogen. At the time, mortality rates of wheels disease at their clinic averaged 32%. Oh my. Which is incredibly high. That's really terrifyingly high. Exactly. And so they wanted to do whatever they could to try to

control the outbreaks by finding the source. They looked for bacteria in blood, urine, feces, you name it. in people who had wheels disease, and when they didn't find anything, they took some blood from these infected individuals and injected it into monkeys, rabbits, rats, guinea pigs. And the guinea pig turned out to be the unlucky or lucky one, depending on your perspective. It developed many of the symptoms that were characteristic of wheels disease, and when they dissected the animal's liver, they found it to be teeming with spirochetes, which they named Spiroketa. ectero hemorrhagiae. Yep, okay.

Yep. Later, of course, leptospira. Almost immediately, after they published their findings in 1915, researchers in Germany also isolated leptospira from infected individuals. But the real first-placed finisher, even though he didn't know it, may have been A.M. Stimson, who observed spirochetes in the blood of someone that had been diagnosed with yellow fever. He figured that what he saw, these little squiggly bacteria that looked like question marks, hence the name he gave them, spirokita interagans, was causing yellow fever. For a long time, people were like, it must be a spirochite that's causing yellow fever. It wasn't, as we know. But in retrospect, he did end up being the first to describe a bacterium that later researchers would link to leperseller.

Leptosporosis. Interesting. The similarity in symptoms between leptosporosis and yellow fever, and not to mention their association with wet marshy areas, also made diagnosis sometimes confusing, and that could have potentially contributed to the delay in identifying both the causative agent of wheels disease and the yellow fever virus. Anyway, soon after Inada and Edo and colleagues identified the causative agent of wheels disease, they next said, their sights on uncovering everything they possibly could about this pathogen. And they did an hugely impressive job, from culturing it in the lab to characterizing the timeline of infection, early vaccination studies, to understanding the transmission route of the pathogen. What they did was

set a really strong foundation for understanding the disease and for growing future research, especially research that was focused on prevention. Because as we know, if you want to stop a disease from spreading, you at the very minimum have to know how it spreads in the first place, which for leptosporosis by the time of the causative agent's discovery was still under debate. They knew it was in marshy, wet marshy areas and associated with water. So could it be mosquito-borne like yellow fever? Several people seemed to think so. And it was a reasonable explanation. nation, given the geographic and climate variables associated with outbreaks. And some researchers even successfully carried out experiments with mosquitoes transmitting leptosporosis to lab animals.

But it was likely that the mosquitoes were acting as mechanical vectors, like just depositing infected blood clinging to the mouth parts into the animal. Wheel himself thought it was something that you ingested, while others thought vertebrate animals played a large role. Enada and Edo and colleagues demonstrated that the leptospheres could be transmitted through the healthy unbroken skin of a guinea pig. The broken skin was more reliable. I had no idea it could be through like unbroken skin.

It can be. Yeah. Usually it's broken skin, but especially if you're submerged in like exposed for a long period of time and especially with wet skin, wet skin really reduces your skins like increases permeability essentially. So then yeah, yeah, it can be unbroken skin. Wow. Okay. Sorry. Yeah. Yeah. Yeah. Well, they also showed that it could cause infection through ingesting it. Yeah. But where did it come from? Yeah. They got the idea to look at rodent kidneys and urine after a different team of researchers observed spirochetes in the kidneys of field mice while working on scrub typhus. Oh, cool.

Yeah. And so they were like, you know what? All right, fine. Gather all of the rodents that we possibly can, house and wild rats, and then look in their kidneys, and boom. They found a bunch of their spirochita at the time, Ictohemorrhagia. And they noticed that the leptospheres seemed restricted to the kidneys and that the rats seemed in excellent health. Until they took out their kidneys. Prior to their dissection.

And that pointed towards their role as reservoirs. And this didn't actually surprise too many people, possibly because, A, rats have been maligned for centuries. But also during trench warfare in World War I, cases of wheels disease shot up, particularly in areas with high rat populations. Okay. Yeah. So they were like, eh, I suspected it. Like, oh, yeah, of course, it's the rat, which is sad for rats. rats are great, by the way. Anyway. All of this clinical and epidemiological and ecological knowledge about leptosporosis, which is like a lot. I mean, that happened in a very short time span, just a few years. And that's pretty remarkable. And even though antibiotics weren't yet

available to help treat the infection, understanding the transmission cycle was enough to enact control measures in some places. And throughout the following, decades into the mid-20th century and beyond, people continued to find out more about this group of pathogens, like how long it can survive in water and under what conditions, what pH is best, what temperature, which animals play a role in the transmission of the disease in certain areas, how disease progression or severity could be tied to certain species or seravars, and also linking all of these previously separate diseases or separate name diseases. into one big picture name, leptosporosis.

And another big development was understanding that other animals may not just be asymptomatic carriers or reservoirs, but that many of them suffered severe infection from these bacteria as well, like domestic cattle, pigs and dogs. The early history of leptosporosis may not be as flashy as some of the diseases or topics that we've covered. on this podcast, and there don't really seem to be, at least that I could find, any major fireworks discoveries during the rest of the 20th century. But that doesn't mean at all that this disease is not hugely important, because despite how much we've learned about this group of pathogens and despite having effective treatment and knowledge of prevention, it's still a

huge problem globally, as you're about to talk about, Aaron, and since it has such close ties to things like weather and temperature, we can expect to see big shifts as a result of climate change and land use change. So, Erin, can you tell me where we stand with these pathogens of one health importance today? I would love to. Let's take a quick break and I'll get into it. Aaron, I know that you know and have very recently felt just how difficult it is to get numbers on some. of these topics that we cover. And I'm always still somehow shocked at just how difficult it can be. And that was the case for leptosporosis. Very, very hard to get an estimate of what the true burden of disease is, as well as looking at the distribution of that burden, because of course, it's not

equal across the globe. So this is a pathogen that is worldwide, everywhere. except like the Arctic where everything is frozen. But it is most common in the tropics, and it's very common both in rural areas associated with things like agricultural or like mining exposure like you talked a lot about, but also in urban, especially poor urban areas where you have lack of access to sanitation and potentially high rat burdens. But to look at actual numbers, if you look at the World Health Organization website, you won't really find any numbers because they don't have any fact sheets on leptosporosis. All of their information is from like 2003. It was almost 20 years ago. Yeah. And now there's just not a page.

The links to like World Health Organization lepto, like it goes to page 404, not found. Interesting. I know. I was shooketh, as they say. Pahoe, which is the Pan American Health Organization, so for the Americas, has some information. The CDC has a page on it. There are probably a lot of other country-specific public health agencies that have data, but it's hard to go through every single country. So there are two numbers that I found, which are wildly different as to global estimates of leptost Some papers and the Pahoe website estimate about 300 to 500,000 cases of leptosporosis globally every year. Which is a huge number. Yeah, well, a paper from 2015 that was trying to estimate the global prevalence as well as mortality from leptosporosis. Granted, this is from 2015, so it's a little bit outdated. but they estimated a million cases annually and just under 60,000 deaths every year. And that's a lot.

It's a lot. And this was really just an estimate of severe cases, cases that are bad enough that people are getting very sick and ending up in the hospital. And again, a lot of times this can be asymptomatic. So how many cases are there? potentially even more. Yeah. Wow. Yeah. And there is a lot of data to suggest that the overall burden of leptosporosis is likely going to continue to rise because of shifts in things like climate change that might worsen storms and flooding events, which are really high risk for leptosporosis outbreaks.

Yep. as well as, like you said, land use changes that might increase urbanization in a way that also puts people at increased exposure to rats and contaminated water sources, et cetera. So it's not like good news looking forward, especially with how little data we have to begin with. It's, it's, I think I'm, I'm still surprised at this. Same. I was actually shocked because a lot of papers say, like, this is,

on the scale of things like schistosomyasis, of things like Leshmaniasis, of things like cholera. And I feel like we don't think of it in that way. I think a lot of people think of leptosporosis as a disease of animals. Or as like recreational exposure. Yeah, exactly, which it is. That's totally true. But it's also just a global serious disease. When it comes to animal infections, by the way, it's even harder to get a sense of

what the magnitude of the problem is worldwide, as you can imagine. Yeah. There are a lot of really interesting papers that look at the overall diversity of animal species that have been shown to be infected. I mean, it really just boils down to, like, all of them. Like, if you try it, they will infect. But it's really hard to get a handle on, like, what percentage of domestic dogs would test positive?

Or, like, how many cattle every year are getting sick from this? How much milk production is lost because cattle gets sick? we just don't have that kind of information. I did find one paper that was looking in the United States at hot spots of leptosporosis, like within the U.S. And one thing that stuck out to me from that paper is that at least from data from the early 2000s, it did seem like zero prevalence in dogs was increasing, which is not great. Why is it increasing?

I have no idea. And there's a vaccine available for dogs as well. Great question. Yes, there's a vaccine. There's a vaccine for humans, too. And for animals, including dogs. Most of the vaccines, as far as I can tell, all of the vaccines that are currently available are whole killed spirokites of some of the more common syrovars, depending on what area you're in. So you asked very early on, Aaron, like how much.

cross-protection do you get? Like, what kind of an immune response are we talking about? And because the vaccines that exist are just for particular syrivar's, they're not universal. So they don't cover every given leptospira serivar. Seems like a great candidate for an MRNA vaccine, huh? Oh, but a bum-bam. Yeah. There's a lot of research mostly on recombinant vaccines, actually, But an MRI-A-1 could be interesting. But recombinant vaccines would allow you to put a whole bunch of different antigens, essentially, antigen components on like one little vaccine and then give that so you could get immunity, a whole bunch of different syravars.

And who gets vaccinated against leptosporosis? Such a great question. I had a really hard time figuring that out. In the U.S., definitely dogs like my puddle liquor, is vaccinated. So domestic animals, livestock, can get vaccinated. In terms of humans, I think it's relatively uncommon, except perhaps during outbreaks or maybe in occupational settings in particularly high-risk environments. It might be that people are vaccinated. But in general, I didn't even know that there was a human vaccine. I don't think it's very common. Yeah. But that is what I know about the status of

leptosporosis worldwide. It's such an interesting, I truly cannot believe how overlooked this is. I can't get over it. I really felt similarly about this. Yeah, it's, I want to do, I want there to be so much more information. Yeah. Yeah. Yeah. Well, sources? Sources. Okay. I have a several. I'm going to shout out two in particular. One, is a 2015 book called Leptospira and Leptosporosis, which the editor of that book is Ben Adler. Then there was a paper from 2001 by Kobayashi, and that is titled Discovery of the Causative Organism of Wheels Disease, Historical View. I had a lot of different papers, a couple of actually book chapters that I wanted to shout out. Two different chapters, one on leptosporosis in humans and one on animal leptosporosis, both from the book.

book Leptospyra and Leptospirosis from 2015. So those were great chapters. And then I had a lot on the genetic diversity and serovar diversity of Leptospira and at least some data on the epidemiology so you can read for yourself. We post all of our sources from this episode and all of our episodes on our website, this podcast, kill you.com. We sure do. Thank you so much again to Umat for sharing your story again. Again. Thank you also to Bloodmobile for providing the music for this episode and all of our episodes. Thank you to the Exactly Right Network.

And thank you to you, listeners. We liked doing this episode. I hope that you really enjoyed it. Thanks for listening. Yeah. And a special thank you, as always, to our wonderful, generous patrons. We appreciate you so very much. So much.

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